Category Archives: inflammation

angiogenesis, Anti-cancer, anti-inflammatory, anti-proliferative, anti-tumor, apoptosis, AR, Chapter 7 Isolates and Cancer Research, Chemoprevention, inflammation, Prostate cancer

Wedelia Chinensis Extract: indole-3-carboxylaldehyde, wedelolactone, luteolin, apigenin

Cancer: Prostate

Action: Anti-inflammatory

Wedelia chinensis [(Osbeck) Merr.], also known as Chinese Wedelia, is widespread throughout China, India, Indochina, Indonesia, Philippines, Japan and Malaysia.

Prostate Cancer; AR Negative

The in vivo efficacy and mechanisms of action of oral administration of a standardized extract of W. chinensis were analyzed in animals bearing a subcutaneous or orthotopic prostate cancer xenograft. Exposure of prostate cancer cells to W. chinensis extract induced apoptosis selectively in androgen receptor (AR)-positive prostate cancer cells and shifted the proportion in each phase of cell-cycle toward G(2)-M phase in AR-negative prostate cancer cells. Oral herbal extract (4 or 40 mg/kg/d for 24–28 days) attenuated the growth of prostate tumors in nude mice implanted at both subcutaneous (31% and 44%, respectively) and orthotopic (49% and 49%, respectively) sites. The tumor suppression effects were associated with increased apoptosis and lower proliferation in tumor cells as well as reduced tumor angiogenesis. The anti-tumor effect of W. chinensis extract was correlated with accumulation of the principal active compounds, wedelolactone, luteolin, and apigenin, in vivo.

Anti-cancer action of W. chinensis extract was due to three active compounds that inhibit the AR signaling pathway. Oral administration of W. chinensis extract impeded prostate cancer tumorigenesis. Future studies of W. chinensis for chemoprevention or complementary medicine against prostate cancer in humans are thus warranted (Tsai et al., 2009).

Prostate Cancer; AR Positive

Reduction of inflammation is an important anti-cancer therapeutic opportunity, and chronic inflammation can augment tumor development in various types of cancers, including prostate cancer (PCa). Four anti-proliferative phytocompounds in Wedelia chinensis have been identified through their ability to modulate the androgen receptor (AR) activation of transcription from prostate-specific antigen promoter in PCa cells. The 50% inhibition concentration values of indole-3-carboxylaldehyde, wedelolactone, luteolin and apigenin, were 34.9, 0.2, 2.4 and 9.8 muM, respectively.

A formula that combined the phytocompounds in the same proportions as in the herbal extract decreased the dosage of each compound required to achieve maximal AR inhibition. In correlation with the AR suppression effect, these active compounds specifically inhibited the growth of AR-dependent PCa cells and as a combination formula they also synergistically suppressed growth in AR-dependent PCa cells. Our study has identified synergistic effects of active compounds in W. chinensis and demonstrated their potential in PCa prevention and therapy (Lin et al., 2007).

References

Lin FM, Chen LR, Lin EH, et al. (2007). Compounds from Wedelia chinensis synergistically suppress androgen activity and growth in prostate cancer cells. Carcinogenesis, 28(12):2521-9.


Tsai CH, Lin FM, Yang YC, et al. (2009). Herbal extract of Wedelia chinensis attenuates androgen receptor activity and orthotopic growth of prostate cancer in nude mice. Clin Cancer Res, 15(17):5435-44.

anti-inflammatory, apoptosis, Apoptotic, Camellia sinensis, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, COX-2, induces apoptosis, inflammation, Pro-apoptotic

Theaflavin-2

Cancer: none noted

Action: Anti-inflammatory, induces apoptosis

Apoptosis

Theaflavin-2 (TF-2), a major component of black tea extract (Camellia sinensis [(L.) Kuntze]), induces apoptosis of human colon cancer cells and suppresses serum-induced cyclooxygenase-2 (COX-2) expression 1. The mechanisms of TF-2 for the activation of apoptosis were examined, and the impact on inflammatory genes in a broader panel of cells was evaluated and tested for whether topical anti-inflammatory effects could be observed in vivo. TF-2 triggered apoptosis in five other transformed cancer cell lines, inducing cell shrinkage, membrane blebbing, and mitochondrial clustering within 3 h of treatment. Topical application with TF-2 significantly reduced ear edema and produced a pattern of gene down-regulation similar to that observed in the cell model. These results suggest that the anti-inflammatory and pro-apoptotic activity of TF-2 may be exploited therapeutically in cancer and other diseases associated with inflammation (Gosslau et al., 2011).

Reference

Gosslau A, En Jao DL, Huang MT et al. (2011). Effects of the black tea polyphenol theaflavin-2 on apoptotic and inflammatory pathways in vitro and in vivo. Molecular Nutrition & Food Research, 55(2):198–208. doi: 10.1002/mnfr.201000165

Chapter 7 Isolates and Cancer Research, inflammation

Terpenoids

Sometimes referred to as isoprenoids, terpenoids are a class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units. These lipids can be found in all classes of living things, and are the largest group of natural products (Specter, 2009).

Terpenes have been found to be essential building blocks of complex plant hormones and molecules, pigments, sterols and even cannabinoids in cannabis. Terpenes also play an incredibly important role by providing the plant with natural protection from bacteria and fungus, insects, and other environmental stresses (Specter, 2009).

Plant terpenoids are used extensively for their aromatic qualities. They play a role in traditional herbal remedies and are under investigation for anti-bacterial, anti-neoplastic, and other pharmaceutical functions. Terpenoids contribute to the scent of eucalyptus, the flavors of cinnamon, cloves, and ginger, the yellow color in sunflowers, and the red color in tomatoes (Specter, 2009). Well-known terpenoids include citral, menthol, camphor, salvinorin (from Salvia divinorum ), and the cannabinoids found in Cannabis ('Terpenoids', n.d.).

Traditional medicine has been a fertile source for revealing novel lead molecules for modern drug discovery. In plants, terpenoids represent a chemical defense against environmental stress and provide a repair mechanism for wounds and injuries. Interestingly, effective ingredients in several plant-derived medicinal extracts are also terpenoid compounds of monoterpenoid, sesquiterpenoid, diterpenoid, triterpenoid and carotenoid groups. Inflammatory diseases and cancer are typical therapeutic indications of traditional medicines. Thus folk medicine supports the studies which have demonstrated that plant-derived terpenoid ingredients can suppress nuclear factor-kappaB (NF-kappaB) signaling, the major regulator in the pathogenesis of inflammatory diseases and cancer. We review the extensive literature on the different types of terpenoid molecules, totaling 43, which have been verified as both inhibiting the NF-kappaB signaling and suppressing the process of inflammation and cancer. It seems that during evolution, plants have established a terpene-based host defense which also represents a cornucopia of effective therapeutic compounds for common human diseases (Salminen, Lehtonen, Suuronen, Kaarniranta, & Huuskonen, 2008).

Several herbal plants improve medical conditions. Such plants contain many bioactive phytochemicals. Terpenoids (also called 'isoprenoids') constitute one of the largest families of natural products, accounting for more than 40,000 individual compounds of both primary and secondary metabolisms. In particular, terpenoids are contained in many herbal plants, and several terpenoids have been shown to be available for pharmaceutical applications. For example, artemisinin and taxol, as malaria and cancer medicines, respectively. Various terpenoids are contained in many plants for not only herbal, but dietary use as well.

Bioactive terpenoids contained in herbal or dietary plants, can modulate the activities of ligand-dependent transcription factors, namely, peroxisome proliferator-activated receptors (PPARs). Because PPARs are dietary lipid sensors that control energy homeostasis, daily eating of these terpenoids might be useful for the management of obesity-induced metabolic disorders, such as type 2 diabetes, hyperlipidemia, insulin resistance, and cardiovascular diseases (Goto, Takahashi, Hirai, & Kawada, 2010).

Sources

Goto T, Takahashi,N, Hirai S, Kawada T. (2010). Various terpenoids derived from herbal and dietary plants function as PPAR modulators and regulate carbohydrate and lipid metabolism. PPAR Research, 2010(2010), 483958. doi: 10.1155/2010/483958.


Salminen A, Lehtonen M, Suuronen T, Kaarniranta K, Huuskonen J. (2008). Terpenoids: Natural inhibitors of NF-kappaB signaling with anti-inflammatory and anti-cancer potential. Cellular and Molecular Life Sciences, 65(19), 2979-2999. doi: 10.1007/s00018-008-8103-5.


Specter M. (2009). A life of its own: Where will synthetic biology lead us? The New Yorker. Retrieved from http://www.newyorker.com/reporting/2009/09/28/090928fa_fact_specter.


Terpenoids. (n.d.). In Wikipedia. Retrieved from http://en.wikipedia.org/wiki/Terpenoid.

Anti-cancer, anti-inflammatory, anti-oxidative, anti-proliferative, apoptosis, Apoptotic, Breast cancer, Caco-2,HCT-116, CDC2, CDK, Chapter 7 Isolates and Cancer Research, chemo-preventive, Colon Cancer or Colorectal cancer, COX-2, Esophageal cancer, growth-inhibitory, IKK, Immunomodulatory, inflammation, p65, Pro-apoptotic, S, TNF, Vaccinium genus

Piceatannol

Cancer: Esophageal, colorectal, breast

Action: Anti-inflammatory, anti-oxidative

Piceatannol, a naturally occurring analogue of resveratrol found in certain plants and berries of the Vaccinium genus, including Picea abies [(L.) H.Karst.], Aiphanes horrida [(Jacq.) Burret], Gnetum cleistostachyum (C. Y. Cheng), Vaccinium arboretum (Marshall), Vaccinium angustifolium (Aiton) and Vaccinium corymbosum (L.). It was previously identified as the active ingredient in herbal preparations in folk medicine. Piceatannol is an anti-inflammatory, immunomodulatory, and anti-proliferative stilbene that has been shown to interfere with the cytokine signaling pathway. It is isolated from various types of berries, grapes, rhubarb and sugar cane.

It has been shown that a diet containing freeze-dried black raspberries (BRB) inhibits the development of chemically-induced cancer in the rat esophagus. To provide insights into possible mechanisms by which BRB inhibit esophageal carcinogenesis, an ethanol (EtOH) extract of BRB was evaluated, and two component anthocyanins (cyanidin-3-O-glucoside and cyanidin-3-O−rutinoside) in BRB, for their effects on growth, apoptosis, and gene expression in rat esophageal epithelial cell lines. The EtOH extract and both anthocyanins selectively caused significant growth inhibition and induction of apoptosis in a highly tumorigenic cell line (RE-149 DHD) but not in a weakly tumorigenic line (RE-149).

The growth-inhibitory and pro-apoptotic effects were enhanced by the daily addition of the EtOH extract and the anthocyanins to the medium.

Esophageal Cancer

This differential effect may have been related to the relative amounts of anthocyanins in the extract vs.when they were added individually to the medium. It was hence concluded that the selective effects of the EtOH extract on the growth and apoptosis of highly tumorigenic rat esophageal epithelial cells in vitro may be due to preferential uptake and retention of its component anthocyanins, and this may also be responsible for the greater inhibitory effects of freeze-dried whole berries on tumor cells in vivo (Schwartz et al., 2009).

Colorectal

The effects of piceatannol on growth, proliferation, differentiation and cell-cycle distribution profile of the human colon carcinoma cell line Caco-2 were investigated. Growth of Caco-2 and HCT-116 cells was analyzed by crystal violet assay, which demonstrated dose- and time-dependent decreases in cell numbers. Treatment of Caco-2 cells with piceatannol reduced proliferation rate. No effect on differentiation was observed.

Determination of cell-cycle distribution by flow cytometry revealed an accumulation of cells in the S phase. Immunoblotting demonstrated that cyclin-dependent kinases (cdk) 2 and 6, as well as cdc2 were expressed at steady-state levels, whereas cyclin D1, cyclin B1 and cdk 4 were down-regulated. The abundance of p27Kip1 was also reduced, whereas the protein level of cyclin E was enhanced. Cyclin A levels were enhanced only at concentrations up to 100 µmol/L. These changes also were observed in studies with HCT-116 cells. On the basis of our findings, piceatannol can be considered to be a promising chemo-preventive or anti-cancer agent (Wolter et al., 2002).

Anti-inflammatory

Treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-κB. In contrast, stilbene or rhaponticin (another analog of piceatannol) had no effect, suggesting the critical role of hydroxyl groups. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF- κB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-κB activated by H2O2, PMA, LPS, okadaic acid, and ceramide.

Piceatannol abrogated the expression of TNF-induced NF-κB-dependent reporter gene and of matrix metalloprotease-9, cyclooxygenase-2, and cyclin D1. When examined for the mechanism, it was found that piceatannol inhibited TNF-induced IκBα phosphorylation, p65 phosphorylation, p65 nuclear translocation, and IκBα kinase activation, but had no significant effect on IκBα degradation. Piceatannol inhibited NF-κB in cells with deleted Syk, indicating the lack of involvement of this kinase.

Overall, these results clearly demonstrate that hydroxyl groups of stilbenes are critical and that piceatannol, a tetrahydroxystilbene, suppresses NF- κB activation induced by various inflammatory agents through inhibition of IκBα kinase and p65 phosphorylation (Ashikawa et al., 2002).

There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis. Abnormal up-regulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the prostaglandin biosynthesis, has been implicated in carcinogenesis. Trans-3,4,3',5'-tetrahydroxystilbene (piceatannol), a naturally occurring hydroxylated stilbene with potent anti-inflammatory and anti-oxidative activities, has been shown to inhibit the proliferation of several cancer cells by inducing apoptosis or blocking cell-cycle progression. The effect of piceatannol was examined on the activation of the nuclear transcription factor NF-κB, one of the major transcription factors that regulate pro-inflammatory COX- 2 gene transcription, in human mammary epithelial (MCF-10A) cells treated with the tumor promoter 12-O-tetradecanoylphorbol- 13-acetate (TPA).

When pre-treated to MCF-10A cells, piceatannol markedly inhibited TPA-induced NF-κB DNA binding to a greater extent than resveratrol and oxyresveratrol, stilbene analogs structurally related to piceatannol. Piceatannol also inhibited TPAinduced phosphorylation and degradation of IκBα as well as nuclear translocation of the phosphorylated form of p65, the functionally active subunit of NF-κB. Likewise, TPA-induced expression of COX-2 was abrogated by piceatannol pre-treatment. The thiol reducing agent dithiothreitol abolished the inhibitory effects of piceatannol on NF-κB DNA binding activity, suggesting that piceatannol may directly modify NF-kB (Liu et al., 2009).

Breast Cancer

Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene; PIC) exhibits immunosuppressive and anti-tumorigenic activities in several cell lines, and it was found that PIC inhibited migration and anchorage-independent growth of human mammary epithelial cells (MCF-10A) treated with the prototypic tumor promoter, 12-O-tetradecanoylphorbol-13-aceate (TPA). PIC treatment suppressed the TPA-induced activation of NF-κB and expression of cyclooxygenase-2 (COX-2) in MCF-10A cells. It was speculated that an electrophilic quinone formed as a consequence of oxidation of PIC bearing the catechol moiety may directly interact with critical cysteine thiols of IKKβ, thereby inhibiting its catalytic activity.

Results show that direct modification of IKKβ by PIC, presumably at the cysteine 179 residue, blocks NF-κB activation signaling and COX-2 induction in TPA-treated MCF-10A cells and also migration and transformation of these cells (Son et al., 2010).

References

Ashikawa K, Majumdar S, Banerjee S, et al. (2002). Piceatannol inhibits TNF-induced NF- κB activation and NF- κ B-mediated gene expression through suppression of IκBα kinase and p65 phosphorylation. The Journal of Immunology, 169(11):6490-7.


Liu D, Kim DH, Park JM. (2009). Piceatannol Inhibits Phorbol Ester-Induced NF- κ B Activation and COX-2 Expression in Cultured Human Mammary Epithelial Cells. Nutrition and Cancer, 61(6):855–63. doi: 10.1080/01635580903285080.


Schwartz SJ and Stoner GD. (2009). Black Raspberry Components Inhibit Proliferation, Induce Apoptosis, and Modulate Gene Expression in Rat Esophageal Epithelial Cells. Nutrition and Cancer, 61(6):816–26. doi: 10.1080/01635580903285148


Son PS, Park SA, Na HK, et al. (2010). Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF- κ B activation and cyclooxygenase-2 expression in human breast epithelial cells: cysteine 179 of IKK β as a potential target. Carcinogenesis, 31(8):1442-1449. doi: 10.1093/carcin/bgq099.


Wolter F, Clausnitzer A, Akoglu B and Stein J. (2001). Down-regulation of the cyclin D1/Cdk4 complex occurs during resveratrol-induced cell-cycle arrest in colon cancer cell lines. J. Nutr, 132(2):298-302.

anti-inflammatory, anti-oxidant, anxiolytic, apoptosis, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, COX-2, COX-2 down-regulation, FasL, G0/G1, G1, Gastric cancer or Stomach cancer, growth-inhibitory, HT-29, IL-1, IL-6, induces apoptosis, inflammation, Nitric Oxide, p27, Paeonia suffruticosa, S, TNF

Paenol

Cancer: Gastric

Action: Attenuates nephrotoxicity, anti-inflammatory, anti-oxidant, inhibits TNF- α , induces apoptosis, COX-2 down-regulation

Inhibits TNF- α

Moutan Cortex, the root bark of Paeonia suffruticosa Andrews, has been used extensively as a traditional medicine for treatment of various diseases such as atherosclerosis, infection, and inflammation. Previous studies have revealed that the extracts of Moutan Cortex can inhibit nitric oxide and TNF- α in activated mouse peritoneal macrophages (Chung et al., 2007).

A variety of compounds including paeonoside, paeonolide, apiopaeonoside, paeoniflorin, oxypaeoniflorin, benzoyloxypaeoniflorin, benzoylpaeoniflorin, paeonol, and sugars have been identified in Moutan Cortex (Chen et al., 2006).

Attenuates Nephrotoxicity

Paeonol, a major compound of Moutan Cortex, has been found to attenuate cisplatin-induced nephrotoxicity in mice. Cisplatin is an effective chemotherapeutic agent that is used for the treatment of a variety of cancers; however, its nephrotoxicity limits the use of this drug.

Balb/c mice (6 to 8  w of age, weighing 20 to 25  g) were administered with Moutan Cortex (300  mg/kg) or paeonol (20 mg/kg) once a day. At day 4, mice received cisplatin (30, 20, or 10   mg/kg) intraperitoneally.

The paeonol-treated group showed marked attenuation of serum creatine and blood urea nitrogen levels as well as reduced levels of pro-inflammatory cytokines and nitric oxide when compared to the control group. In addition, the paeonol-treated group showed prolonged survival and marked attenuation of renal tissue injury. Taken together, these results demonstrated that paeonol can prevent the renal toxic effects of cisplatin (Lee et al., 2013).

Paeonol, a major phenolic component of Moutan Cortex, has various biological activities such as anti-aggregatory, anti-oxidant, anxiolytic-like, and anti-inflammatory functions (Ishiguro et al., 2006). In this study, paeonol treatment significantly reduced the elevated levels of serum creatinine and BUN. In addition, the role of pro-inflammatory cytokines in cisplatin-induced acute renal failure has been well documented (Faubel et al., 2007; Ramesh & Reeves, 2002), and elevation of the pro-inflammatory cytokines TNF-α and IL-1β as well as that of IL-6 has been demonstrated in humans with acute renal failure (Simmons et al., 2004).

Apoptosis-inducing & Gastric Cancer

Paeonol has significantly growth-inhibitory and apoptosis-inducing effects in gastric cancer cells both in vitro and in vivo. In vitro, paeonol caused dose-dependent inhibition on cell proliferation and induced apoptosis. Cell cycle analysis revealed a decreased proportion of cells in G0/G1 phase, with arrest at S. Paeonol treatment in gastric cancer cell line MFC and SGC-790 cells significantly reduced the expression of Bcl-2 and increased the expression of Bax in a concentration-related manner. Administration of paeonol to MFC tumor-bearing mice significantly lowered the tumor growth and caused tumor regression (Li et al., 2010).

COX-2 Down-regulation

One of the apoptotic mechanisms of paeonol is down-regulation of COX-2. p27 is up-regulated simultaneously and plays an important part in controlling cell proliferation and is a crucial factor in the Fas/FasL apoptosis pathway. Cell proliferation was inhibited by different concentrations of paeonol. By immunocytochemical staining, Ye et al. (2009) found that HT-29 cells treated with paeonol (0.024-1.504 mmol/L) reflected reduced expression of COX-2 and increased expression of p27 in a dose-dependent manner. RT-PCR showed that paeonol down-regulated COX-2 and up-regulated p27 in a dose- and time-dependent manner in HT-29 cells.

References

Chen G, Zhang L, Zhu Y. (2006). Determination of glycosides and sugars in moutan cortex by capillary electrophoresis with electrochemical detection. Journal of Pharmaceutical and Biomedical Analysis, 41(1):129–134.


Chung HS, M. Kang, C. Cho et al. (2007). Inhibition of nitric oxide and tumor necrosis factor-alpha by moutan cortex in activated mouse peritoneal macrophages. Biological and Pharmaceutical Bulletin, 30(5):912–916.


Faubel F, Lewis EC, Reznikov L et al. (2007). Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1 β , IL-18, IL-6, and neutrophil infiltration in the kidney. Journal of Pharmacology and Experimental Therapeutics, 322(1):8–15.


Ishiguro K, Ando T, Maeda O et al. (2006). Paeonol attenuates TNBS-induced colitis by inhibiting NF- κ B and STAT1 transactivation. Toxicology and Applied Pharmacology, 217(1):35–42.


Lee HJ, Lee GY, Kim Hs, Bae Hs. (2013). Paeonol, a Major Compound of Moutan Cortex, Attenuates Cisplatin-Induced Nephrotoxicity in Mice. Evidence-Based Complementary and Alternative Medicine, 2013(2013), http://dx.doi.org/10.1155/2013/310989


Li N, Fan LL, Sun GP, et al. (2010). Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. World J Gastroenterol., 16(35):4483-90.


Ramesh G, Reeves wb. (2002). TNF- α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. Journal of Clinical Investigation, 110(6):835–842.


Simmons EM, Himmelfarb j, Sezer MT et al. (2004). Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney International, 65(4):1357–1365.


Ye JM, Deng T, Zhang JB. (2009) Influence of paeonol on expression of COX-2 and p27 in HT-29 cells. World J Gastroenterol, 15(35):4410-4.

A549, Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-tubulin, apoptosis, bFGF, Breast cancer, c-Jun, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, Cytostatic, cytotoxic, Dendrobrium loddigesii, ERK1, G1, G2/M, HCT-116, HIF, induces apoptosis, inflammation, iNOS, JNK, Lung cancer, MDA-MB-231, metastasis, Rectal cancer, ROS, Twist, VEGF, VEGF

Moscatilin

Cancers:
Colon, lung, placenta, stomach, breast metastasis

Action: Anti-angiogenic, anti-metastatic, anti-tubulin, cytostatic, cytotoxic, cell-cycle arrest, anti-inflammatory

Stomach Cancer, Lung Cancer, Placental

The efficacy of using moscatilin, a natural anti-platelet agent extracted from the stems of Dendrobrium loddigesii, as an anti-cancer agent was studied. Results demonstrated that moscatilin exerts potent cytotoxic effect against cancer cell lines derived from different tissue origins, including those from the placenta, stomach, and lung, but not those from the liver. In addition, the mechanism of action of moscatilin may be related to its ability to induce a G2 phase arrest in responsive cells.

However, unlike some G2 arresting agents, moscatilin has no detectable inhibitory effect on cyclin B–cdc-2 kinase activity. Thus, the precise nature of its cytotoxic mechanism remains to be determined.

Results suggest that moscatilin is potentially efficacious for chemo-prevention and/or chemotherapy against some types of cancer (Ho & Chen, 2003).

Colorectal Cancer

The growth inhibition of moscatilin was screened on several human cancer cell lines. The effect of moscatilin on tubulin was detected in vitro. Following moscatilin treatment on colorectal HCT-116 cells, c-Jun NH(2)-terminal protein kinase (JNK) and caspase activation was studied by Western blot analysis, and DNA damage was done by Comet assay. Moscatilin induced a time-dependent arrest of the cell-cycle at G2/M, with an increase of cells at sub-G1. Moscatilin inhibited tubulin polymerization, suggesting that it might bind to tubulins. A parallel experiment showed that SP600125 significantly inhibits Taxol and vincristine induced HCT-116 cell apoptosis. This suggests that the JNK activation may be a common mechanism for tubulin-binding agents.

Collectively, results suggest that moscatilin induces apoptosis of colorectal HCT-116 cells via tubulin depolymerization and DNA damage leading to the activation of JNK and mitochondria-involved intrinsic apoptosis pathway (Chen et al., 2008).

Anti-inflammatory

Results showed that moscatilin (10-100 microM) had a significant inhibition in a concentration-dependent manner on pro-inflammatory enzymes (COX-2 and iNOS) expression and macrophage activation under LPS (100 ng/mL) treatment.

Hypoxia-inducible factor 1 (HIF-1) alpha was reported to initiate inflammation under cytokine stimulation or hypoxic conditions. Moscatilin had significant inhibition on HIF-1 expression via down-regulation of HIF-1 mRNA without affecting cell viability, translation machinery, or proteasome-mediated degradation of HIF-1. Collective data demonstrarted that moscatilin inhibited both COX-2 and iNOS expressions after LPS treatment in RAW264.7. Furthermore, moscatilin's inhibitory effect appears to be dependent on the repression of HIF-1alpha accumulation and NF-kappaB activation (Liu et al., 2010).

Lung Cancer; Angiogenesis

Moscatilin significantly inhibited growth of lung cancer cell line A549 (NSCLC) and suppressed growth factor-induced neovascularization. In addition, VEGF- and bFGF-induced cell proliferation, migration, and tube formation of HUVECs was markedly inhibited by moscatilin. Western blotting analysis of cell signaling molecules indicated that moscatilin inhibited ERK1/2, Akt, and eNOS signaling pathways in HUVECs.

Results suggest that inhibition of angiogenesis by moscatilin may be a major mechanism in cancer therapy (Tsai et al., 2010).

Lung Cancer

Investigation demonstrated that non-toxic concentrations of moscatilin were able to inhibit human non-small-cell lung cancer H23 cell migration and invasion. The inhibitory effect of moscatilin was associated with an attenuation of endogenous reactive oxygen species (ROS), in which hydroxyl radical was identified as a dominant species in the suppression of filopodia formation.

Results indicate a novel molecular basis of moscalitin inhibiting lung cancer cell motility and invasion. Moscalitin may have promising anti-metastatic potential as an agent for lung cancer therapy (Kowitdamrong, Chanvorachote, Sritularak & Pongrakhananon, 2013).

Breast Cancer; Metastasis

Moscatilin, derived from the orchid Dendrobrium loddigesii, has shown anti-cancer activity. The mechanism by which moscatilin suppresses the migration and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo was evaluated.

Moscatilin was found to significantly inhibit breast cancer MDA-MB-231 cell migration by using scratch assays and Boyden chambers.

In an MDA-MB-231 metastatic animal model, moscatilin (100 mg/kg) significantly suppressed breast cancer metastasis to the lungs and reduced the number of metastatic lung nodules and lung weight without causing any toxicity.

Results indicated that moscatilin inhibited MDA-MB-231 cell migration via Akt- and Twist-dependent pathways, consistent with moscatilin's anti-metastatic activity in vivo. Therefore, moscatilin may be an effective compound for the prevention of human breast cancer metastasis (Pai et al., 2013).

References

Chen TH, Pan SL, Guh JH, et al. (2008). Moscatilin induces apoptosis in human colorectal cancer cells: a crucial role of c-Jun NH2-terminal protein kinase activation caused by tubulin depolymerization and DNA damage. Clinical Cancer Research, 14(13), 4250-4258. doi: 10.1158/1078-0432.CCR-07-4578.


Ho CK, Chen CC. (2003). Moscatilin from the orchid Dendrobrium loddigesii is a potential anti-cancer agent. Cancer Investigation, 21(5), 729-736.


Kowitdamrong A, Chanvorachote P, Sritularak B, Pongrakhananon V. (2013). Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species. BioMed Research International., 2013, 765894. doi: 10.1155/2013/765894.


Liu YN, Pan SL, Peng CY, et al. (2010). Moscatilin repressed lipopolysaccharide-induced HIF-1alpha accumulation and NF-kappaB activation in murine RAW264.7 cells. Shock, 33(1), 70-5. doi: 10.1097/SHK.0b013e3181a7ff4a.


Pai HC, Chang LH, Peng CY, et al. (2013). Moscatilin inhibits migration and metastasis of human breast cancer MDA-MB-231 cells through inhibition of Akt and Twist signaling pathway.

Journal of Molecular Medicine (Berlin), 91(3), 347-56. doi: 10.1007/s00109-012-0945-5.

Tsai AC, Pan SL, Liao CH, et al. (2010). Moscatilin, a bibenzyl derivative from the India orchid Dendrobrium loddigesii, suppresses tumor angiogenesis and growth in vitro and in vivo. Cancer Letters, 292(2), 163-70. doi: 10.1016/j.canlet.2009.11.020.

Anti-cancer, anti-inflammatory, apoptosis, Bladder cancer, Chapter 7 Isolates and Cancer Research, Chemotherapy, inflammation, Lung cancer, Neuropathy, Ovarian cancer, Rectal cancer

Matricaria chamomilla/Matricaria recutita

Cancer: Colorectal., ovarian, testicular, bladder, lung

Action: Neuropathy, anti-inflammatory

Colorectal Cancer; Ovarian Cancer; Testicular Cancer; Bladder Cancer; Lung Cancer; Chemotherapy

Studies have shown that cisplatin could have painful effects on human and animal models. Matricaria chamomilla (MC) has analgesic and anti-inflammatory effects, and may hence be an effective treatment for ciplatin-induced peripheral neuropathy as a replacement for morphine. Experiments were performed on 60 NMRI male mice weighed 25 g to 30 g, which have been divided into 6 groups. The first group received normal saline; the second group received MC hydroalcoholic extract; the third group received cisplatin; the fourth group received MC hydroalcoholic extract and cisplatin, 96 hours before formalin test; the fifth group received morphine and the sixth group received cisplatin and morphine.

Results showed that formalin induced significant (P < 0.05) pain response (the first phase: 0–5 min and the second phase: 15–40 min after injection). Administration of MC extract before formalin injection showed significant (P < 0.05) decrease of pain responses in the first and second phase. Administration of cisplatin produced significant (P < 0.05) increase in pain response in both phases of formalin test. Injection of MC extract and cisplatin together have shown that MC is able to decrease the second phase of cisplatin-induced pain significantly (P < 0.05).

In comparison morphine has analgesic effects in the first phase and MC extract has anti- inflammatory effects in the second phase of formalin test significantly (P < 0.05). MC and cisplatin have analgesic and painful neuropathic respective effects, and MC hydroalcoholic extract is able to decrease cisplatin-induced pain and inflammation better than morphine (Abad et al., 2011).

Anti-inflammatory

Flavonoid-7-glycosides, major constituents of chamomile flowers, may be responsible for the anti-inflammatory action, which is due to the inhibition of neutrophil elastase and gastric metalloproteinase-9 activity and secretion; the inhibition occurring in a concentration dependent manner (Bulgari et al., 2012).

The anti-cancer properties of aqueous and methanolic extracts of Matricaria chamomilla against various human cancer cell lines were investigated. Chamomile exposure resulted in differential apoptosis in cancer cells but not in normal cells at similar doses. HPLC analysis of chamomile extract confirmed apigenin 7-O-glucoside as the major constituent of chamomile; some minor glycoside components were also observed. Apigenin glucosides inhibited cancer cell growth but to a lesser extent than the parent aglycone, apigenin (Srivastava & Gupta, 2007).

References

Abad NA, Nouri MHK, Gharjanie A, Tavakoli F. (2011). Effect of Matricaria chamomilla Hydroalcoholic Extract on Cisplatin-induced Neuropathy in Mice. Chinese Journal of Natural Medicines, 9(2):126–131


Bulgari M, Sangiovanni E, Colombo E, et al. (2012). Inhibition of neutrophil elastase and metalloprotease-9 of human adenocarcinoma gastric cells by chamomile (Matricaria recutita L.) infusion. Phytother Res, 26(12):1817-22. doi: 10.1002/ptr.4657.


Srivastava JK, Gupta S. (2007). Anti-proliferative and apoptotic effects of chamomile extract in various human cancer cells. J Agric Food Chem, 55(23):9470-8.

AhR, Akt, angiogenesis, Anti-cancer, anti-proliferative, anti-proliferative effect, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BCR, Breast cancer, CDK, CDK2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, CYP1A1, CYP1B1, FAK, G1, G2/M, Head and neck cancer, inflammation, inhibits angiogenesis, Isatis (L.) genus, Lung cancer, MCF-7, metastasis, Prostate cancer, RS4;11 and MV4;1, STAT3

Indirubin

Cancer:
Chronic myelogenous leukemia, lung, breast, head and neck, prostate, acute myeloid leukemia, prostate

Action: Aryl hydrocarbon Receptor (AhR) regulator, inhibits angiogenesis

Indirubin is the active component of many plants from the Isatis (L.) genus, including Isatis tinctoria (L.).

Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases. Indirubin and its analogues are potent inhibitors of cyclin-dependent kinases (CDKs). The crystal structure of CDK2 in complex with indirubin derivatives shows that indirubin interacts with the kinase's ATP-binding site through van der Waals interactions and three hydrogen bonds. Indirubin-3'-monoxime inhibits the proliferation of a large range of cells, mainly through arresting the cells in the G2/M phase of the cell-cycle. These results have implications for therapeutic optimization of indigoids (Hoessel et al., 1999).

Formula; Huang Lian (Rhizoma Coptidis Recens), Huang Qin (Radix Scutellariae Baicalensis), Huang Bai (Cortex Phellodendri), Zhi Zi (Fructus Gardeniae Jasminoidis), Dang Gui (Radix Angelicae Sinensis), Lu Hui (Herba Aloes), Long Dan Cao (Radix Gentianae Longdancao), Da Huang (Radix et Rhizoma Rhei), Mu Xiang (Radix Aucklandiae Lappae), Qing Dai (Indigo Pulverata Levis), She Xiang (Secretio Moschus)

Leukemia

Indirubin, a 3, 2' bisindole isomer of indigo was originally identified as the active principle of a traditional Chinese preparation and has been proven to exhibit anti-leukemic effectiveness in chronic myelocytic leukemia. Indirubin was detected to represent a novel lead structure with potent inhibitory potential towards cyclin-dependent kinases (CDKs) resulting from high affinity binding into the enzymes ATP binding site. This seminal finding triggered research to improve the pharmacological activities of the parent molecule within comprehensive structure-activity studies. Molecular modifications made novel anti-cancer compounds accessible with strongly improved CDK inhibitory potential and with broad-spectrum anti-tumor activity.

This novel family of compounds holds strong promise for clinical anti-cancer activity and might be useful also in several important non-cancer indications, including Alzheimer's disease or diabetes (Eisenbrand et al., 2004).

Aryl Hydrocarbon Receptor (AhR) Regulator; Breast Cancer

The aryl hydrocarbon receptor (AhR), when activated by exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), regulates expression of several phase I and phase II enzymes and is also involved in the regulation of cell proliferation. One putative endogenous ligand is indirubin, which was recently identified in human urine and bovine serum. We determined the effect of indirubin in MCF-7 breast cancer cells on induction of the activities of cytochromes P450 (CYP) 1A1 and 1B1. With 4 hours exposure, the effects of indirubin and TCDD at 10nM on CYP activity were comparable, but the effects of indirubin, unlike those of TCDD, were transitory. Indirubin-induced ethoxyresorufin-O-deethylase activity was maximal by 6–9 hours post-exposure and had disappeared by 24 hours, whereas TCDD-induced activities remained elevated for at least 72 hours.

Thus, if indirubin is an endogenous AhR ligand, then AhR-mediated signaling by indirubin is likely to be transient and tightly controlled by the ability of indirubin to induce CYP1A1 and CYP1B1, and hence its own metabolism (Spink et al., 2003).

Chronic Myelogenous Leukemia (CML)

Indirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). In a study investigating its mechanism of action, indirubin derivatives (IRDs) were found to potently inhibit Signal Transducer and Activator of Transcription 5 (Stat5) protein in CML cells.

Compound E804, which is the most potent in this series of IRDs, blocked Stat5 signaling in human K562 CML cells, imatinib-resistant human KCL-22 CML cells expressing the T315I mutant Bcr-Abl (KCL-22M), and CD34-positive primary CML cells from patients.

In sum, these findings identify IRDs as potent inhibitors of the SFK/Stat5 signaling pathway downstream of Bcr-Abl, leading to apoptosis of K562, KCL-22M and primary CML cells. IRDs represent a promising structural class for development of new therapeutics for wild type or T315I mutant Bcr-Abl-positive CML patients (Nam et al., 2012).

Lung Cancer

A novel indirubin derivative, 5'-nitro-indirubinoxime (5'-NIO), exhibits a strong anti-cancer activity against human cancer cells. Here, the 5'-NIO-mediated G1 cell-cycle arrest in lung cancer cells was associated with a decrease in protein levels of polo-like kinase 1 (Plk1) and peptidyl-prolyl cis/trans isomerase Pin1. These findings suggest that 5'-NIO have potential anti-cancer efficacy through the inhibition of Plk1 or/and Pin1 expression (Yoon et al., 2012).

The control lung tissue showed a normal architecture with clear alveolar spaces. Interestingly, the indirubin-3-monoxime treated groups showed reduced adenocarcinoma with appearance of alveolar spaces. Transmission Electron Microscopic (TEM) studies of lung sections of [B(α)P]-induced lung cancer mice showed the presence of phaemorphic cells with dense granules and increased mitochondria.

The lung sections of mice treated with indirubin-3-monoxime showed the presence of shrunken, fragmented, and condensed nuclei implying apoptosis. The effects were dose-dependent and prominent in 10 mg/kg/5 d/week groups, suggesting the therapeutic role of indirubin analogue against this deadly human malignancy. These results indicate that indirubin-3-monoxime brings anti-tumor effect against [B(α)P]-induced lung cancer by its apoptotic action in A/J mice (Ravichandran et al., 2010).

Head and Neck Cancer

The effects of 5'-nitro-indirubinoxime (5'-NIO), an indirubin derivative, on metastasis of head and neck cancer cells were investigated and the underlying molecular mechanisms involved in this process explored.

After treatment of head and neck cancer cells with 5'-NIO, cell metastatic behaviors such as colony formation, invasion, and migration were inhibited in a concentration-dependent manner. 5'-NIO inhibited the beta1 Integrin/FAK/Akt pathway which can then facilitate invasion and/or migration of cancer cells through the extracellular matrix (ECM). Moreover, treatment of head and neck cancer cell with Integrin β1 siRNA or FAK inhibitor effectively inhibited the invasion and migration, suggesting their regulatory role in invasiveness and migration of head and neck cancer cells. It was concluded that 5'-NIO inhibits the metastatic ability of head and neck cancer cells by blocking the Integrin β1/FAK/Akt pathway (Kim et al., 2011).

Prostate Cancer; Inhibits Angiogenesis

Indirubin, the active component of a traditional Chinese herbal medicine, Banlangen, has been shown to exhibit anti-tumor and anti-inflammation effects; however, its role in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is unknown.

To address this shortfall in the existing research, it was identified that indirubin inhibited prostate tumor growth through inhibiting tumor angiogenesis. It was found that indirubin inhibited angiogenesis in vivo. The inhibition activity of indirubin in endothelial cell migration, tube formation and cell survival in vitro has also been shown. Furthermore, indirubin suppressed vascular endothelial growth factor receptor 2-mediated Janus kinase (JAK)/STAT3 signaling pathway. This study provided the first evidence for anti-tumor angiogenesis activity of indirubin and the related molecular mechanism.

These investigations suggest that indirubin is a potential drug candidate for angiogenesis-related diseases (Zhang et al., 2011).

Acute Myeloid Leukemia

Indirubin derivatives were identified as potent FLT3 tyrosine kinase inhibitors with anti-proliferative activity at acute myeloid leukemic cell lines, RS4;11 and MV4;11 which express FLT3-WT and FLT3-ITD mutation, respectively. Among several 5 and 5'-substituted indirubin derivatives, 5-fluoro analog, 13 exhibited potent inhibitory activity at FLT3 (IC(50)=15 nM) with more than 100-fold selectivity versus 6 other kinases and potent anti-proliferative effect for MV4;11 cells (IC(50)=72 nM) with 30-fold selectivity versus RS4;11 cells.

Cell cycle analysis indicated that compound 13 induced cell-cycle arrest at G(0)/G(1) phase in MV4;11 cells (Choi et al., 2010).

References

Choi SJ, Moon MJ, Lee SD, et al. (2010). Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative activity of acute myeloid leukemic cells. Bioorg Med Chem Lett, 20(6):2033-7.


Eisenbrand G, Hippe F, Jakobs S, Muehlbeyer S. (2004). Molecular mechanisms of indirubin and its derivatives: novel anti-cancer molecules with their origin in traditional Chinese phytomedicine. J Cancer Res Clin Oncol, 130(11):627-35


Hoessel R, Leclerc S, Endicott JA, et al. (1999). Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol, 1(1):60-7.


Kim SA, Kwon SM, Kim JA, et al. (2011). 5'-Nitro-indirubinoxime, an indirubin derivative, suppresses metastatic ability of human head and neck cancer cells through the inhibition of Integrin β 1/FAK/Akt signaling. Cancer Lett, 306(2):197-204.


Nam S, Scuto A, Yang F, et al. (2012). Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol Oncol, 6(3):276-83.


Ravichandran K, Pal A, Ravichandran R. (2010). Effect of indirubin-3-monoxime against lung cancer as evaluated by histological and transmission electron microscopic studies. Microsc Res Tech, 73(11):1053-8.


Spink BC, Hussain MM, Katz BH, Eisele L, Spink DC. (2003). Transient induction of cytochromes P450 1A1 and 1B1 in MCF-7 human breast cancer cells by indirubin. Biochem Pharmacol, 66(12):2313-21.


Yoon HE, Kim SA, Choi HS, et al. (2012). Inhibition of Plk1 and Pin1 by 5'-nitro-indirubinoxime suppresses human lung cancer cells. Cancer Lett, 316(1):97-104.


Zhang X, Song Y, Wu Y, et al. (2011). Indirubin inhibits tumor growth by anti-tumor angiogenesis via blocking VEGFR2-mediated JAK/STAT3 signaling in endothelial cell. Int J Cancer, 129(10):2502-11. doi: 10.1002/ijc.25909.

Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, Anti-oxidation, anti-proliferative, anti-tumor, anti-tumor activity, apoptosis, apoptosis-inducing, Apoptotic, AR, BAX, Bcl-2, BCR, Bladder cancer, Breast cancer, Breast cancer cell lines, CAM, cancer stem cells, CCNE2, CDC2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-enhancing, chemo-preventive, Chemo-protective, Chemo-sensitizer, chemo-sensitzer, Chemoprevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, CSCs, down-regulate COX-2, EGFR, ERK, G2/M, GSTP1, HER2, HIF, HO-1, IL-1, IL-6, IL-8, inflammation, inhibits angiogenesis, Liver cancer, Lymphoma, MAPK, Melanoma, metastasis, MTOR, Multi-Drug Resistance, Multi-drug resistance, Nitric Oxide, NQO1, Osteosarcoma, Ovarian cancer, p38, p65, P70S6K, Pancreatic cancer, PARP, PI3K, Pro-apoptotic, Prostate cancer, Rectal cancer, Rh-123, ROS, Sarcoma, SHH, TAM resistance, TNF, Topo-II, VEGF, VEGF

Dietary Flavones

Cancer:
Prostate, colorectal., breast, pancreatic, bladder, ovarian, leukemia, liver, glioma, osteosarcoma, melanoma

Action: Anti-inflammatory, TAM resistance, cancer stem cells, down-regulate COX-2, apoptosis, cell-cycle arrest, anti-angiogenic, chemo-sensitzer, adramycin (ADM) resistance

Sulforaphane, Phenethyl isothiocyanate (PEITC), quercetin, epicatechin, catechin, Luteolin, apigenin

Anti-inflammatory

The anti-inflammatory activities of celery extracts, some rich in flavone aglycones and others rich in flavone glycosides, were tested on the inflammatory mediators tumor necrosis factor α (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lipopolysaccharide-stimulated macrophages. Pure flavone aglycones and aglycone-rich extracts effectively reduced TNF-α production and inhibited the transcriptional activity of NF-κB, while glycoside-rich extracts showed no significant effects.

Celery diets with different glycoside or aglycone contents were formulated and absorption was evaluated in mice fed with 5% or 10% celery diets. Relative absorption in vivo was significantly higher in mice fed with aglycone-rich diets as determined by HPLC-MS/MS (where MS/MS is tandem mass spectrometry). These results demonstrate that deglycosylation increases absorption of dietary flavones in vivo and modulates inflammation by reducing TNF-α and NF-κB, suggesting the potential use of functional foods rich in flavones for the treatment and prevention of inflammatory diseases (Hostetler et al., 2012).

Colorectal Cancer

Association between the 6 main classes of flavonoids and the risk of colorectal cancer was examined using data from a national prospective case-control study in Scotland, including 1,456 incident cases and 1,456 population-based controls matched on age, sex, and residence area.

Dietary, including flavonoid, data were obtained from a validated, self-administered food frequency questionnaire. Risk of colorectal cancer was estimated using conditional logistic regression models in the whole sample and stratified by sex, smoking status, and cancer site and adjusted for established and putative risk factors.

The significant dose-dependent reductions in colorectal cancer risk that were associated with increased consumption of the flavonols quercetin, catechin, and epicatechin, remained robust after controlling for overall fruit and vegetable consumption or for other flavonoid intake. The risk reductions were greater among nonsmokers, but no interaction beyond a multiplicative effect was present.

This was the first of several a priori hypotheses to be tested in this large study and showed strong and linear inverse associations of flavonoids with colorectal cancer risk (Theodoratou et al., 2007).

Anti-angiogenic, Prostate Cancer

Luteolin is a common dietary flavonoid found in fruits and vegetables. The anti-angiogenic activity of luteolin was examined using in vitro, ex vivo, and in vivo models. Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis; hence, examination of this mechanism of tumor growth is essential to understanding new chemo-preventive targets. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay.

Pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the down-regulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions.

Taken together, these findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis (Pratheeshkumar et al., 2012).

Pancreatic Cancer; Chemo-sensitizer

The potential of dietary flavonoids apigenin (Api) and luteolin (Lut) were assessed in their ability to enhance the anti-proliferative effects of chemotherapeutic drugs on BxPC-3 human pancreatic cancer cells; additionally, the molecular mechanism of the action was probed.

Simultaneous treatment with either flavonoid (0,13, 25 or 50µM) and chemotherapeutic drugs 5-fluorouracil (5-FU, 50µM) or gemcitabine (Gem, 10µM) for 60 hours resulted in less-than-additive effect (p<0.05). Pre-treatment for 24 hours with 13µM of either Api or Lut, followed by Gem for 36 hours was optimal to inhibit cell proliferation. Pre-treatment of cells with 11-19µM of either flavonoid for 24 hours resulted in 59-73% growth inhibition when followed by Gem (10µM, 36h). Lut (15µM, 24h) pre-treatment followed by Gem (10µM, 36h), significantly decreased protein expression of nuclear GSK-3β and NF-κB p65 and increased pro-apoptotic cytosolic cytochrome c. Pre-treatment of human pancreatic cancer cells BxPC-3 with low concentrations of Api or Lut hence effectively aid in the anti-proliferative activity of chemotherapeutic drugs (Johnson et al., 2013).

Breast Cancer; Chemo-sensitizer, Tamoxifen

The oncogenic molecules in human breast cancer cells are inhibited by luteolin treatment and it was found that the level of cyclin E2 (CCNE2) mRNA was higher in tumor cells than in normal paired tissue samples as assessed using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis (n=257).

Combined treatment with 4-OH-TAM and luteolin synergistically sensitized the TAM-R cells to 4-OH-TAM. These results suggest that luteolin can be used as a chemo-sensitizer to target the expression level of CCNE2 and that it could be a novel strategy to overcome TAM resistance in breast cancer patients (Tu et al., 2013).

Breast Cancer

Consumers of higher levels of Brassica vegetables, particularly those of the genus Brassica (broccoli, Brussels sprouts and cabbage), reduce their susceptibility to cancer at a variety of organ sites. Brassica vegetables contain high concentrations of glucosinolates that can be hydrolyzed by the plant enzyme, myrosinase, or intestinal microflora to isothiocyanates, potent inducers of cytoprotective enzymes and inhibitors of carcinogenesis. Oral administration of either the isothiocyanate, sulforaphane, or its glucosinolate precursor, glucoraphanin, inhibits mammary carcinogenesis in rats treated with 7,12-dimethylbenz[a]anthracene. To determine whether sulforaphane exerts a direct chemo-preventive action on animal and human mammary tissue, the pharmacokinetics and pharmacodynamics of a single 150 µmol oral dose of sulforaphane were evaluated in the rat mammary gland.

Sulforaphane metabolites were detected at concentrations known to alter gene expression in cell culture. Elevated cytoprotective NAD(P)H:quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1) gene transcripts were measured using quantitative real-time polymerase chain reaction. An observed 3-fold increase in NQO1 enzymatic activity, as well as 4-fold elevated immunostaining of HO-1 in rat mammary epithelium, provide strong evidence of a pronounced pharmacodynamic action of sulforaphane. In a subsequent pilot study, eight healthy women undergoing reduction mammoplasty were given a single dose of a broccoli sprout preparation containing 200 µmol of sulforaphane. Following oral dosing, sulforaphane metabolites were readily measurable in human breast tissue enriched for epithelial cells. These findings provide a strong rationale for evaluating the protective effects of a broccoli sprout preparation in clinical trials of women at risk for breast cancer (Cornblatt et al., 2007).

In a proof of principle clinical study, the presence of disseminated tumor cells (DTCs) was demonstrated in human breast tissue after a single dose of a broccoli sprout preparation containing 200 µmol of sulforaphane. Together, these studies demonstrate that sulforaphane distributes to the breast epithelial cells in vivo and exerts a pharmacodynamic action in these target cells consistent with its mechanism of chemo-protective efficacy.

Such efficacy, coupled with earlier randomized clinical trials revealing the safety of repeated doses of broccoli sprout preparations , supports further evaluation of broccoli sprouts in the chemoprevention of breast and other cancers (Cornblatt et al., 2007).

CSCs

Recent research into the effects of sulforaphane on cancer stem cells (CSCs) has drawn a great deal of interest. CSCs are suggested to be responsible for initiating and maintaining cancer, and to contribute to recurrence and drug resistance. A number of studies have indicated that sulforaphane may target CSCs in different types of cancer through modulation of NF- κB, SHH, epithelial-mesenchymal transition and Wnt/β-catenin pathways. Combination therapy with sulforaphane and chemotherapy in preclinical settings has shown promising results (Li et al., 2013).

Anti-inflammatory

Sulforaphane has been found to down-regulate COX-2 expression in human bladder transitional cancer T24 cells at both transcriptional- and translational levels. Cyclooxygenase-2 (COX-2) overexpression has been associated with the grade, prognosis and recurrence of transitional cell carcinoma (TCC) of the bladder. Sulforaphane (5-20 microM) induced nuclear translocation of NF-kappaB and reduced its binding to the COX-2 promoter, a key mechanism for suppressing COX-2 expression by sulforaphane. Moreover, sulforaphane increased expression of p38 and phosphorylated-p38 protein. Taken together, these data suggest that p38 is essential in sulforaphane-mediated COX-2 suppression and provide new insights into the molecular mechanisms of sulforaphane in the chemoprevention of bladder cancer (Shan et al., 2009).

Bladder Cancer

An aqueous extract of broccoli sprouts potently inhibits the growth of human bladder carcinoma cells in culture and this inhibition is almost exclusively due to the isothiocyanates. Isothiocyanates are present in broccoli sprouts as their glucosinolate precursors and blocking their conversion to isothiocyanates abolishes the anti-proliferative activity of the extract.

Moreover, the potency of isothiocyanates in the extract in inhibiting cancer cell growth was almost identical to that of synthetic sulforaphane, as judged by their IC50 values (6.6 versus 6.8 micromol/L), suggesting that other isothiocyanates in the extract may be biologically similar to sulforaphane and that nonisothiocyanate substances in the extract may not interfere with the anti-proliferative activity of the isothiocyanates. These data show that broccoli sprout isothiocyanate extract is a highly promising substance for cancer prevention/treatment and that its anti-proliferative activity is exclusively derived from isothiocyanates (Tang et al., 2006).

Ovarian Cancer

Sulforaphane is an extract from the mustard family recognized for its anti-oxidation abilities, phase 2 enzyme induction, and anti-tumor activity. The cell-cycle arrest in G2/M by sulforaphane and the expression of cyclin B1, Cdc2, and the cyclin B1/CDC2 complex in PA-1 cells using Western blotting and co-IP Western blotting. The anti-cancer effects of dietary isothiocyanate sulforaphane on ovarian cancer were investigated using cancer cells line PA-1.

Sulforaphane -treated cells accumulated in metaphase by CDC2 down-regulation and dissociation of the cyclin B1/CDC2 complex.

These findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may also provide anti-tumor activity in established ovarian cancer (Chang et al., 2013).

Leukemia Stem Cells

Isolated leukemia stem cells (LSCs) showed high expression of Oct4, CD133, β-catenin, and Sox2 and imatinib (IM) resistance. Differentially, CD34(+)/CD38(-) LSCs demonstrated higher BCR-ABL and β-catenin expression and IM resistance than CD34(+)/CD38(+) counterparts. IM and sulforaphane (SFN) combined treatment sensitized CD34(+)/CD38(-) LSCs and induced apoptosis, shown by increased caspase 3, PARP, and Bax while decreased Bcl-2 expression. Mechanistically, imatinib (IM) and sulforaphane (SFN) combined treatment resensitized LSCs by inducing intracellular reactive oxygen species (ROS). Importantly, β-catenin-silenced LSCs exhibited reduced glutathione S-transferase pi 1 (GSTP1) expression and intracellular GSH level, which led to increased sensitivity toward IM and sulforaphane.

It was hence demonstrated that IM and sulforaphane combined treatment effectively eliminated CD34(+)/CD38(-) LSCs. Since SFN has been shown to be well tolerated in both animals and human, this regimen could be considered for clinical trials (Lin et al., 2012).

DCIS Stem Cells

A miR-140/ALDH1/SOX9 axis has been found to be critical to basal cancer stem cell self-renewal and tumor formation in vivo, suggesting that the miR-140 pathway may be a promising target for preventive strategies in patients with basal-like Ductal Carcinoma in Situ (DCIS). The dietary compound sulforaphane has been found to decrease Transcription factor SOX-9 and Acetaldehyde dehydrogenases (ALDH1), and thereby reduced tumor growth in vivo (Li et al., 2013).

Glioma, Prostate Cancer, Colon Cancer, Breast Cancer, Liver Cancer

Phenethyl isothiocyanate (PEITC), a natural dietary isothiocyanate, inhibits angiogenesis. The effects of PEITC were examined under hypoxic conditions on the intracellular level of the hypoxia inducible factor (HIF-1α) and extracellular level of the vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Gupta et al., (2013) observed that PEITC suppressed the HIF-1α accumulation during hypoxia in human glioma U87, human prostate cancer DU145, colon cancer HCT116, liver cancer HepG2, and breast cancer SkBr3 cells. PEITC treatment also significantly reduced the hypoxia-induced secretion of VEGF.

Suppression of HIF-1α accumulation during treatment with PEITC in hypoxia was related to PI3K and MAPK pathways.

Taken together, these results suggest that PEITC inhibits the HIF-1α expression through inhibiting the PI3K and MAPK signaling pathway and provide a new insight into a potential mechanism of the anti-cancer properties of PEITC.

Breast Cancer Metastasis

Breast tumor metastasis is a leading cause of cancer-related deaths worldwide. Breast tumor cells frequently metastasize to brain and initiate severe therapeutic complications. The chances of brain metastasis are further elevated in patients with HER2 overexpression. The MDA-MB-231-BR (BR-brain seeking) breast tumor cells stably transfected with luciferase were injected into the left ventricle of mouse heart and the migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent imaging system.

Results demonstrate that the growth of metastatic brain tumors in PEITC treated mice was about 50% less than that of control. According to Kaplan Meir's curve, median survival of tumor-bearing mice treated with PEITC was prolonged by 20.5%. Furthermore, as compared to controls, we observed reduced HER2, EGFR and VEGF expression in the brain sections of PEITC treated mice. These results demonstrate the anti-metastatic effects of PEITC in vivo in a novel breast tumor metastasis model and provides the rationale for further clinical investigation (Gupta et al., 2013).

Osteosarcoma, Melanoma

Phenethyl isothiocyanate (PEITC) has been found to induce apoptosis in human osteosarcoma U-2 OS cells. The following end points were determined in regard to human malignant melanoma cancer A375.S2 cells: cell morphological changes, cell-cycle arrest, DNA damage and fragmentation assays and morphological assessment of nuclear change, reactive oxygen species (ROS) and Ca2+ generations, mitochondrial membrane potential disruption, and nitric oxide and 10-N-nonyl acridine orange productions, expression and activation of caspase-3 and -9, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, poly (adenosine diphosphate-ribose) polymerase, and cytochrome c release, apoptosis-inducing factor and endonuclease G. PEITC

It was therefore concluded that PEITC-triggered apoptotic death in A375.S2 cells occurs through ROS-mediated mitochondria-dependent pathways (Huang et al., 2013).

Prostate Cancer

The glucosinolate-derived phenethyl isothiocyanate (PEITC) has recently been demonstrated to reduce the risk of prostate cancer (PCa) and inhibit PCa cell growth. It has been shown that p300/CBP-associated factor (PCAF), a co-regulator for the androgen receptor (AR), is upregulated in PCa cells through suppression of the mir-17 gene. Using AR-responsive LNCaP cells, the inhibitory effects of PEITC were observed on the dihydrotestosterone-stimulated AR transcriptional activity and cell growth of PCa cells.

Expression of PCAF was upregulated in PCa cells through suppression of miR-17. PEITC treatment significantly decreased PCAF expression and promoted transcription of miR-17 in LNCaP cells. Functional inhibition of miR-17 attenuated the suppression of PCAF in cells treated by PEITC. Results indicate that PEITC inhibits AR-regulated transcriptional activity and cell growth of PCa cells through miR-17-mediated suppression of PCAF, suggesting a new mechanism by which PEITC modulates PCa cell growth (Yu et al., 2013).

Bladder Cancer; Adramycin (ADM) Resistance

The role of PEITC on ADM resistance reversal of human bladder carcinoma T24/ADM cells has been examined, including an increased drug sensitivity to ADM, cell apoptosis rates, intracellular accumulation of Rhodamine-123 (Rh-123), an increased expression of DNA topoisomerase II (Topo-II), and a decreased expression of multi-drug resistance gene (MDR1), multi-drug resistance-associated protein (MRP1), bcl-2 and glutathione s transferase π (GST-π). The results indicated that PEITC might be used as a potential therapeutic strategy to ADM resistance through blocking Akt and activating MAPK pathway in human bladder carcinoma (Tang et al., 2013).

Breast Cancer; Chemo-enhancing

The synergistic effect between paclitaxel (taxol) and phenethyl isothiocyanate (PEITC) on the inhibition of breast cancer cells has been examined. Two drug-resistant breast cancer cell lines, MCF7 and MDA-MB-231, were treated with PEITC and taxol. Cell growth, cell-cycle, and apoptosis were examined.

The combination of PEITC and taxol significantly decreased the IC50 of PEITC and taxol over each agent alone. The combination also increased apoptosis by more than 2-fold over each single agent in both cell lines. A significant increase of cells in the G2/M phases was detected. Taken together, these results indicated that the combination of PEITC and taxol exhibits a synergistic effect on growth inhibition in breast cancer cells. This combination deserves further study in vivo (Liu et al., 2013).

References

Chang CC, Hung CM, Yang YR, Lee MJ, Hsu YC. (2013). Sulforaphane induced cell-cycle arrest in the G2/M phase via the blockade of cyclin B1/CDC2 in human ovarian cancer cells. J Ovarian Res, 6(1):41. doi: 10.1186/1757-2215-6-41


Cornblatt BS, Ye LX, Dinkova-Kostova AT, et al. (2007). Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis, 28(7):1485-1490. doi: 10.1093/carcin/bgm049


Gupta B, Chiang L, Chae K, Lee DH. (2013). Phenethyl isothiocyanate inhibits hypoxia-induced accumulation of HIF-1 α and VEGF expression in human glioma cells. Food Chem, 141(3):1841-6. doi: 10.1016/j.foodchem.2013.05.006.


Gupta P, Adkins C, Lockman P, Srivastava SK. (2013). Metastasis of Breast Tumor Cells to Brain Is Suppressed by Phenethyl Isothiocyanate in a Novel In Vivo Metastasis Model. PLoS One, 8(6):e67278. doi:10.1371/journal.pone.0067278


Hostetler G, Riedl K, Cardenas H, et al. (2012). Flavone deglycosylation increases their anti-inflammatory activity and absorption. Molecular Nutrition & Food Research, 56(4):558-569. doi: 10.1002/mnfr.201100596


Huang SH, Hsu MH, Hsu SC, et al. (2013). Phenethyl isothiocyanate triggers apoptosis in human malignant melanoma A375.S2 cells through reactive oxygen species and the mitochondria-dependent pathways. Hum Exp Toxicol. doi: 10.1177/0960327113491508


Johnson JL, Gonzalez de Mejia E. (2013). Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem Toxicol, 60:83-91. doi: 10.1016/j.fct.2013.07.036.


Li Q, Yao Y, Eades G, Liu Z, Zhang Y, Zhou Q. (2013). Down-regulation of miR-140 promotes cancer stem cell formation in basal-like early stage breast cancer. Oncogene. doi: 10.1038/onc.2013.226.


Li Y, Zhang T. (2013). Targeting cancer stem cells with sulforaphane, a dietary component from broccoli and broccoli sprouts. Future Oncol, 9(8):1097-103. doi: 10.2217/fon.13.108.


Lin LC, Yeh CT, Kuo CC, et al. (2012). Sulforaphane potentiates the efficacy of imatinib against chronic leukemia cancer stem cells through enhanced abrogation of Wnt/ β-catenin function. J Agric Food Chem, 60(28):7031-9. doi: 10.1021/jf301981n.


Liu K, Cang S, Ma Y, Chiao JW. (2013). Synergistic effect of paclitaxel and epigenetic agent phenethyl isothiocyanate on growth inhibition, cell-cycle arrest and apoptosis in breast cancer cells. Cancer Cell Int, 13(1):10. doi: 10.1186/1475-2867-13-10.


Pratheeshkumar P, Son YO, Budhraja A, et al. (2012). Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. PLoS One, 7(12):52279. doi: 10.1371/journal.pone.0052279.


Tang K, Lin Y, Li LM. (2013). The role of phenethyl isothiocyanate on bladder cancer ADM resistance reversal and its molecular mechanism. Anat Rec (Hoboken), 296(6):899-906. doi: 10.1002/ar.22677.


Tang L, Zhang Y, Jobson HE, et al. (2006). Potent activation of mitochondria-mediated apoptosis and arrest in S and M phases of cancer cells by a broccoli sprout extract. Mol Cancer Ther, 5(4):935-44. doi: 10.1158/1535-7163.MCT-05-0476


Theodoratou E, Kyle J, Cetnarskyj R, et al. (2007). Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev,16(4):684-93.


Tu SH, Ho CT, Liu MF, et al. (2013). Luteolin sensitizes drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression. Food Chem, 141(2):1553-61. doi: 10.1016/j.foodchem.2013.04.077.


Shan Y, Wu K, Wang W, et al. (2009). Sulforaphane down-regulates COX-2 expression by activating p38 and inhibiting NF-kappaB-DNA-binding activity in human bladder T24 cells. Int J Oncol, 34(4):1129-34.


Yu C, Gong AY, Chen D, et al. (2013). Phenethyl isothiocyanate inhibits androgen receptor-regulated transcriptional activity in prostate cancer cells through suppressing PCAF. Mol Nutr Food Res. doi: 10.1002/mnfr.201200810.

anti-apoptotic, Anti-cancer, anti-inflammatory, anti-oxidative, anti-proliferative, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, AR, BAX, Bcl-2, Bcl-xL, Breast cancer, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, COX-2, CYP3A, DU145, G1, G2/M, hepato-protective, ICAM-1, inflammation, JNK, MAPK, metastasis, MMP2, MMP9, MTOR, p38, PGE2, Prostate cancer, STAT3, STAT3 (Tyr705), TNF, VCAM-1

Cryptotanshinone (See also Tanshinone)

Cancer:
Prostate, breast, cervical., leukemia, hepatocellular carcinoma

Action: Anti-inflammatory, cell-cycle arrest, inhibits dihydrotestosterone (DHT), anti-proliferative, hepato-protective

Cryptotanshinone is a major constituent of tanshinones from Salvia miltiorrhiza (Bunge).

Tanshinone IIA and cryptotanshinone could induce CYP3A activity (Qiu et al., 2103).

Anti-proliferative Agent

Cryptotanshinone (CPT), a natural compound, is a potential anti-cancer agent. Chen et al., (2010) have shown that CPT inhibited cancer cell proliferation by arresting cells in G(1)-G(0) phase of the cell-cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation.

Furthermore, they found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I- or 10% fetal bovine serum-stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration- and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel anti-proliferative agent.

Anti-inflammatory; COX-2, PGE2

Cyclooxygenase-2 (COX-2) is a key enzyme that catalyzes the biosynthesis of prostaglandins from arachidonic acid and plays a critical role in some pathologies including inflammation, neurodegenerative diseases and cancer. Cryptotanshinone is a major constituent of tanshinones and has well-documented anti-oxidative and anti-inflammatory effects.

This study confirmed the remarkable anti-inflammatory effect of cryptotanshinone in the carrageenan-induced rat paw edema model. Since the action of cryptotanshinone on COX-2 has not been previously described, in this study, Jin et al. (2006) examined the effect of cryptotanshinone on cyclooxygenase activity in the exogenous arachidonic acid-stimulated insect sf-9 cells, which highly express human COX-2 or human COX-1, and on cyclooxygenases expression in human U937 promonocytes stimulated by lipopolysaccharide (LPS) plus phorbolmyristate acetate (PMA).

Cryptotanshinone reduced prostaglandin E2 synthesis and reactive oxygen species generation catalyzed by COX-2, without influencing COX-1 activity in cloned sf-9 cells. In PMA plus LPS-stimulated U937 cells, cryptotanshinone had negligible effects on the expression of COX-1 and COX-2, at either a mRNA or protein level. These results demonstrate that the anti-inflammatory effect of cryptotanshinone is directed against enzymatic activity of COX-2, not against the transcription or translation of the enzyme.

Prostate Cancer

Cryptotanshinone was identified as a potent STAT3 inhibitor. Cryptotanshinone rapidly inhibited STAT3 Tyr705 phosphorylation in DU145 prostate cancer cells and the growth of the cells through 96 hours of the treatment. Inhibition of STAT3 Tyr705 phosphorylation in DU145 cells decreased the expression of STAT3 downstream target proteins such as cyclin D1, survivin, and Bcl-xL.

Cryptotanshinone can suppress Bcl-2 expression and augment Fas sensitivity in DU145 prostate cancer cells. Park et al. (2010) show that JNK and p38 MAPK act upstream of Bcl-2 expression in Fas-treated DU145 cells, and that cryptotanshinone significantly blocked activation of these kinases. Moreover, cryptotanshinone sensitized several tumor cells to a broad range of anti-cancer agents. Collectively, the data suggest that cryptotanshinone has therapeutic potential in the treatment of human prostate cancer (Park et al., 2010).

Cryptotanshinone was colocalized with STAT3 molecules in the cytoplasm and inhibited the formation of STAT3 dimers. Computational modeling showed that cryptotanshinone could bind to the SH2 domain of STAT3. These results suggest that cryptotanshinone is a potent anti-cancer agent targeting the activation STAT3 protein. It is the first report that cryptotanshinone has anti-tumor activity through the inhibition of STAT3 (Shin et al., 2009).

Prostate Cancer; Androgen Receptor Positive

Anti-androgens to reduce or prevent androgens binding to androgen receptor (AR) are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a short period of time. Xu et al., (2012) found that cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Their results indicated that 0.5 µM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells.

Furthermore, data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR-coregulator complex formation.

Furthermore, they showed that CTS effectively inhibits CWR22Rv1 cell growth and expressions of AR target genes in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa.

Breast Cancer, Cervical Cancer, Leukemia, Hepatocellular Carcinoma

The three tanshinone derivatives, tanshinone I, tanshinone IIA, and cryptotanshinone, exhibited significant in vitro cytotoxicity against several human carcinoma cell lines (Wang et al., 2007).

Tanshinone I was found to inhibit the growth and invasion of breast cancer cells both in vitro and in vivo through regulation of adhesion molecules including ICAM-1 and VCAM-1 (Nizamutdinova et al., 2008), and induce apoptosis of leukemia cells by interfering with the mitochondrial transmembrane potential (ΔΨm), increasing the expression of Bax, as well as activating caspase-3 (Liu et al., 2010). Tanshinone IIA has been reported to inhibit the growth of cervical cancer cells through disrupting the assembly of microtubules, and induces G2/M phase arrest and apoptosis (Pan et al., 2010).

This compound can also inhibit invasion and metastasis of hepatocellular carcinoma (HCC) cells both in vitro and in vivo, by suppressing the expression of the metalloproteinases, MMP2 and MMP9 and interfering with the NFκB signaling pathway (Xu et al., 2009).

Breast Cancer

Cryptotanshione was reported to induce cell-cycle arrest at the G1-G0 phase, which was accompanied by the inhibition of cyclin D1 expression, retinoblastoma (Rb) protein phosphorylation, and of the rapamycin (mTOR) signaling pathway (Chen et al., 2010).

Hepato-protective Effect

Cryptotanshinone (20 or 40mg/kg) was orally administered 12 and 1h prior to GalN (700mg/kg)/LPS (10µg/kg) injection. The increased mortality and TNF- α levels by GalN/LPS were declined by cryptotanshinone pre-treatment. In addition, cryptotanshinone attenuated GalN/LPS-induced apoptosis, characterized by the blockade of caspase-3, -8, and -9 activation, as well as the release of cytochrome c from the mitochondria. Furthermore, cryptotanshinone significantly inhibited the activation of NF-κB and suppressed the production of pro-inflammatory cytokines.

These findings suggest that the hepato-protective effect of cryptotanshinone is likely to be associated with its anti-apoptotic activity and the down-regulation of MAPKs and NF-κB associated at least in part with suppressing TAK1 phosphorylation (Jin et al., 2013).

References

Chen W, Luo Y, Liu L, Zhou H, Xu B, Han X, Shen T, Liu Z, Lu Y, Huang S. (2010). Cryptotanshinone Inhibits Cancer Cell Proliferation by Suppressing Mammalian Target of Rapamycin–Mediated Cyclin D1 Expression and Rb Phosphorylation. Cancer Prev Res (Phila), 3(8):1015-25. doi: 10.1158/1940-6207.CAPR-10-0020. Epub 2010 Jul 13.

Jin DZ, Yina LL, Jia XQ, Zhu XZ. (2006). Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression. European Journal of Pharmacology, 549(1-3):166-72. doi:10.1016/j.ejphar.2006.07.055

Jin VQ, Jiang S, Wu YL, et al. (2013). Hepato-protective effect of cryptotanshinone from Salvia miltiorrhiza in d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure. Phytomedicine. doi:10.1016/j.phymed.2013.07.016

Liu JJ, Liu WD, Yang HZ, et al. (2010). Inactivation of PI3k/Akt signaling pathway and activation of caspase-3 are involved in tanshinone I-induced apoptosis in myeloid leukemia cells in vitro. Ann Hematol, 89:1089–1097. doi: 10.1007/s00277-010-0996-z.

Nizamutdinova IT, Lee GW, Lee JS, et al. (2008). Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation of adhesion molecules. Carcinogenesis, 29(10):1885-1892. doi:10.1093/carcin/bgn151

Pan TL, Hung YC, Wang PW, et al. (2010). Functional proteomic and structural insights into molecular targets related to the growth-inhibitory effect of tanshinone IIA on HeLa cells. Proteomics,10:914–929.

Park IJ, Kim MJ, Park OJ, et al. (2010). Cryptotanshinone sensitizes DU145 prostate cancer cells to Fas(APO1/CD95)-mediated apoptosis through Bcl-2 and MAPK regulation. Cancer Lett, 298:88–98. doi: 10.1016/j.canlet.2010.06.006.

Qiu F, Jiang J, Ma Ym, et al. (2013). Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers. Evidence-Based Complementary and Alternative Medicine, 2013(2013) http://dx.doi.org/10.1155/2013/730734

Shin DS, Kim HN, Shin KD, et al. (2009). Cryptotanshinone Inhibits Constitutive Signal Transducer and Activator of Transcription 3 Function through Blocking the Dimerization in DU145 Prostate Cancer Cells. Cancer Research, 69:193. doi: 10.1158/0008-5472.CAN-08-2575

Wang X, Morris-Natschke SL, Lee KH. (2007). New developments in the chemistry and biology of the bioactive constituents of Tanshen. Med Res Rev, 27:133–148. doi: 10.1002/med.20077.

Xu D, Lin TH, Li S, Da J, et al. (2012). Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells. Cancer Lett, 316(1):11-22. doi: 10.1016/j.canlet.2011.10.006.

Xu YX, Feng T, Li R, Liu ZC. (2009). Tanshinone II-A inhibits invasion and metastasis of human hepatocellular carcinoma cells in vitro and in vivo. Tumori, 95:789–795.

A2058, Akt, anti-carcinogenic, anti-inflammatory, Anti-metastatic, anti-mitogenic, anti-oxidant, anti-proliferative, apoptosis, Apoptotic, Breast cancer, Breast cancer cell lines, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemotherapy, Cytostatic, cytotoxic, EMT, ER, FAK, honeybee hives, Immune, Immunomodulatory, inflammation, inhibits NF-κB, JNK, Lung cancer, MAPK, MCF-7/Adr, MCF-7/wt, Mcl-1, Melanoma, Oral cancer, p38, p65, PANC-1, Pancreatic cancer, Prostate cancer, ROS, S, SCC-9, TIMP-2, TNF, Twist

Caffeic acid phenethyl ester (CAPE)

Cancer:
Breast, prostate, leukemia, cervical., oral., melanoma

Action: EMT, anti-mitogenic, anti-carcinogenic, anti-inflammatory, immunomodulatory

Anti-mitogenic, Anti-carcinogenic, Anti-inflammatory, Immunomodulatory Properties

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory properties. A variety of in vitro pharmacology for CAPE has been reported. A study using CAPE showed a positive effect on reducing carcinogenic incidence. It is known to have anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory properties in vitro (Orban et al., 2000) Another study also showed that CAPE suppresses acute immune and inflammatory responses and holds promise for therapeutic uses to reduce inflammation (Huang et al., 1996).

Caffeic acid phenethyl ester (CAPE) specifically inhibits NF-κB at µM concentrations and shows ability to stop 5-lipoxygenase-catalyzed oxygenation of linoleic acid and arachidonic acid. Previous studies have demonstrated that CAPE exhibits anti-oxidant, anti-inflammatory, anti-proliferative, cytostatic, anti-viral., anti-bacterial., anti-fungal., and, most importantly, anti-neoplastic properties (Akyol et al., 2013).

Multiple Immunomodulatory and Anti-inflammatory Activities

The results show that the activation of NF-kappa B by tumor necrosis factor (TNF) is completely blocked by CAPE in a dose- and time-dependent manner. Besides TNF, CAPE also inhibited NF-kappa B activation induced by other inflammatory agents including phorbol ester, ceramide, hydrogen peroxide, and okadaic acid. Since the reducing agents reversed the inhibitory effect of CAPE, it suggests the role of critical sulfhydryl groups in NF-kappa B activation. CAPE prevented the translocation of the p65 subunit of NF-kappa B to the nucleus and had no significant effect on TNF-induced I kappa B alpha degradation, but did delay I kappa B alpha resynthesis. When various synthetic structural analogues of CAPE were examined, it was found that a bicyclic, rotationally constrained, 5,6-dihydroxy form was superactive, whereas 6,7-dihydroxy variant was least active.

Thus, overall our results demonstrate that CAPE is a potent and a specific inhibitor of NF-kappa B activation and this may provide the molecular basis for its multiple immunomodulatory and anti-inflammatory activities (Natarajan et al., 1996).

Breast Cancer

Aqueous extracts from Thymus serpyllum (ExTs), Thymus vulgaris (ExTv), Majorana hortensis (ExMh), and Mentha piperita (ExMp), and the phenolic compounds caffeic acid (CA), rosmarinic acid (RA), lithospermic acid (LA), luteolin-7-O-glucuronide (Lgr), luteolin-7-O-rutinoside (Lr), eriodictiol-7-O-rutinoside (Er), and arbutin (Ab), were tested on two human breast cancer cell lines: Adriamycin-resistant MCF-7/Adr and wild-type MCF-7/wt.

ExMh showed the highest cytotoxicity, especially against MCF-7/Adr, whereas ExMp was the least toxic; particularly against MCF-7/wt cells. RA and LA exhibited the strongest cytotoxicity against both MCF-7 cell lines, over 2-fold greater than CA and Lgr, around 3-fold greater than Er, and around 4- to 7-fold in comparison with Lr and Ab. Except for Lr and Ab, all other phytochemicals were more toxic against MCF-7/wt, and all extracts exhibited higher toxicity against MCF-7/Adr. It might be concluded that the tested phenolics exhibited more beneficial properties when they were applied in the form of extracts comprising their mixtures (Berdowska et al., 2013).

Prostate Cancer

Evidence is growing for the beneficial role of selective estrogen receptor modulators (SERM) in prostate diseases. Caffeic acid phenethyl ester (CAPE) is a promising component of propolis that possesses SERM activity. CAPE-induced inhibition of AKT phosphorylation was more prominent (1.7-folds higher) in cells expressing ER-α such as PC-3 compared to LNCaP. In conclusion, CAPE enhances the anti-proliferative and cytotoxic effects of DOC and PTX in prostate cancer cells (Tolba et al., 2013).

EMT, Prostate Cancer

CAPE suppressed the expression of Twist 2 and growth of PANC-1 xenografts without significant toxicity. CAPE could inhibit the orthotopic growth and EMT of pancreatic cancer PANC-1 cells accompanied by down-regulation of vimentin and Twist 2 expression (Chen et al., 2013).

CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells (Lin et al., 2013). Combined treatments of CAPE with chemotherapeutic drugs exhibit synergistic suppression effects. Pharmacokinetic studies suggest that intraperitoneal injection of CAPE at concentration of 10mg/kg is not toxic. CAPE treatment sensitizes cancer cells to chemotherapy and radiation treatments. In addition, CAPE treatment protects therapy-associated toxicities (Liu et al., 2013).

Cervical Cancer

CAPE preferentially induced S- and G2 /M-phase cell-cycle arrests and initiated apoptosis in human cervical cancer lines. The effect was found to be associated with increased expression of E2F-1, as there is no CAPE-mediated induction of E2F-1 in the pre-cancerous cervical Z172 cells. CAPE also up-regulated the E2F-1 target genes cyclin A, cyclin E and apoptotic protease activating of factor 1 (Apaf-1) but down-regulated cyclin B and induced myeloid leukemia cell differentiation protein (Mcl-1) (Hsu et al., 2013).

Oral Cancer

CAPE attenuated SCC-9 oral cancer cells migration and invasion at noncytotoxic concentrations (0  µM to 40 µM). CAPE exerted its inhibitory effects on MMP-2 expression and activity by upregulating tissue inhibitor of metalloproteinase-2 (TIMP-2) and potently decreased migration by reducing focal adhesion kinase (FAK) phosphorylation and the activation of its downstream signaling molecules p38/MAPK and JNK (Peng et al., 2012).

Melanoma

CAPE is suggested to suppress reactive-oxygen species (ROS)-induced DNA strand breakage in human melanoma A2058 cells when compared to other potential protective agents. CAPE can be applied not only as a chemo-preventive agent but also as an anti-metastatic therapeutic agent in lung cancer and because CAPE is a nuclear factor-κB (NF-κB) inhibitor and 5α reductase inhibitor, it has potential for the treatment of prostate cancer (Ozturk et al., 2012).

References

Akyol S, Ozturk G, Ginis Z, et al. (2013). In vivo and in vitro antõneoplastic actions of caffeic acid phenethyl ester (CAPE): therapeutic perspectives. Nutr Cancer, 65(4):515-26. doi: 10.1080/01635581.2013.776693.


Berdowska I, Ziel iński B, Fecka I, et al. (2013). Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells. Food Chem, 15;141(2):1313-21. doi: 10.1016/j.foodchem.2013.03.090.


Chen MJ, Shih SC, Wang HY, et al. (2013). Caffeic Acid phenethyl ester inhibits epithelial-mesenchymal transition of human pancreatic cancer cells. Evid Based Complement Alternat Med, 2013:270906. doi: 10.1155/2013/270906.


Hsu TH, Chu CC, Hung MW, et al. (2013). Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells. FEBS J, 280(11):2581-93. doi: 10.1111/febs.12242.


Huang MT, Ma W, Yen P, et al. (1996). Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis, 17(4):761–5. doi:10.1093/carcin/17.4.761.


Lin HP, Lin CY, Liu CC, et al. (2013). Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling. Int J Mol Sci, 14(3):5264-83. doi: 10.3390/ijms14035264.


Liu CC, Hsu JM, Kuo LK, et al. (2013). Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer. Med Hypotheses, 80(5):617-9. doi: 10.1016/j.mehy.2013.02.003.


Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB. (1996). Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA, 93(17):9090-5.


Orban Z, Mitsiades N, Burke TR, Tsokos M, Chrousos GP. (2000). Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation, 7(2): 99–105. doi:10.1159/000026427.


Ozturk G, Ginis Z, Akyol S, et al. (2012). The anti-cancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers. Eur Rev Med Pharmacol Sci, 16(15):2064-8.


Peng CY, Yang HW, Chu YH, et al. (2012). Caffeic Acid phenethyl ester inhibits oral cancer cell metastasis by regulating matrix metalloproteinase-2 and the mitogen-activated protein kinase pathway. Evid Based Complement Alternat Med, 2012:732578. doi: 10.1155/2012/732578.


Tolba MF, Esmat A, Al-Abd AM, et al. (2013). Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells. IUBMB Life, 65(8):716-29. doi: 10.1002/iub.1188.

A375 and Hs294, A431, angiogenesis, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, anti-oxidant, anti-oxidative, anti-proliferative, anti-proliferative effect, apoptosis, apoptosis induction, Apoptotic, Autophagy, BAX, Bcl-2, Bcl-xL, BCRP/ABCG2, Berberis amurensis, BIU-87 and T24, Breast cancer, Breast cancer cell lines, CDK, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-enhancing, chemo-preventive, Chemo-preventive agent, Chemoprevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, cytotoxic, Diarrhea or Constipation, ER, ER-negative, ER-positive, FAK, G0/G1, G1, growth-inhibitory, hepato-protective, HIF, HL-60, inflammation, Leukemia, Liver cancer, LNCaP, DU145, PC-3, Lymphoma, MCF-7, MCF-7, MDA-MB-231, Melanoma, metastasis, Nitric Oxide, OVCAR-3, SKOV-3, PARP, PC3, PGE2, Pro-apoptotic, Prostate cancer, Radio-sensitizer, radiotherapy, ROS, SiHa and CaSki, Skin cancer, T98G, type, u-PA, VEGF, VEGF

Berberine

Cancer:
Liver,leukemia, breast, prostate, epidermoid (squamous-cell carcinoma), cervical.,testicular, melanoma, lymphoma, hepatoma

Action: Radio-sensitizer, anti-inflammatory, cell-cycle arrest, angiogenesis, chemo-enhancing, anti-metastatic, anti-oxidative

Berberine is a major phytochemical component of the roots and bark of herbal plants such as Berberis, Hydrastis canadensis and Coptis chinensis. It has been implicated in the cytotoxic effects on multiple cancer cell lines.

Anti-inflammatory

Berberine is an isoquinoline alkaloid widely distributed in natural herbs, including Rhizoma Coptidis chinensis and Epimedium sagittatum (Sieb. et Zucc.), a widely prescribed Chinese herb (Chen et al., 2008). It has a broad range of bioactivities, such as anti-inflammatory, anti-bacterial., anti-diabetes, anti-ulcer, sedation, protection of myocardial ischemia-reperfusion injury, expansion of blood vessels, inhibition of platelet aggregation, hepato-protective, and neuroprotective effects (Lau et al., 2001; Yu et al., 2005; Kulkarni & Dhir, 2010; Han et al., 2011; Ji, 2011). Berberine has been used in the treatment of diarrhea, neurasthenia, arrhythmia, diabetes, and so forth (Ji, 2011).

Angiogenesis, Chemo-enhancing

Inhibition of tumor invasion and metastasis is an important aspect of berberine's anti-cancer activities (Tang et al., 2009; Ho et al., 2009). A few studies have reported berberine's inhibition of tumor angiogenesis (Jie et al., 2011; Hamsa & Kuttan, 2012). In addition, its combination with chemotherapeutic drugs or irradiation could enhance the therapeutic effects (Youn et al., 2008; Hur et al., 2009).

Cell-cycle Arrest

The potential molecular targets and mechanisms of berberine are rather complicated. Berberine interacts with DNA or RNA to form a berberine-DNA or a berberine-RNA complex, respectively (Islam & Kumar. 2009; Li et al., 2012). Berberine is also identified as an inhibitor of several enzymes, such as N-acetyltransferase (NAT), cyclooxygenase-2 (COX-2), and telomerase (Sun et al., 2009).

Other mechanisms of berberine are mainly related to its effect on cell-cycle arrest and apoptosis, including regulation of cyclin-dependent kinase (CDK) family of proteins (Sun et al., 2009; Mantena, Sharma, & Katiyar, 2006) and expression regulation of B-cell lymphoma 2 (Bcl-2) family of proteins (such as Bax, Bcl-2, and Bcl-xL) (Sun et al., 2009), and caspases (Eom et al., 2010; Mantena, Sharma, & Katiyar, 2006). Furthermore, berberine inhibits the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and induces the formation of intracellular reactive oxygen species (ROS) in cancer cells (Sun et al., 2009; Eom et al., 2010). Interestingly, these effects might be specific for cancer cells (Sun et al., 2009).

Several studies have shown that berberine has anti-cancer potential by interfering with the multiple aspects of tumorigenesis and tumor progression in both in vitro and in vivo experiments. These observations have been well summarized in recent reports (Sun et al., 2009; Tan et al., 2011). Berberine inhibits the proliferation of multiple cancer cell lines by inducing cell-cycle arrest at the G1 or G 2 / M phases and by apoptosis (Sun et al., 2009; Eom et al., 2010; Burgeiro et al., 2011). In addition, berberine induces endoplasmic reticulum stress (Chang et al., 1990; Eom et al., 2010) and autophagy (Wang et al., 2010) in cancer cells.

However, compared with clinically prescribed anti-cancer drugs, the cytotoxic potency of berberine is much lower, with an IC50 generally at 10 µM to 100 µM depending on the cell type and treatment duration in vitro (Sun et al., 2009). Besides, berberine also induces morphologic differentiation in human teratocarcinoma (testes) cells (Chang et al., 1990).

Anti-metastatic

The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-κB, urokinase-type plasminogen-activator (u-PA), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP-9) (Ho et al., 2009; Hamsa & Kuttan. (2011); reduction of Rho kinase-mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-2, prostaglandin E, and prostaglandin E receptors (Singh et al., 2011); down-regulation of hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), pro-inflammatory mediators (Jie et al., 2011; Hamsa & Kuttan, 2012).

Hepatoma, Leukaemia

The cytotoxic effects of Coptis chinensis extracts and their major constituents on hepatoma and leukaemia cells in vitro have been investigated. Four human liver cancer cell lines, namely HepG2, Hep3B, SK-Hep1 and PLC/PRF/5, and four leukaemia cell lines, namely K562, U937, P3H1 and Raji, were investigated. C. chinensis exhibited strong activity against SK-Hep1 (IC50 = 7 microg/mL) and Raji (IC50 = 4 microg/mL) cell lines. Interestingly, the two major compounds of C. chinensis, berberine and coptisine, showed a strong inhibition on the proliferation of both hepatoma and leukaemia cell lines. These results suggest that the C. chinensis extract and its major constituents berberine and coptisine possess active anti-hepatoma and anti-leukaemia activities (Lin, 2004).

Leukemia

The steady-state level of nucleophosmin/B23 mRNA decreased during berberine-induced (25 g/ml, 24 to 96 hours) apoptosis of human leukemia HL-60 cells. A decline in telomerase activity was also observed in HL-60 cells treated with berberine. A stable clone of nucleophosmin/B23 over-expressed in HL-60 cells was selected and found to be less responsive to berberine-induced apoptosis. About 35% to 63% of control vector–transfected cells (pCR3) exhibited morphological characteristics of apoptosis, while about 8% to 45% of nucleophosmin/B23-over-expressed cells (pCR3-B23) became apoptotic after incubation with 15 g/ml berberine for 48 to 96 hours.

These results indicate that berberine-induced apoptosis is associated with the down-regulation of nucleophosmin/B23 and telomerase activity. Nucleophosmin/B23 may play an important role in the control of the cellular response to apoptosis induction (Hsing, 1999).

Prostate Cancer

In vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24–72 hours) manner. Berberine significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential., and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase.

The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy (Mantena, 2006).

In another study, the treatment of human prostate cancer cells (PC-3) with berberine-induced dose-dependent apoptosis; however, this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential., release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins.

Berberine-induced apoptosis was blocked in the presence of the anti-oxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. Taken together, these results suggest that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer (Meeran, 2008).

Breast Cancer

DNA microarray technology has been used to understand the molecular mechanism underlying the anti-cancer effect of berberine carcinogenesis in two human breast cancer cell lines, the ER-positive MCF-7 and ER-negative MDA-MB-231 cells; specifically, whether it affects the expression of cancer-related genes. Treatment of the cancer cells with berberine markedly inhibited their proliferation in a dose- and time-dependent manner. The growth-inhibitory effect was much more profound in MCF-7 cell line than that in MDA-MB-231 cells.

IFN-β is among the most important anti-cancer cytokines, and the up-regulation of this gene by berberine is, at least in part, responsible for its anti-proliferative effect. The results of this study implicate berberine as a promising extract for chemoprevention and chemotherapy of certain cancers (Kang, 2005).

Breast Cancer Metastasis

Berberine also inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Anoikis, or detachment-induced apoptosis, may prevent cancer progression and metastasis by blocking signals necessary for survival of localized cancer cells. Resistance to anoikis is regarded as a prerequisite for metastasis; however, little is known about the role of berberine in anoikis-resistance.

The anoikis-resistant cells have a reduced growth rate and are more invasive than their respective adherent cell lines. The effect of berberine on growth was compared to that of doxorubicine, which is a drug commonly used to treat breast cancer, in both the adherent and anoikis-resistant cell lines. Berberine promoted the growth inhibition of anoikis-resistant cells to a greater extent than doxorubicine treatment. Treatment with berberine-induced cell-cycle arrest at G0/G1 in the anoikis-resistant MCF-7 and MDA-MB-231 cells was compared to untreated control cells. These results reveal that berberine can efficiently inhibit growth by inducing cell-cycle arrest in anoikis-resistant MCF-7 and MDA-MB-231 cells. Further analysis of these phenotypes is essential for understanding the effect of berberine on anoikis-resistant breast cancer cells, which would be relevant for the therapeutic targeting of breast cancer metastasis (Kim, 2010).

Melanoma

Berberine inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. The effects and associated molecular mechanism of berberine on human melanoma cancer cell migration using melanoma cell lines A375 and Hs294 were probed in an in vitro cell migration assay, indicating that over- expression of cyclo-oxygenase (COX)-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells.

Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF-kB), an up- stream regulator of COX-2, in A375 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kB, inhibited cell migration. Together, these results indicate that berberine inhibits melanoma cell migration, an essential step in invasion and metastasis, by inhibition of COX-2, PGE2 and PGE2 receptors (Sing, 2011).

Cell-cycle Arrest, Squamous-cell Carcinoma

The in vitro treatment of human epidermoid carcinoma A431 cells with berberine decreases cell viability and induces cell death in a dose (5-75 microM)- and time (12–72 hours)-dependent manner, which was associated with an increase in G(1) arrest. G(0)/G(1) phase of the cell-cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin kinase inhibitors (Cdki) and cyclins.

Pre-treatment of A431 cells with the pan-caspase inhibitor (z-VAD-fmk) significantly blocked the berberine-induced apoptosis in A431 cells confirmed that berberine-induced apoptosis is mediated through activation of caspase 3-dependent pathway.

Together, these results indicate berberine as a chemotherapeutic agent against human epidermoid carcinoma A431 (squamous-cell) cells in vitro; further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of non-melanoma skin cancers (Mantena, 2006).

Cervical Cancer, Radio-sensitizer

Cervical cancer remains one of the major killers amongst women worldwide. In India, a cisplatin based chemo/radiotherapy regimen is used for the treatment of advanced cervical cancer. Evidence shows that most of the chemotherapeutic drugs used in current clinical practice are radio-sensitizers. Natural products open a new avenue for treatment of cancer, as they are generally tolerated at high doses. Animal studies have confirmed the anti-tumorigenic activity of natural products, such as curcumin and berberine.

Berberine is a natural chemo-preventive agent, extracted from Berberis aristata, which has been shown to suppress and retard carcinogenesis by inhibiting inflammation.

The combined therapy of cisplatin/berberine and radiotherapy produced up-regulation of pro-apoptotic proteins Bax and p73, while causing down regulation of the anti-apoptotic proteins Bcl-xL, COX-2, cyclin D1. This additionally was accompanied by increased activity of caspase-9 and caspase-3, and reduction in telomerase activity. Results demonstrated that the treatment combination of berberine/cisplatin had increased induction of apoptosis relative to cisplatin alone (Komal., Singh, & Deshwal., 2013).

Anti-oxidative; Breast, Liver and Colon Cancer

The effect of B. vulgaris extract and berberine chloride on cellular thiobarbituric acid reactive species (TBARS) formation (lipid peroxidation), diphenyle–alpha-picrylhydrazyl (DPPH) oxidation, cellular nitric oxide (NO) radical scavenging capability, superoxide dismutase (SOD), glutathione peroxidase (GPx), acetylcholinesterase (AChE) and alpha-gulcosidase activities were spectrophotometrically determined.

Barberry crude extract contains 0.6 mg berberine/mg crude extract. Barberry extract showed potent anti-oxidative capacity through decreasing TBARS, NO and the oxidation of DPPH that is associated with GPx and SOD hyperactivation. Both berberine chloride and barberry ethanolic extract were shown to have inhibitory effect on the growth of breast, liver and colon cancer cell lines (MCF7, HepG2 and CACO-2, respectively) at different incubation times starting from 24 hours up to 72 hours and the inhibitory effect increased with time in a dose-dependent manner.

This work demonstrates the potential of the barberry crude extract and its active alkaloid, berberine, for suppressing lipid peroxidation, suggesting a promising use in the treatment of hepatic oxidative stress, Alzheimer and idiopathic male factor infertility. As well, berberis vulgaris ethanolic extract is a safe non-toxic extract as it does not inhibit the growth of PBMC that can induce cancer cell death (Abeer et al., 2013).

Source:

Alkaloids Isolated from Natural Herbs as the Anti-cancer Agents. Evidence-Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/485042

References

Burgeiro A, Gajate C, Dakir EH, et al. (2011). Involvement of mitochondrial and B-RAF/ERK signaling pathways in berberine-induced apoptosis in human melanoma cells. Anti-Cancer Drugs, 22(6):507–518.


Chang KSS, Gao C, Wang LC. (1990). Berberine-induced morphologic differentiation and down-regulation of c-Ki-ras2 protooncogene expression in human teratocarcinoma cells. Cancer Letters, 55(2):103–108.


Chen J, ZHao H, Wang X, et al. (2008). Analysis of major alkaloids in Rhizoma coptidis by capillary electrophoresis-electrospray-time of flight mass spectrometry with different background electrolytes. Electrophoresis, 29(10):2135–2147.


Eom KS, Kim HJ, So HS, et al. (2010). Berberine-induced apoptosis in human glioblastoma T98G Cells Is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction. Biological and Pharmaceutical Bulletin, 33(10):1644–1649.


El-Wahab AEA, Ghareeb DA, et al. (2013). In vitro biological assessment of berberis vulgaris and its active constituent, berberine: anti-oxidants, anti-acetylcholinesterase, anti-diabetic and anti-cancer effects. BMC Complementary and Alternative Medicine, 13:218 doi:10.1186/1472-6882-13-218


Hamsa TP & Kuttan G. (2011). Berberine inhibits pulmonary metastasis through down-regulation of MMP in metastatic B16F-10 melanoma cells. Phytotherapy Research, 26(4):568–578.


Hamsa TP & Kuttan G. (2012). Anti-angiogenic activity of berberine is mediated through the down-regulation of hypoxia-inducible factor-1, VEGF, and pro-inflammatory mediators. Drug and Chemical Toxicology, 35(1):57–70.


Han J, Lin H, Huang W. (2011). Modulating gut microbiota as an anti-diabetic mechanism of berberine. Medical Science Monitor, 17(7):RA164–RA167.


Ho YT, Yang JS, Li TC, et al. (2009). Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-κB, u-PA and MMP-2 and -9. Cancer Letters, 279(2):155–162.


Hur JM, Hyun MS, Lim SY, Lee WY, Kim D. (2009). The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. Journal of Cellular Biochemistry, 107(5):955–964.


Islam MM & Kumar GS. (2009). RNA-binding potential of protoberberine alkaloids: spectroscopic and calorimetric studies on the binding of berberine, palmatine, and coralyne to protonated RNA structures. DNA and Cell Biology, 28(12):637–650.


Ji JB. (2011). Active Ingredients of Traditional Chinese Medicine: Pharmacology and Application, People's Medical Publishing House Cp., LTD.


Jie S, Li H, Tian Y, et al. (2011). Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down-regulation in vitro. Journal of Gastroenterology and Hepatology, 26(1):179–185.


Kang JX, Liu J, Wang J, He C, Li FP. (2005). The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by up-regulation of interferon-β and TNF-α in human breast cancer cells. Carcinogenesis, 26(11):1934-1939. doi:10.1093/carcin/bgi154


Kim JB, Yu JH, Ko E, et al. (2010). The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Phytomedicine, 17(6):436-40. doi: 10.1016/j.phymed.2009.08.012.


Komal Singh M, & Deshwal VK. (2013). Natural plant product berberine/cisplatin based radiotherapy for cervical cancer: The new and effective method to treat cervical cancer. Global Journal of Research on Medicinal Plants and Indigenous Medicine, 2(5), 278-291.


Kulkarni SK & Dhir A. (2010). Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytotherapy Research, 24(3):317–324.


Lau CW, X. Q. Yao XQ, et al. (2001). Cardiovascular actions of berberine. Cardiovascular Drug Reviews, 19(3):234–244.


Li, XL Hu XJ, Wang H, et al. (2012). Molecular spectroscopy evidence for berberine binding to DNA: comparative binding and thermodynamic profile of intercalation. Biomacromolecules, 13(3):873–880.


Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC. (2004). Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth. Clin Exp Pharmacol Physiol, 31(1-2):65-9.


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine, a natural product, induces G1-phase cell-cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther, 5(2):296-308. doi: 10.1158/1535-7163.MCT-05-0448


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki–Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Carcinogenesis, 27(10):2018-27. doi: 10.1093/carcin/bgl043


Meeran SM, Katiyar S & Katiyar SK. (2008). Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicology and Applied Pharmacology, 229(1):33-43. doi:10.1016/j.taap.2007.12.027


Singh T, Vaid M, Katiyar N, et al. (2011). Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E and prostaglandin E receptors. Carcinogenesis, 32(1):86–92.


Sun Y, Xun K, Wang Y, Chen X. (2009). A systematic review of the anti-cancer properties of berberine, a natural product from Chinese herbs. Anti-Cancer Drugs, 20(9):757–769.


Tan W, Lu J, Huang M, et al. (2011). Anti-cancer natural products isolated from chinese medicinal herbs. Chinese Medicine, 6(1):27.


Tang F, Wang D, Duan C, et al. (2009) Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting rho kinase-mediated ezrin phosphorylation at threonine 567. Journal of Biological Chemistry, 284(40):27456–27466.


Wang N, Feng Y, Zhu M et al. (2010). Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism. Journal of Cellular Biochemistry, 111(6):1426–1436.


Wu HL, Hsu CY, Liu WH, Yung BYM. (1999). Berberine‐induced apoptosis of human leukemia HL‐60 cells is associated with down‐regulation of nucleophosmin/B23 and telomerase activity. International Journal of Cancer, 81(6):923–929.


Youn MJ, So HS, Cho HJ, et al. (2008). Berberine, a natural product, combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cells. Biological and Pharmaceutical Bulletin, 31(5):789–795.


Yu HH, Kim KJ, Cha JD, et al. (2005). Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Journal of Medicinal Food, 8(4):454–461.

anti-oxidant, anti-tumor, anti-tumor activity, apoptosis, Bcl-2, Chapter 7 Isolates and Cancer Research, chemo-preventive, G2/M, hepato-protective, inflammation, Prostate cancer, S

β Solanine

Cancer: Liver, prostate

Action: Hepato-protective, apoptosis

The black nightshade (Solanum nigrum Linn.) has been widely used in Chinese traditional medicine as a remedy for the treatment of cancer. Solanum nigrum fruit extract could be used as an anti-oxidant and cancer chemo-preventive material. Solanum nigrum is an herbal plant that has been used as hepato-protective and anti-inflammation agent. The anti-tumor activity of solanine, a steroid alkaloid and active constituent isolated from the nightshade has been demonstrated in various cancer cell lines.

Observation of the cell-cycle showed that cells in the G2/M phases disappeared while the number of cells in the S phase increased significantly for treated groups. Western blot showed that solanine decreased the expression of Bcl-2 protein. Therefore, the target of solanine in inducing apoptosis in HepG2 cells seems to be mediated by the inhibition in the expression of Bcl-2 protein (Ji et al., 2008).

Apoptosis

HepG 2 cells were double stained with AO/EB, and morphological changes of the cells treated with solanine were observed using laser confocal scanning microscopy. Cells in treated groups showed typical signs of apoptosis. Staining with TMRE showed that solanine could lower membrane potential, and staining with Fluo-3/AM showed that solanine could increase the concentration of calcium in tumor cells; those double stained with TMRE and Fluo-3/AM showed that solanine could increase the concentration of calcium in the cells at the same time as it lowered the membrane potential of mitochondria.

Sola was found to open up the PT channels in the membrane by lowering the membrane potential, leading to calcium being transported down its concentration gradient, which in turn led to the rise of the concentration of calcium in the cell, turning on the mechanism for apoptosis (Gao et al., 2006).

Hepato-protective

Solanine (SNE) also has hepato-protective activity against CCl4-induced hepatic damage in rats. The results of the study suggest that Solanum nigrum protects liver against the CCl4-induced oxidative damage in rats, and this hepato-protective effect might be contributed to its modulation on detoxification enzymes and its anti-oxidant and free radical scavenger effects. Oral administration of SNE significantly reduces Thioacetamide -induced hepatic fibrosis in mice, probably through the reduction of transforming growth factor-β1 secretion. It also protects against hepatitis B virus infection B10 (Kaushik et al., 2009).

Prostate Cancer

Solanine has an anti-prostate cancer effect by inhibiting PC-3 cell proliferation, arresting the S phase, inducing cell apoptosis, up-regulating the protein expression of I(kappa)B(alpha) and down-regulating that of Bcl-2. Solanine suppressed the growth of PC-3 cells in a dose- and time-dependent manner in vitro, with significant differences among different concentration and time groups (P < 0.05).

The cycle of the PC-3 cells was arrested in the S phase (P < 0.05), with a significantly higher rate of apoptosis in the treated groups than in the controls (P < 0.05). The protein expression of I(kappa)B(alpha) was obviously up-regulated and that of Bcl-2 down-regulated in all the solanine concentration groups (Zhang & Shi, 2011).

References

Gao SY, Wang QJ, Ji YB. (2006). Effect of solanine on the membrane potential of mitochondria in HepG2 cells and [Ca2+] i in the cells. World J Gastroenterol, 12(21):3359-3367


Ji YB,Gao SY, Ji CF, Zou X. (2008). Induction of apoptosis in HepG2 cells by solanine and Bcl-2 protein. Journal of Ethnopharmacology, 115(2):194-202. doi:10.1016/j.jep.2007.09.023


Kaushik D, Jogpal V, Kaushik P, Lal S et al. (2009). Evaluation of activities of Solanum nigrum fruit extract. Archives of Applied Science Research, 1(1):43-50


Zhang J, Shi GW. (2011). Inhibitory effect of solanine on prostate cancer cell line PC-3 in vitro. Zhonghua Nan Ke Xue, 17(3):284-7.

Angelica gigas, Angelica gigas (Nakai), angiogenesis, anti-tumor, apoptosis, Apoptotic, AR, Breast cancer, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Fibrosarcoma, IL-8, inflammation, JAK2, MDR, MTOR, p53, PARP, Pro-apoptotic, Prostate cancer, Sarcoma, STAT3, TNF

Decursin

Cancer: Prostate, breast, fibrosarcoma, sarcoma

Action: MDR, inflammation, anti-cancer, angiogenesis

Decursin is isolated from Angelica gigas (Nakai).

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The physicochemical and toxicological characterization of compounds in A. gigas NAKAI, decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin, have been extensively studied (Mahat et al., 2012).

Sarcoma; Anti-cancer

The in vivo anti-tumor activities of decursinol angelate (1) and decursin (2) isolated from the roots of Angelica gigas were investigated. These two compounds, when administered consecutively for 9 days at 50 and 100 mg/kg i.p. in mice, caused a significant increase in the life span and a significant decrease in the tumor weight and volume of mice inoculated with Sarcoma-180 tumor cells. These results suggest that decursinol angelate (1) and decursin (2) from A. gigas have anti-tumor activities (Lee et al., 2003).

Fibrosarcoma

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumor necrosis factor α) in the presence or absence of CSL-32. Treatment of HT1080 cells with a derivative of decursin (CSL-32) inhibited their proliferation, without affecting cell viability, and TNF α-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8) (Lee et al., 2012).

Prostate Cancer

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to patients. As current chemotherapy is largely ineffective for PCa and has serious toxic side-effects, a collaborative effort has been initiated to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. The discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent has been highlighted and the mechanisms to account for the specific anti-AR actions have been identified: rapid block of AR nuclear translocation, inhibition of binding of 5-dihydrotestesterone to AR, and increased proteasomal degradation of AR protein. Structure-activity analyzes reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell-cycle arrest and pro-apoptotic activities.

This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/AR agents from complex herbal mixtures (Lu et al., 2007).

MDR

Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, Jang et al (2013) investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. The combined treatment reduced mitochondrial membrane potential., suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells.

Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

Breast Cancer

Decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Kim et al (2013) found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between peptidyl-prolyl cis/trans isomerase Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, the study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1.

References

Jang J, Jeong SJ, Kwon HY, Jung JH, et al. (2013). Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells. Evid Based Complement Alternat Med. 2013:506324. doi: 10.1155/2013/506324.

Kim JH, Jung JH, Kim SH, Jeong SJ. (2013). Decursin Exerts Anti-cancer Activity in MDA-MB-231 Breast Cancer Cells Via Inhibition of the Pin1 Activity and Enhancement of the Pin1/p53 Association.Phytother Res. doi: 10.1002/ptr.4986.

Lee S, Lee YS, Jung SH, et al. (2003). Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch Pharm Res, 26(9):727-30.

Lee SH, Lee JH, Kim EJ, et al. (2012). A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF- κB activities in HT1080 cells. Cell Biol Int, 36(7):683-8. doi: 10.1042/CBI20110257.

Lu JX, Kim SH, Jiang C, Lee JJ, Guo JM. (2007). Oriental herbs as a source of novel anti-androgen and prostate cancer chemo-preventive agents. Acta Pharmacologica Sinica, 28, 1365–1372. doi:10.1111/j.1745-7254.2007.00683.x

Mahat B, Chae JW, Baek IH, et al. (2012). Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas. Biol Pharm Bull, 35(7):1084-90.

Akt, Anti-cancer, anti-inflammatory, anti-proliferative, apoptosis, Apoptotic, Bcl-2, Breast cancer, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Colon Cancer or Colorectal cancer, COX-2, G1, induces apoptosis, Induces cell-cycle arrest, inflammation, Lung cancer, MCP-1, Melanoma, Nigella sativa, Osteosarcoma, p21, p53, Pro-apoptotic, Sarcoma, TNF

Thymoquinone

Cancer: Osteosarcoma, pancreatic, colorectal., lung, liver, melanoma, breast

Action: Anti-inflammatory

For centuries, the black seed (Nigella sativa (L.)) herb and oil have been used in Asia, Middle East and Africa to promote health and fight disease. Thymoquinone (TQ) is the major phytochemical constituent of Nigella sativa (L.) oil extract. Phytochemical compounds are emerging as a new generation of anti-cancer agents with limited toxicity in cancer patients.

Osteosarcoma

The anti-proliferative and pro-apoptotic effects of TQ were evaluated in two human osteosarcoma cell lines with different p53 mutation status. TQ decreased cell survival dose-dependently and, more significantly, in p53-null MG63 cells (IC(50) = 17 muM) than in p53-mutant MNNG/HOS cells (IC(50) = 38 muM). Cell viability was reduced more selectively in MG63 tumor cells than in normal human osteoblasts.

It was therefore suggested that the resistance of MNNG/HOS cells to drug-induced apoptosis is caused by the up-regulation of p21(WAF1) by the mutant p53 (transcriptional activity was shown by p53 siRNA treatment) which induces cell-cycle arrest and allows repair of DNA damage.

Collectively, these findings show that TQ induces p53-independent apoptosis in human osteosarcoma cells. As the loss of p53 function is frequently observed in osteosarcoma patients, these data suggest the potential clinical usefulness of TQ for the treatment of these malignancies (Roepke et al., 2007).

Pancreatic Ductal Adenocarcinoma

Inflammation has been identified as a significant factor in the development of solid tumor malignancies. It has recently been shown that thymoquinone (Tq) induces apoptosis and inhibited proliferation in PDA cells. The effect of Tq on the expression of different pro-inflammatory cytokines and chemokines was analyzed by real-time polymerase chain reaction (PCR). Tq dose- and time-dependently significantly reduced PDA cell synthesis of MCP-1, TNF-alpha, interleukin (IL)-1beta and Cox-2. Tq also inhibited the constitutive and TNF-alpha-mediated activation of NF-kappaB in PDA cells and reduced the transport of NF-kappaB from the cytosol to the nucleus. Our data demonstrate previously undescribed anti-inflammatory activities of Tq in PDA cells, which are paralleled by inhibition of NF-kappaB. Tq as a novel inhibitor of pro-inflammatory pathways provides a promising strategy that combines anti-inflammatory and pro-apoptotic modes of action (Chehl et al., 2009).

Lung cancer, Hepatoma, Melanoma, Colon Cancer, Breast Cancer

The potential impact of thymoquinone (TQ) was investigated on the survival., invasion of cancer cells in vitro, and tumor growth in vivo. Exposure of cells derived from lung (LNM35), liver (HepG2), colon (HT29), melanoma (MDA-MB-435), and breast (MDA-MB-231 and MCF-7) tumors to increasing TQ concentrations resulted in a significant inhibition of viability through the inhibition of Akt phosphorylation leading to DNA damage and activation of the mitochondrial-signaling pro-apoptotic pathway. Administration of TQ (10 mg/kg/i.p.) for 18 days inhibited the LNM35 tumor growth by 39% (P < 0.05). Tumor growth inhibition was associated with significant increase in the activated caspase-3. In this context, it has been demonstrated that TQ treatment resulted in a significant inhibition of HDAC2 proteins. In view of the available experimental findings, it is contended that thymoquinone and/or its analogues may have clinical potential as an anti-cancer agent alone or in combination with chemotherapeutic drugs such as cisplatin (Attoub et al., 2012).

Colon Cancer

It was reported that TQ inhibits the growth of colon cancer cells which was correlated with G1 phase arrest of the cell-cycle. Furthermore, TUNEL staining and flow cytometry analysis indicate that TQ triggers apoptosis in a dose- and time-dependent manner. These results indicate that TQ is anti-neoplastic and pro-apoptotic against colon cancer cell line HCT116. The apoptotic effects of TQ are modulated by Bcl-2 protein and are linked to and dependent on p53. Our data support the potential for using the agent TQ for the treatment of colon cancer (Gali-Muhtasib et al., 2004).

References

Attoub S, Sperandio O, Raza H, et al. (2012). Thymoquinone as an anti-cancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam Clin Pharmacol, 27(5):557-569. doi: 10.1111/j.1472-8206.2012.01056.x


Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. (2009). Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford), 11(5):373-81. doi: 10.1111/j.1477-2574.2009.00059.x.


Gali-Muhtasib H, Diab-Assaf M, Boltze C, et al. (2004). Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol, 25(4):857-66


Roepke M, Diestel A, Bajbouj K, et al. (2007). Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol Ther, 6(2):160-9.

A431, Akt, Anti-cancer, anti-inflammatory, anti-proliferative, apoptosis, Apoptotic, Bcl-2, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, COX-2, G1, HCT-116, Hep2, HepG2, HT29, induces apoptosis, Induces cell-cycle arrest, inflammation, inhibits proliferation, Liver cancer, LNM35, MCP-1, MDA-MB-231 and MCF-7, MDA-MB-435, Melanoma, Nigella sativa, Osteosarcoma, p21, p53, Pancreatic cancer, Pro-apoptotic, Saos-2, Sarcoma, TNF

Thymoquinone

Cancer: Osteosarcoma, pancreatic, colorectal., lung, liver, melanoma, breast

Action: Anti-inflammatory

For centuries, the black seed (Nigella sativa (L.)) herb and oil have been used in Asia, Middle East and Africa to promote health and fight disease. Thymoquinone (TQ) is the major phytochemical constituent of Nigella sativa (L.) oil extract. Phytochemical compounds are emerging as a new generation of anti-cancer agents with limited toxicity in cancer patients.

Osteosarcoma

The anti-proliferative and pro-apoptotic effects of TQ were evaluated in two human osteosarcoma cell lines with different p53 mutation status. TQ decreased cell survival dose-dependently and, more significantly, in p53-null MG63 cells (IC(50) = 17 muM) than in p53-mutant MNNG/HOS cells (IC(50) = 38 muM). Cell viability was reduced more selectively in MG63 tumor cells than in normal human osteoblasts.

It was therefore suggested that the resistance of MNNG/HOS cells to drug-induced apoptosis is caused by the up-regulation of p21(WAF1) by the mutant p53 (transcriptional activity was shown by p53 siRNA treatment) which induces cell-cycle arrest and allows repair of DNA damage.

Collectively, these findings show that TQ induces p53-independent apoptosis in human osteosarcoma cells. As the loss of p53 function is frequently observed in osteosarcoma patients, these data suggest the potential clinical usefulness of TQ for the treatment of these malignancies (Roepke et al., 2007).

Pancreatic Ductal Adenocarcinoma

Inflammation has been identified as a significant factor in the development of solid tumor malignancies. It has recently been shown that thymoquinone (Tq) induces apoptosis and inhibited proliferation in PDA cells. The effect of Tq on the expression of different pro-inflammatory cytokines and chemokines was analyzed by real-time polymerase chain reaction (PCR). Tq dose- and time-dependently significantly reduced PDA cell synthesis of MCP-1, TNF-alpha, interleukin (IL)-1beta and Cox-2. Tq also inhibited the constitutive and TNF-alpha-mediated activation of NF-kappaB in PDA cells and reduced the transport of NF-kappaB from the cytosol to the nucleus. Our data demonstrate previously undescribed anti-inflammatory activities of Tq in PDA cells, which are paralleled by inhibition of NF-kappaB. Tq as a novel inhibitor of pro-inflammatory pathways provides a promising strategy that combines anti-inflammatory and pro-apoptotic modes of action (Chehl et al., 2009).

Lung cancer, Hepatoma, Melanoma, Colon Cancer, Breast Cancer

The potential impact of thymoquinone (TQ) was investigated on the survival., invasion of cancer cells in vitro, and tumor growth in vivo. Exposure of cells derived from lung (LNM35), liver (HepG2), colon (HT29), melanoma (MDA-MB-435), and breast (MDA-MB-231 and MCF-7) tumors to increasing TQ concentrations resulted in a significant inhibition of viability through the inhibition of Akt phosphorylation leading to DNA damage and activation of the mitochondrial-signaling pro-apoptotic pathway. Administration of TQ (10 mg/kg/i.p.) for 18 days inhibited the LNM35 tumor growth by 39% (P < 0.05). Tumor growth inhibition was associated with significant increase in the activated caspase-3. In this context, it has been demonstrated that TQ treatment resulted in a significant inhibition of HDAC2 proteins. In view of the available experimental findings, it is contended that thymoquinone and/or its analogues may have clinical potential as an anti-cancer agent alone or in combination with chemotherapeutic drugs such as cisplatin (Attoub et al., 2012).

Colon Cancer

It was reported that TQ inhibits the growth of colon cancer cells which was correlated with G1 phase arrest of the cell-cycle. Furthermore, TUNEL staining and flow cytometry analysis indicate that TQ triggers apoptosis in a dose- and time-dependent manner. These results indicate that TQ is anti-neoplastic and pro-apoptotic against colon cancer cell line HCT116. The apoptotic effects of TQ are modulated by Bcl-2 protein and are linked to and dependent on p53. Our data support the potential for using the agent TQ for the treatment of colon cancer (Gali-Muhtasib et al., 2004).

References

Attoub S, Sperandio O, Raza H, et al. (2012). Thymoquinone as an anti-cancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam Clin Pharmacol, 27(5):557-569. doi: 10.1111/j.1472-8206.2012.01056.x


Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. (2009). Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford), 11(5):373-81. doi: 10.1111/j.1477-2574.2009.00059.x.


Gali-Muhtasib H, Diab-Assaf M, Boltze C, et al. (2004). Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol, 25(4):857-66


Roepke M, Diestel A, Bajbouj K, et al. (2007). Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol Ther, 6(2):160-9.

anti-apoptotic, anti-inflammatory, Antibiotic, apoptosis, Apoptotic, cardiovascular disease, Chapter 7 Isolates and Cancer Research, Fibrosarcoma, IL-1, IL-6, immunomodulating, inflammation, MCP-1, MMPs regulation, neuro-protective, Pro-apoptotic, Sarcoma, TNF

Qingkailing

Cancer: Leukemia, sarcoma

Action: Antibiotic, anti-apoptotic, anti-inflammatory, neuro-protective, pro-apoptotic, immunomodulating, MMPs regulation

Anti-inflammatory and Immunomodulating

Qingkailing and Shuanghuanglian (SHHL) are two commonly used Chinese herbal preparations with reported anti-inflammatory activity. The effects of these two preparations on the capacity of staphylococcal toxic shock syndrome toxin 1 (TSST-1), to stimulate the production of cytokines (IL-1β, IL-6, TNF-α, IFN-γ) and chemokines (MIP-1α, MIP-1β and MCP-1) by peripheral blood mononuclear cell (PBMC), was tested. Their effect on LPS-stimulated NF-κB transcriptional activity in a THP-1 cell line, and on human monocyte chemotactic response to chemoattractants, was also evaluated.

The results suggested that the pharmacological basis for the anti-inflammatory effects of Qingkailing and SHHL is the result of suppression of NF-κB regulated gene transcription, leading to suppressed production of pro-inflammatory cytokines and chemokines. Interference with leukocyte chemotaxis also contributes to the anti-inflammatory and immunomodulating effects of these medicinals. Identification of the responsible components in these two herbal preparations may yield compounds suitable for structural modification into potent novel drugs (Chen et al., 2002).

Leukemia

The MTT assay, cell morphology, DNA gel electrophoresis, and flow-cytometry were utilized to study the apoptotic effect of Qingkailing, and its active compounds, on the human acute promyelocytic leukemia (HL-60) cell line.

Qingkailing and its active compounds, Baicalin and hyodeoxycholic acid, exhibited strong cytotoxicity in inhibiting HL-60 cells, while Bezoar cholic acid showed a weaker effect. Apoptosis could be induced after being treated for 6 h by the former two compounds, displaying a typical apoptosis peak under flow-cytometry, but could not be induced by the latter.

Qingkailing could induce apoptosis in leukemia cells in vitro, which could serve as a mechanism of Qingkailing in the treatment of acute promyelocytic leukemia (Chen, Dong, & Zhang, 2001).

Qingkailing injection could prevent the decrease of MMP induced by injury of hypoxia-hypoglycemia-reoxygenation, stabilize MMP, inhibit cell apoptosis, and protect hippocampal neurons (Tsing, 2006).

Matrix Metalloproteinases (MMPs) Regulation

Matrix metalloproteinases (MMPs) play vital roles in many pathological conditions, including cancer, cardiovascular disease, arthritis and inflammation. Modulating MMP activity may therefore be a useful therapeutic approach in treating these diseases. Qingkailing is a popular Chinese anti-inflammatory formulation used to treat symptoms such as rheumatoid arthritis, acute hypertensive cerebral hemorrhage, hepatitis and upper respiratory tract infection.

One of the components of Qingkailing, Fructus gardeniae, strongly inhibits MMP activity. The IC50 values for the primary herbal extract and water extract against MMP-16 were 32 and 27 µg/ml, respectively. In addition, the herbal extracts influenced HT1080 human fibrosarcoma cell growth and morphology.

These data may provide molecular mechanisms for the therapeutic effects of Qingkailing and herbal medicinal Fructus gardenia (Yang et al., 2008).

Sources

Chen X, Howard OM, Yang X, Wang L, Oppenheim JJ, Krakauer T. (2002). Effects of Shuanghuanglian and Qingkailing, two multi-components of traditional Chinese medicinal preparations, on human leukocyte function. Life Sciences, 70(24), 2897-2913.


Chen ZT, Dong Q, Zhang L. (2001). Study on the effect of Qingkailing injection and its active principle in inducing cell apoptosis in human acute promyelocytic leukemia. Chinese Journal of Integrated Traditional and Western Medicine, 21(11), 840-842.


Tsing H. (2006). Influences of Qingkailing Injection on neuron apoptosis and mitochondrial membrane potential. Journal of Beijing University of Traditional Chinese Medicine, 2006(2), R285.5.


Yang JG, Shen YH, Hong Y, Jin FH, Zhao SH, Wang MC, Shi XJ,   Fang XX. (2008). Stir-baked Fructus gardeniae (L.) extracts inhibit matrix metalloproteinases and alter cell morphology. Journal of Ethnopharmacology, 117(2), 285-289.

Akt, angiogenesis, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-oxidant, anti-proliferative, AP-1, apoptosis, apoptosis-inducing, Apoptotic, Bcl-xL, Breast cancer, CCNE2, CDK2, CDK4, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, chemo-preventive, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, CSCs, EpCAM, G2/M, hepato-protective, IL-6, Immunomodulatory, including Terminalia chebula, inflammation, inhibits VEGF, iNOS, JNK, Lung cancer, Mcl-1, metastasis, Nitric Oxide, Ovarian cancer, p53, p65, Pancreatic cancer, PGE2, Pro-apoptotic, Radio-protective, TAM chemo-sensitizer, TAM resistance, TNF, TRAIL, VEGF, VEGF

Luteolin

Cancer: Colorectal., pancreatic, ovarian, breast

Action: Anti-inflammatory, radio-protective, TAM chemo-sensitizer

Luteolin is a flavonoid found in many plants and foods, including Terminalia chebula (Retz.), Prunella vulgaris (L.) and Perilla frutescens [(L.) Britton].

Luteolin is contained in Ocimum sanctum L. or Ocimum tenuiflorum L, commonly known as Holy Basil in English or Tulsi in various Indian languages; it is an important medicinal plant in the various traditional and folk systems of medicine in Southeast Asia. Scientific studies have shown it to possess anti-inflammatory, anti-analgesic, anti-pyretic, anti-diabetic, hepato-protective, hypolipidemic, anti-stress, and immunomodulatory activities. It has been found to prevent chemical-induced skin, liver, oral., and lung cancers and mediates these effects by increasing the anti-oxidant activity, altering the gene expressions, inducing apoptosis, and inhibiting angiogenesis and metastasis.

Radio-protective

The aqueous extract of Tulsi has been shown to protect mice against γ-radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. The chemo-preventive and radio-protective properties of Tulsi emphasize aspects that warrant future research to establish its activity and utility in cancer prevention and treatment (Baliga et al., 2013).

Anti-inflammatory

Pre-treatment of RAW 264.7 with luteolin, luteolin-7-glucoside, quercetin, and the isoflavonoid genistein inhibited both the LPS-stimulated TNF-αand interleukin-6 release, whereas eriodictyol and hesperetin only inhibited TNF-αrelease. From the compounds tested luteolin and quercetin were the most potent in inhibiting cytokine production with an IC50 of less than 1 and 5 µM for TNF-αrelease, respectively. Pre-treatment of the cells with luteolin attenuated LPS-induced tyrosine phosphorylation of many discrete proteins. Luteolin inhibited LPS-induced phosphorylation of Akt. Treatment of macrophages with LPS resulted in increased IκB-αphosphorylation and reduced the levels of IκB-α. It was concluded that luteolin inhibits protein tyrosine phosphorylation, nuclear factor-κB-mediated gene expression and pro-inflammatory cytokine production in murine macrophages (Xagorari et al., 2001).

Luteolin (Lut) possesses significant anti-inflammatory activity in well established models of acute and chronic inflammation, such as xylene-induced ear edema in mice (ED50= 107 mg/ kg), carrageenin-induced swellingof the ankle, acetic acid-induced pleurisy and croton oil-induced gaseous pouch granuloma in rats. Its combined immunostimulatory and anti-inflammatory activity, and inhibitory effect upon immediate hypersensitive response provide the pharmacologic bases for the beneficial effects of Lut in the treatment of chronic bronchitis (Chen et al., 1986).

Anti-inflammatory; Lung

Luteolin dose-dependently inhibited the expression and production of nitric oxide (NO) and prostaglandin E2 (PGE2), as well as the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Luteolin also reduced the DNA binding activity of nuclear factor-kappa B (NF-κB) in LPS-activated macrophages. Moreover, luteolin blocked the degradation of IκB-α and nuclear translocation of NF-κB p65 subunit.

In sum, these data suggest that, by blocking NF-κ>B and AP-1 activation, luteolin acts to suppress the LPS-elicited inflammatory events in mouse alveolar macrophages, and this effect was mediated, at least in part, by inhibiting the generation of reactive oxygen species. These observations suggest a possible therapeutic application of this agent for treating inflammatory disorders in the lung (Chen et al., 2007).

Anti-inflammatory; Neuroinflammation

Pre-treatment of primary murine microglia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. Whereas luteolin had no effect on the LPS-induced increase in NF-κB DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 hours after injection. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation (Jang et al., 2008).

Colon Cancer

Activities of CDK4 and CDK2 decreased within 2 hours after luteolin treatment, with a 38% decrease in CDK2 activity (P < 0.05) observed in cells treated with 40 µmol/l luteolin. Luteolin inhibited CDK2 activity in a cell-free system, suggesting that it directly inhibits CDK2.

tLuteolin promoted G2/M arrest at 24 hours post-treatment  by down-regulating cyclin B1 expression and inhibiting cell division cycle (CDC)2 activity. Luteolin promoted apoptosis with increased activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and decreased expression of p21CIP1/WAF1, survivin, Mcl-1, Bcl-xL, and Mdm-2. Decreased expression of these key antiapoptotic proteins could contribute to the increase in p53-independent apoptosis that was observed in HT-29 cells. Lim et al., (2007) demonstrated that luteolin promotes both cell-cycle arrest and apoptosis in the HT-29 colon cancer cell line, providing insight about the mechanisms underlying its anti-tumorigenic activities.

Pancreatic Cancer; Chemotherapy

Simultaneous treatment or pre-treatment (0, 6, 24 and 42 hours) of flavonoids and chemotherapeutic drugs and various concentrations (0-50µM) were assessed using the MTS cell proliferation assay. Simultaneous treatment with either flavonoid (0,13, 25 or 50µM) and chemotherapeutic drugs 5-fluorouracil (5-FU, 50µM) or gemcitabine (Gem, 10µM) for 60h resulted in less-than-additive effect (p<0.05). Pre-treatment for 24 hours with 13µM of either Api or Lut, followed by Gem for 36 hours was optimal to inhibit cell proliferation.

Pre-treatment of cells with 11-19µM of either flavonoid for 24 hours resulted in 59-73% growth inhibition when followed by Gem (10µM, 36h). Lut (15µM, 24h) Pre-treatment followed by Gem (10µM, 36h), significantly decreased protein expression of nuclear GSK-3βand NF-κB p65 and increased pro-apoptotic cytosolic cytochrome c. Pre-treatment of human pancreatic cancer cells BxPC-3 with low concentrations of Lut effectively aid in the anti-proliferative activity of chemotherapeutic drugs (Johnson et al., 2013).

Ovarian Cancer

Luteolin has been found to repress NF-kappaB (NF-κ>B, a pro-inflammatory transcription factor) and inhibit pro-inflammatory cytokines such as TNF-αand IL-6. Additionally, it has been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance.

Recent studies further indicate that luteolin potently inhibits VEGF production and suppresses ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Chemo-sensitizer

The sensitization effect of luteolin on cisplatin-induced apoptosis is p53 dependent, as such effect is only found in p53 wild-type cancer cells but not in p53 mutant cancer cells. Moreover, knockdown of p53 by small interfering RNA made p53 wild-type cancer cells resistant to luteolin and cisplatin. Second, Shi et al., (2007) observed a significant increase of p53 protein level in luteolin-treated cancer cells without increase of p53 mRNA level, indicating the possible effect of luteolin on p53 posttranscriptional regulation.

In summary, data from this study reveal a novel molecular mechanism involved in the anti-cancer effect of luteolin and support its potential clinical application as a chemo-sensitizer in cancer therapy.

Breast Cancer; TAM Chemo-sensitizer

This study found that the level of cyclin E2 (CCNE2) mRNA was higher in tumor cells (4.89-fold, (∗)P=0.005) than in normal paired tissue samples as assessed using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis (n=257). Further, relatively high levels of CCNE2 protein expression were detected in tamoxifen-resistant (TAM-R) MCF-7 cells.

These results showed that the level of CCNE2 protein expression was specifically inhibited in luteolin-treated (5µM) TAM-R cells, either in the presence or absence of 4-OH-TAM (100nM). Combined treatment with 4-OH-TAM and luteolin synergistically sensitized the TAM-R cells to 4-OH-TAM. The results of this study suggest that luteolin can be used as a chemo-sensitizer to target the expression level of CCNE2 and that it could be a novel strategy to overcome TAM resistance in breast cancer patients (Tu et al., 2013).

References

Baliga MS, Jimmy R, Thilakchand KR, et al. (2013). Ocimum sanctum L (Holy Basil or Tulsi) and its phytochemicals in the prevention and treatment of cancer. Nutr Cancer, 65(1):26-35. doi: 10.1080/01635581.2013.785010.


Chen CY, Peng WH, Tsai KD and Hsu SL. (2007). Luteolin suppresses inflammation-associated gene expression by blocking NF-κB and AP-1 activation pathway in mouse alveolar macrophages. Life Sciences, 81(23-24):1602-1614. doi:10.1016/j.lfs.2007.09.028


Chen MZ, Jin WZ, Dai LM, Xu SY. (1986). Effect of luteolin on inflammation and immune function. Chinese Journal of Pharmacology and Toxicology, 1986-01.


Chen SS, Michael A, Butler-Manuel SA. (2012). Advances in the treatment of ovarian cancer: a potential role of anti-inflammatory phytochemicals. Discov Med, 13(68):7-17.


Jang S, Kelley KW, Johnson RW. (2008). Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. PNAS, 105(21):7534-7539


Johnson JL, Gonzalez de Mejia E. (2013). Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem Toxicol, S0278-6915(13)00491-2. doi: 10.1016/j.fct.2013.07.036.


Lim DY, Jeong Y, Tyner Al., Park JHY. (2007). Induction of cell-cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am J Physiol Gastrointest Liver Physiol, 292: G66-G75. doi:10.1152/ajpgi.00248.2006.


Shi R, Huang Q, Zhu X, et al. (2007). Luteolin sensitizes the anti-cancer effect of cisplatin via c-Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization. Molecular Cancer Therapeutics, 6(4):1338-1347. doi: 10.1158/1535-7163.MCT-06-0638.


Tu SH, Ho CT, Liu MF, et al. (2013). Luteolin sensitizes drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression. Food Chem, 141(2):1553-61. doi: 10.1016/j.foodchem.2013.04.077.


Xagorari A, Papapetropoulos A, Mauromatis A, et al. (2001). Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and pro-inflammatory cytokine production in macrophages. JPET, 296(1):181-187.

180, Angelica gigas, Angelica gigas (Nakai), angiogenesis, Anti-cancer, anti-tumor, apoptosis, Apoptotic, AR, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, Chemotherapy, Fibrosarcoma, HT1080, IL-8, inflammation, JAK2, MDR, MTOR, p53, Pro-apoptotic, Prostate cancer, Sarcoma, STAT3, TNF

Decursin

Cancer: Prostate, breast, fibrosarcoma, sarcoma

Action: MDR, inflammation, anti-cancer, angiogenesis

Decursin is isolated from Angelica gigas (Nakai).

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The physicochemical and toxicological characterization of compounds in A. gigas NAKAI, decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin, have been extensively studied (Mahat et al., 2012).

Sarcoma; Anti-cancer

The in vivo anti-tumor activities of decursinol angelate (1) and decursin (2) isolated from the roots of Angelica gigas were investigated. These two compounds, when administered consecutively for 9 days at 50 and 100 mg/kg i.p. in mice, caused a significant increase in the life span and a significant decrease in the tumor weight and volume of mice inoculated with Sarcoma-180 tumor cells. These results suggest that decursinol angelate (1) and decursin (2) from A. gigas have anti-tumor activities (Lee et al., 2003).

Fibrosarcoma

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumor necrosis factor α) in the presence or absence of CSL-32. Treatment of HT1080 cells with a derivative of decursin (CSL-32) inhibited their proliferation, without affecting cell viability, and TNF α-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8) (Lee et al., 2012).

Prostate Cancer

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to patients. As current chemotherapy is largely ineffective for PCa and has serious toxic side-effects, a collaborative effort has been initiated to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. The discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent has been highlighted and the mechanisms to account for the specific anti-AR actions have been identified: rapid block of AR nuclear translocation, inhibition of binding of 5-dihydrotestesterone to AR, and increased proteasomal degradation of AR protein. Structure-activity analyzes reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell-cycle arrest and pro-apoptotic activities.

This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/AR agents from complex herbal mixtures (Lu et al., 2007).

MDR

Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, Jang et al (2013) investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. The combined treatment reduced mitochondrial membrane potential., suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells.

Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

Breast Cancer

Decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Kim et al (2013) found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between peptidyl-prolyl cis/trans isomerase Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, the study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1.

References

Jang J, Jeong SJ, Kwon HY, Jung JH, et al. (2013). Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells. Evid Based Complement Alternat Med. 2013:506324. doi: 10.1155/2013/506324.

Kim JH, Jung JH, Kim SH, Jeong SJ. (2013). Decursin Exerts Anti-cancer Activity in MDA-MB-231 Breast Cancer Cells Via Inhibition of the Pin1 Activity and Enhancement of the Pin1/p53 Association.Phytother Res. doi: 10.1002/ptr.4986.

Lee S, Lee YS, Jung SH, et al. (2003). Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch Pharm Res, 26(9):727-30.

Lee SH, Lee JH, Kim EJ, et al. (2012). A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF- κB activities in HT1080 cells. Cell Biol Int, 36(7):683-8. doi: 10.1042/CBI20110257.

Lu JX, Kim SH, Jiang C, Lee JJ, Guo JM. (2007). Oriental herbs as a source of novel anti-androgen and prostate cancer chemo-preventive agents. Acta Pharmacologica Sinica, 28, 1365–1372. doi:10.1111/j.1745-7254.2007.00683.x

Mahat B, Chae JW, Baek IH, et al. (2012). Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas. Biol Pharm Bull, 35(7):1084-90.

Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, Anti-tumoral, Anti-tumoral., AP-1, Apoptotic, Breast cancer, c-Jun, Chapter 8 Injectables and Cancer Research, chemo-preventive, Chemoprevention, Colon Cancer or Colorectal cancer, COX-2, ERK1, inflammation, Melanoma, p38, PKC, Prostate cancer, Skin cancer

Carnosol

Cancer: Breast, prostate, skin, colon, leukemia, stomach

Action: Anti-inflammatrory, anti-angiogenic

Carnosol is found in certain Mediterranean meats, fruits, vegetables, and olive oil. In particular, it is sourced from rosemary (Rosmarinus officinalis (L.)) and desert sage (Salvia pachyphylla (Epling ex Munz)).

Prostate Cancer, Breast Cancer, Skin Cancer, Colon Cancer, Leukemia

One agent, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals.

This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent (Johnson, 2011).

Literature evidence from animal and cell culture studies demonstrates the anti-cancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells (Ngo et al., 2011).

Anti-inflammatory

Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anti-cancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity.

Carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms (Subbaramaiah, 2002).

Breast Cancer

Two rosemary components, carnosol and ursolic acid, appear to be partly responsible for the anti-tumorigenic activity of rosemary. Supplementation of diets for 2 weeks with rosemary extract (0.5% by wt) but not carnosol (1.0%) or ursolic acid (0.5%) resulted in a significant decrease in the in vivo formation of rat mammary DMBA-DNA adducts, compared to controls. When injected intraperitoneally (i.p.) for 5 days at 200 mg/kg body wt, rosemary and carnosol, but not ursolic acid, significantly inhibited mammary adduct formation by 44% and 40%, respectively, compared to controls. Injection of this dose of rosemary and carnosol was associated with a significant 74% and 65% decrease, respectively, in the number of DMBA-induced mammary adenocarcinomas per rat, compared to controls. Ursolic acid injection had no effect on mammary tumorigenesis.

Therefore, carnosol is one rosemary constituent that can prevent DMBA-induced DNA damage and tumor formation in the rat mammary gland, and, thus, has potential for use as a breast cancer chemopreventative agent (Singletary et al., 1996).

Anti-angiogenic

The anti-angiogenic activity of carnosol and carnosic acid could contribute to the chemo-preventive, anti-tumoral and anti-metastatic activities of rosemary extracts and suggests that there is potential in the treatment of other angiogenesis-related malignancies (L-pez-JimŽnez et al., 2013).

References:

Johnson JJ. (2011). Carnosol: A promising anti-cancer and anti-inflammatory agent. Cancer Letters, 305(1):1-7. doi:10.1016/j.canlet.2011.02.005.


L-pez-JimŽnez A, Garc'a-Caballero M, Medina Mç, Quesada AR. (2013). Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary. Eur J Nutr, 52(1):85-95. doi: 10.1007/s00394-011-0289-x.


Ngo SN, Williams DB, Head RJ. (2011). Rosemary and cancer prevention: preclinical perspectives. Crit Rev Food Sci Nutr, 51(10):946-54. doi: 10.1080/10408398.2010.490883.


Singletary K, MacDonald C & Wallig M. (1996). Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation. Cancer Letters, 104(1):43-8. doi: 10.1016/0304-3835(96)04227-9


Subbaramaiah K, Cole PA, Dannenberg AJ. (2002). Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription by CREB-binding Protein/p300-dependent and -independent Mechanisms. Cancer Res, 62:2522