Category Archives: Chapter 7 Isolates and Cancer Research

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.

Akt, Anti-cancer, Anti-metastatic, anti-tumor, anti-tumor activity, apoptosis, BAX, Bcl-2, BCR, Breast cancer, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, Chemotherapy, G0/G1, G1, HL-60 and K562, induces apoptosis, inhibits proliferation, Leukemia, Liver cancer, MDR, NB4, p65, SMAD3, VEGF, VEGF

Berbamine

Cancer: Breast, leukemia, liver, neutropenia

Action: Anti-metastatic, chemo-sensitizer

Breast Cancer, Leukemia

Berbamine (BER), isolated from the Chinese herb Berberis amurensis and Berberis vulgaris (L.), selectively induces apoptosis in certain breast cancer and leukemia cell lines.

Studies have shown that berbamine suppresses the growth, migration and invasion in highly-metastatic human breast cancer cells by possibly inhibiting Akt and NF-kappaB signaling with their upstream target c-Met and downstream targets Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2.

BER has synergistic effects with anti-cancer agents trichostatin A, celecoxib and carmofur on inhibiting the growth of MDA-MB-231 cells and reducing the ratio of Bcl-2/Bax and/or VEGF expressions in the cancer cells. These findings suggest that berbamine may have wide therapeutic and/or adjuvant therapeutic application in the treatment of human breast cancer and other cancers (Wang, 2009).

MDR, Leukemia stem cells

Previous studies have shown that berbamine selectively induces apoptosis of imatinib (IM)-resistant-Bcr/Abl-expressing leukemia cells from the K562 cell line and CML patients. Berbamine derivatives obtained by synthesis were found to have very high activity in vitro. Six of these exhibited consistent high anti-tumor activity for imatinib-resistant K562 leukemia cells. Their IC(50) values at 48h were 0.36-0.55 microM, whereas berbamine IC(50) value was 8.9 microM. Cell cycle analysis results showed that compound 3h could reduce G0/G1 cells. In particular, these compounds displayed potent inhibition of the cytoplasm-to-nucleus translocation of NF-kappaB p65 which plays a critical role in the survival of leukemia stem cells (Xie, 2009).

Liver Cancer, Leukemia

Meng et al. (2013) reported that berbamine and one of its derivatives, bbd24, potently suppressed liver cancer cell proliferation and induced cancer cell death by targeting Ca2+/calmodulin-dependent protein kinase II (CAMKII). Furthermore, berbamine inhibited the in vivo tumorigenicity of liver cancer cells in NOD/SCID mice and downregulated the self-renewal abilities of liver cancer-initiating cells. Berbamine inhibits proliferation and induces apoptosis of KU812 leukaemia cells by increasing Smad3 activity (Kapoor, 2012).

Chronic Myeloid Leukemia, Leukopenia

During imatinib therapy, many patients with chronic myeloid leukemia (CML) develop severe neutropenia, leading to treatment interruptions, and potentially compromising response to imatinib. Berbamine (a bisbenzylisoquinoline alkaloid) has been widely used in Asian countries for managing leukopenia associated with chemotherapy. With berbamine support, the time to achieve complete cytogenetic response was significantly shorter (median, 6.5 vs. 10 months, p = 0.007). There were no severe adverse events associated with berbamine treatment. In conclusion, the present study reveals the potential clinical value of berbamine in the treatment of CML with imatinib-induced neutropenia (Zhao et al., 2011).

References

Kapoor S. (2012). Emerging role of berbamine as an anti-cancer agent in systemic malignancies besides chronic myeloid leukemia. Zhejiang Univ Sci B, 13(9):761-2.


Meng Z, Li T, Ma X, et al. (2013). Berbamine Inhibits the Growth of Liver Cancer Cells and Cancer-Initiating Cells by Targeting Ca2+/Calmodulin-Dependent Protein Kinase II. Mol Cancer Ther.


Wang S, Liu Q, Zhang Y, et al. (2009). Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action. Mol Cancer, 8:81.


Xie J, Ma T, Gu Y, et al. (2009). Berbamine derivatives: A novel class of compounds for anti-leukemia activity. Eur J Med Chem, 44(8):3293-8. doi: 10.1016/j.ejmech.2009.02.018


Zhao Y, Tan Y, Wu G, et al. (2011). Berbamine overcomes imatinib-induced neutropenia and permits cytogenetic responses in Chinese patients with chronic-phase chronic myeloid leukemia. Int J Hematol, 94(2):156-62. doi: 10.1007/s12185-011-0887-7.

AGS, MKN74, Akt, Anti-cancer, Artemisia annua, Breast cancer, Chapter 7 Isolates and Cancer Research, Chemoprevention, ERK, Gastric cancer or Stomach cancer, HL-60, Nausea and Vomiting, p53, PI3K, PKC, SGC7901

Artemisinin

Cancer: Breast, leukemia, gastric

Action: Anti-cancer

Artemisinin is isolated from Artemisia annua (L.).

Anti-cancer

Artemisinin and related compounds (artemisinins) is a frontline treatment for malaria. According to experimental evidence from more than 400 literature studies, 558 key proteins were derived and the artemisinins-rewired protein interaction network was constructed. Topological properties were analyzed to show that the protein network was a scale-free biological system. Five key pathways including PI3K-Akt, T cell receptor, Toll-like receptor, TGF-beta and insulin signaling pathways were involved in artemisinins-mediated anti-cancer effects (Huang et al., 2013).

Breast Cancer

Artemisinin has previously been shown to have selective toxicity towards cancer cells in vitro. The potential of artemisinin to prevent breast cancer development has been investigated in rats treated with a single oral dose (50 mg/kg) of 7,12-dimethylbenz[a]anthracene (DMBA), known to induce multiple breast tumors. Starting from the day immediately after DMBA treatment, one group of rats was provided with a powdered rat-chow containing 0.02% artemisinin, whereas a control group was provided with plain powdered food. For 40 weeks, both groups of rats were monitored for breast tumors.

Oral artemisinin significantly delayed (P<.002) and in some animals prevented (57% of artemisinin-fed versus 96% of the controls developed tumors, P<.01) breast cancer development in the monitoring period. In addition, breast tumors in artemisinin-fed rats were significantly fewer (P<.002) and smaller in size (P<.05) when compared with controls. Since artemisinin is a relatively safe compound that causes no known side-effects even at high oral doses, the present data indicate that artemisinin may be a potent chemoprevention agent (Lai, 2006).

Leukemia

Artemisinin is also a well-known anti-leukemic agent. The effect of artemisinin on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system has been investigated. Artemisinin markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with low doses of 1α,25-dihydoxyvitamin D3 [1,25-(OH)2D3] or all-trans retinoic acid (all-trans RA).

Extracellular-regulated kinase (ERK) inhibitors markedly inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)2D3 or all-trans RA, whereas phosphatidylinositol 3-kinase (PI3-K) inhibitors did not. Particularly, protein kinase C (PKC) inhibitors inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)2D3 but not with all-trans RA. Artemisinin enhanced PKC activity and protein level of PKCβI isoform in only 1,25-(OH)2D3-treated HL-60 cells.

Taken together, these results indicate that artemisinin strongly enhances the action of low doses of 1α,25-dihydoxyvitamin D3 [1,25-(OH)2D3] and all-trans retinoic acid in leukemia cell differentiation (Kim, 2003).

Gastric Cancer

Zhang et al. (2013) found that artemisinin inhibited growth and modulated expression of cell-cycle regulators in gastric cancer cells (AGS and MKN74 cells). Treatment with artemisinin was also associated with induction of p27kip1 and p21kip1, two negative cell-cycle regulators. Furthermore, we revealed that artemisinin treatment led to an increased expression of p53.

The side-effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, anorexia, and dizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect is allergic reaction (Leonardi et al., 2001).

References

Huang C, Ba Q, Yue Q, et al. (2013). Artemisinin rewires the protein interaction network in cancer cells: network analysis, pathway identification, and target prediction. Mol Biosyst. Kim SH, Kim HJ, Kim TS. (2003). Differential involvement of protein kinase C in human promyelocytic leukemia cell differentiation enhanced by artemisinin. European Journal of Pharmacology, 482(1–3):67–76. doi:10.1016/j.ejphar.2003.09.057.


Lai H, Singh NP. (2006). Oral artemisinin prevents and delays the development of 7, 12-dimethylbenz [a] anthracene (DMBA)-induced breast cancer in the rat. Cancer Letters, 231(1):43–48. doi: 10.1016/j.canlet.2005.01.019.


Leonardi E, Gilvary G, White NJ, Nosten F. (2001). Severe allergic reactions to oral artesunate: a report of two cases'. Trans. R. Soc. Trop. Med. Hyg, 95(2):182–3. doi:10.1016/S0035-9203(01)90157-9.


Sun H, Meng X, Han J, et al. (2013) Anti-cancer activity of DHA on gastric cancer-an in vitro and in vivo study. Tumor Biol.


Zhang HT, Wang YL, Zhang J, Zhang QX. (2013). Artemisinin inhibits gastric cancer cell proliferation through up-regulation of p53. Tumor Biol.

Akt, Anti-cancer, anti-tumor, apoptosis, Apoptotic, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, CHK2, Colon Cancer or Colorectal cancer, ER, ER-positive, G0/G1, G1, HER-2, HER-2/neu, Ovarian cancer, PARP, PI3K, PI3K/Akt

Antrodia camphorata

 

Cancer: Leukemia, colorectal., ER+ ovarian cancer

Action: Anti-cancer

Antrodia Camphorata [(M. Zang & C.H. Su) Sheng H. Wu, Ryvarden & T.T.] is a native Taiwanese mushroom which is used in Asian folk medicine. It is also known as Ganoderma camphoratum (M. Zang & C.H. Su) and Taiwanofungus camphoratus [(M. Zang & C.H. Su) Sheng H. Wu, Z.H. Yu, Y.C. Dai & C.H. Su].

Anti-tumor

Mycotherapy is defined as the study of the use of extracts and compounds obtained from mushrooms as medicines or health-promoting agents. An increasing number of studies in the past few years have revealed mushroom extracts as potent anti-tumor agents. Also, numerous studies have been conducted on bioactive compounds isolated from mushrooms reporting the heteropolysaccharides, β-glucans, α-glucans, proteins, complexes of polysaccharides with proteins, fatty acids, nucleoside antagonists, terpenoids, sesquiterpenes, lanostanoids, sterols and phenolic acids, as promising anti-tumor agents (Popović et al., 2013).

Leukemia

Antrodia camphorata (AC) is a native Taiwanese mushroom, which is used in Asian folk medicine as a chemo-preventive agent. The triterpenoid-rich fraction (FEA) was obtained from the ethanolic extract of AC and characterized by high performance liquid chromatography (HPLC). FEA caused DNA damage in leukemia HL60 cells which was characterized by phosphorylation of H2A.X and Chk2. It also exhibited apoptotic effect which was correlated to the enhancement of PARP cleavage and to the activation of caspase 3.

Taken together, these results provide the first evidence that pure AC component inhibits tumor growth in an in vivo model, thereby backing the traditional anti-cancer use of AC in Asian countries (Du et al., 2012).

Colon Cancer

Antrodia camphorata (AC) grown on germinated brown rice (CBR) was studied in HT-29 human colon cancer cells. CBR 80% ethanol EtOAc fraction showed the strongest inhibitory activity against HT-29 cell proliferation. Induction of G0/G1 cell-cycle arrest on human colon carcinoma cell was observed in CBR EtOAc fraction-treated cells. We found that CBR decreased the level of proteins involved in G0/G1 cell-cycle arrest and apoptosis. CBR EtOAc fraction inhibited the β-catenin signaling pathway, supporting its suppressive activity on the level of cyclin D1 (Park, Lim, & Park, 2013).

A new enynyl-benzenoid, antrocamphin O (1,4,7-dimethoxy-5-methyl-6-(3'-methylbut-3-en-1-ynyl)benzo[d][1,3]dioxide), and the known benzenoids antrocamphin A and 7-dimethoxy-5-methyl-1,3-benzodioxole, were isolated from the fruiting bodies of Antrodia camphorata (Taiwanofungus camphoratus). The benzenoids were tested successfully for cytotoxicity against the HT29, HTC15, DLD-1, and COLO 205 colon cancer cell lines (Chen et al., 2013).

ER+ Ovarian Cancer

MTT and colony formation assays showed that Antrodia camphorata (AC) induced a dose-dependent reduction in SKOV-3 cell growth. Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC. Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector β-catenin (Yang et al., 2013).

References

Chen PY, Wu JD, Tang KY, et al. (2013). Isolation and synthesis of a bioactive benzenoid derivative from the fruiting bodies of Antrodia camphorata. Molecules, 18(7):7600-8. doi: 10.3390/molecules18077600.


Du YC, Chang FR, Wu TY, et al. (2012). Anti-leukemia component, dehydroeburicoic acid from Antrodia camphorata induces DNA damage and apoptosis in vitro and in vivo models. Phytomedicine. doi:10.1016/j.phymed.2012.03.014


Park DK, Lim YH, Park HJ. (2013). Antrodia camphorata Grown on Germinated Brown Rice Inhibits HT-29 Human Colon Carcinoma Proliferation Through Inducing G0/G1 Phase Arrest and Apoptosis by Targeting the β -Catenin Signaling. J Med Food, 16(8):681-91. doi: 10.1089/jmf.2012.2605.


Popovi ć V, Zivkovi ć J, Davidovi ć S, et al. (2013). Mycotherapy Of Cancer: An Update On Cytotoxic And Anti-tumor Activities Of Mushrooms, Bioactive Principles And Molecular Mechanisms Of Their Action. Curr Top Med Chem.


Yang HL, Lin KY, Juan YC, et al. (2013). The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway. J Ethnopharmacol, 148(1):254-65. doi: 10.1016/j.jep.2013.04.023.

Akt, anti-apoptotic, Anti-cancer, anti-proliferative, apoptosis, apoptosis-inducing, Apoptotic, Aurantti Fructus Immaturus, Bcl-2, Bcl-xL, Chapter 7 Isolates and Cancer Research, ER, ER-positive, FasL, induces apoptosis, Mcl-1, Neuroblastoma, PI3K, PI3K/Akt, SH-SY5Y

Angelicin

Cancer: Leukemia, colon, ER+ Ovarian

Action: Apoptotic, anti-cancer

Angelicin is a furanocoumarin. It can be found in Bituminaria bituminosa and is structurally related to psoralens, a well-known chemical class of photosensitizers used for its anti-proliferative activity in treatment of different skin diseases.

Induces Apoptosis

The cellular cytotoxicity of angelicin was examined by cell viability assay, DNA fragmentation by DNA ladder assay, and activation of caspases and Bcl-2 family proteins by Western blot analyzes. The results suggest that angelicin increased cellular cytotoxicity in a dose- and time-dependent manner with IC(50) of 49.56 µM at 48 hours of incubation.

In addition, angelicin dose-dependently downregulated the expression of anti-apoptotic proteins including Bcl-2, Bcl-xL, and Mcl-1 suggesting the involvement of the intrinsic mitochondria-mediated apoptotic pathway which did not participate in Fas/FasL-induced caspase-8-mediated extrinsic, MAP kinases, and PI3K/AKT/GSK-3β pathway.

Taken together, these data indicate that angelicin is an effective apoptosis-inducing natural compound of human SH-SY5Y neuroblastoma cells which suggests that this compound may have a role in future therapies for human neuroblastoma cancer (Rahman et al., 2012).

Anti-cancer

Three crude drugs Saussureae Radix, Psoraleae Semen and Aurantti Fructus Immaturus significantly inhibited the proliferation of temperature-sensitive rat lymphatic endothelial (TR-LE) cells in vitro. Angelicin isolated from Aurantti Fructus Immaturus showed selective inhibition of the proliferation of TR-LE cells (Jeong et al., 2013). Angelicin, isolated from Bituminaria morisiana was subjected to cytotoxicity screening against a panel of human cancer cells (Leonti et al., 2010).

References

Jeong D, Watari K, Shirouzu T, et al. (2013). Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs. Biol Pharm Bull, 36(1):152-7.


Leonti M, Casu L, Gertsch J, et al. (2010). A pterocarpan from the seeds of Bituminaria morisiana. J Nat Med. 64(3):354-7. doi: 10.1007/s11418-010-0408-7.


Rahman MA, Kim NH, Yang H, Huh SO. (2012). Angelicin induces apoptosis through intrinsic caspase-dependent pathway in human SH-SY5Y neuroblastoma cells. Mol Cell Biochem, 369(1-2):95-104. doi: 10.1007/s11010-012-1372-1.

Anti-cancer, Anti-cancer effect, apoptosis, Apoptotic, BAX, Breast cancer, CDC2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, chemo-preventive, chemo-sensitizing, Chemotherapy, Cytostatic, ER, G1, G2/M, Glioblastoma, H460, Liver cancer, Lung cancer, Oral cancer, p21, p53, PARP, PKC, radio-sensitizing, S, U87

Aloe-emodin (See also Emodin)

Cancer:
Nasopharyngeal., ER α degradation, Lung, breast, oral., glioblastoma, liver cancer prevention

Action: Cytostatic, radio-sensitizing, chemo-sensitizing

Nasopharyngeal Carcinoma

Aloe-emodin (AE), a natural., biologically active compound from Aloe vera leaves has been shown to induce apoptosis in several cancer cell lines in vitro. Investigation showed that AE induced G2/M phase arrest by increasing levels of cyclin B1 bound to Cdc2, and also caused an increase in apoptosis of nasopharyngeal carcinoma (NPC) cells, which was characterized by morphological changes, nuclear condensation, DNA fragmentation, caspase-3 activation, cleavage of poly (ADP-ribose) polymerase (PARP) and increased sub-G(1) population. Treatment of NPC cells with AE also resulted in a decrease in Bcl-X(L) and an increase in Bax expression.

Collectively, results indicate that the caspase-8-mediated activation of the mitochondrial death pathway plays a critical role in AE-induced apoptosis of NPC cells (Lin et al., 2010).

Glioblastoma

Aloe emodin arrested the cell-cycle in the S phase and promoted the loss of mitochondrial membrane potential in glioblastoma U87 cells that indicated the early event of the mitochondria-induced apoptotic pathway. It plays an important role in the regulation of cell growth and death (Ismail et al., 2013).

Breast Cancer

The anthraquinones emodin and aloe-emodin are also abundant in the rhizome Rheum palmatum and can induce cytosolic estrogen receptor α (ER α) degradation; it primarily affected nuclear ER α distribution similar to the action of estrogen when protein degradation was blocked. In conclusion, our data demonstrate that emodin and aloe-emodin specifically suppress breast cancer cell proliferation by targeting ER α protein stability through distinct mechanisms (Huang et al., 2013).

Lung Cancer

Photoactivated aloe-emodin induced anoikis and changes in cell morphology, which were in part mediated through its effect on cytoskeleton in lung carcinoma H460 cells. The expression of protein kinase Cδ (PKCδ) was triggered by aloe-emodin and irradiation in H460 cells. Furthermore, the photoactivated aloe-emodin-induced cell death and translocation of PKCδ from the cytosol to the nucleus was found to be significantly inhibited by rottlerin, a PKCδ-selective inhibitor (Chang et al., 2012).

Oral Cancer; Radio-sensitizing, Chemo-sensitizing

The treatment of cancer with chemotherapeutic agents and radiation has two major problems: time-dependent development of tumor resistance to therapy (chemoresistance and radioresistance) and nonspecific toxicity toward normal cells. Many plant-derived polyphenols have been studied intensively for their potential chemo-preventive properties and are pharmacologically safe.

These compounds include genistein, curcumin, resveratrol, silymarin, caffeic acid phenethyl ester, flavopiridol, emodin, green tea polyphenols, piperine, oleandrin, ursolic acid, and betulinic acid. Recent research has suggested that these plant polyphenols might be used to sensitize tumor cells to chemotherapeutic agents and radiation therapy by inhibiting pathways that lead to treatment resistance. These agents have also been found to be protective from therapy-associated toxicities.

Treatment with aloe-emodin at 10 to 40 microM resulted in cell-cycle arrest at G2/M phase. The alkaline phosphatase (ALP) activity in KB cells increased upon treatment with aloe-emodin when compared to controls. This is one of the first studies to focus on the expression of ALP in human oral carcinomas cells treated with aloe-emodin. These results indicate that aloe-emodin has anti-cancer effect on oral cancer, which may lead to its use in chemotherapy and chemo-prevention of oral cancer (Xiao et al., 2007).

Liver Cancer Prevention

In Hep G2 cells, aloe-emodin-induced p53 expression and was accompanied by induction of p21 expression that was associated with a cell-cycle arrest in G1 phase. In addition, aloe-emodin had a marked increase in Fas/APO1 receptor and Bax expression. In contrast, with p53-deficient Hep 3B cells, the inhibition of cell proliferation of aloe-emodin was mediated through a p21-dependent manner that did not cause cell-cycle arrest or increase the level of Fas/APO1 receptor, but rather promoted aloe-emodin-induced apoptosis by enhancing expression of Bax.

These findings suggest that aloe-emodin may be useful in liver cancer prevention (Lian et al., 2005).

References

Chang WT, You BJ, Yang WH, et al. (2012). Protein kinase C delta-mediated cytoskeleton remodeling is involved in aloe-emodin-induced photokilling of human lung cancer cells. Anti-cancer Res, 32(9):3707-13.

Huang PH, Huang CY, Chen MC, et al. (2013). Emodin and Aloe-Emodin Suppress Breast Cancer Cell Proliferation through ER α Inhibition. Evid Based Complement Alternat Med, 2013:376123. doi: 10.1155/2013/376123.

Ismail S, Haris K, Abdul Ghani AR, et al. (2013). Enhanced induction of cell-cycle arrest and apoptosis via the mitochondrial membrane potential disruption in human U87 malignant glioma cells by aloe emodin. J Asian Nat Prod Res.

Lian LH, Park EJ, Piao HS, Zhao YZ, Sohn DH. (2005). Aloe Emodin‐Induced Apoptosis in Cells Involves a Mitochondria‐Mediated Pathway. Basic & Clinical Pharmacology & Toxicology, 96(6):495–502.

Lin, ML, Lu, YC, Chung, JG, et al. (2010). Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway. Cancer Letters, 291(1), 46-58. doi: 10.1016/j.canlet.2009.09.016.

Xiao B, Guo J, Liu D, Zhang S. (2007). Aloe-emodin induces in vitro G2/M arrest and alkaline phosphatase activation in human oral cancer KB cells. Oral Oncol, 43(9):905-10.

Anti-cancer, Anti-cancer effect, anti-proliferative, apoptosis, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, G1, Rectal cancer

Alkanna

Cancer: Colorectal

Action: Anti-cancer effect, apoptosis

In a continuing program to discover new anti-cancer agents from plants, especially naphthoquinones from the Alkanna genus, Alkanna cappadocica was investigated. Bioassay-guided fractionation of a dichloromethane/methanol (1:1) extract of the roots led to the isolation of four new and four known naphthoquinones. The known compounds are 11-deoxyalkannin (1), beta,beta-dimethylacrylalkannin (2), 11-O-acetylalkannin (3), and alkannin (4). The new compounds 5-O-methyl-11-deoxyalkannin (5), 8-O-methyl-11-deoxyalkannin (6), 5-O-methyl-11-O-acetylalkannin (7), and 5-O-methyl-beta,beta-dimethylacrylalkannin (8) were characterized by spectroscopic analyzes (LC-ESIMS, 1D and 2D NMR).

Cytotoxicity of the isolated compounds was evaluated versus 12 human cancer cell lines, HT-29, MDA-MB-231, PC-3, AU565, Hep G2, LNCaP, MCF7, HeLa, SK-BR-3, DU 145, Saos-2, and Hep 3B together with two normal cell lines, VERO and 3T3, by using the MTT assay. Compound 7 showed remarkable cytotoxicity with IC(50) values between 0.09 and 14.07 muM. It was more potent than the other compounds in six out of 12 cancer cell lines and the positive controls doxorubicin and etoposide (Sevimli-Gur et al., 2010).

Colorectal Cancer

The isolation of active compounds against human colorectal cancer from the root of Alkanna tinctoria (L.) Tausch led to the isolation of two naphthoquinones, alkannin (1) and angelylalkannin (2). Both of the two compounds showed significant inhibitory effects on the cancer cells. For alkannin (1) and angelylalkannin (2), the median inhibitory concentration (IC₅₀) values were 2.38 and 4.76  µM for HCT-116 cells, while for SW-480 cells they were 4.53 and 7.03  µM, respectively. The potential anti-proliferative mechanisms were also explored. At concentrations between 1-10  µM, both compounds arrested the cell-cycle at the G1 phase and induced cell apoptosis (Tung et al., 2013a).

To explore active anti-colorectal cancer compounds, we carried out phytochemical studies on Alkanna tinctoria and isolated eight quinone compounds. Using different spectral methods, compounds were identified as alkannin (1), acetylalkannin (2), angelylalkannin (3), 5-methoxyangenylalkannin (4), dimethylacryl alkannin (5), arnebifuranone (6), alkanfuranol (7), and alkandiol (8).

Among the eight compounds, alkannin (1), angelylalkannin (3), and 5-methoxyangenylalkannin (4) showed strong anti-proliferative effects, whereas compound 4 showed the most potent effects.   The structural-functional relationship assay suggested that to increase anti-cancer potential., future modifications on alkannin (1) should focus on the hydroxyl groups at C-5 and C-8 (Tung et al., 2013b).

References

Sevimli-Gur, C, Akgun, IH, Deliloglu-Gurhan, I, Korkmaz, KS, Bedir, E. (2010). Cytotoxic naphthoquinones from Alkanna cappadocica (perpendicular). J Nat Prod, 73(5):860-4. doi: 10.1021/np900778j.


Tung, NH, Du, GJ, Wang, CZ, Yuan, CS, Shoyama, Y. (2013a). Naphthoquinone components from Alkanna tinctoria (L.) Tausch show significant anti-proliferative effects on human colorectal cancer cells. Phytother Res, 27(1):66-70. doi: 10.1002/ptr.4680.


Tung, NH, Du, GJ, Yuan, CS, Shoyama, Y, Wang, CZ. (2013b). Isolation and chemo-preventive evaluation of novel naphthoquinone compounds from Alkanna tinctoria. Anti-cancer Drugs, 24(10):1058-68. doi: 10.1097/CAD.0000000000000017.

Anti-cancer, Chapter 7 Isolates and Cancer Research

Alkaloids

Plants have provided medicines since prehistoric times. We know that some animals dose themselves with biologically active plants when ill and, of course, most native populations of humans use plants indigenous to their area for medicines (Alkaloids in medicine, n.d.).

Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen, sulfur, and more rarely, other elements such as chlorine, bromine, and phosphorus (Alkaloids, n.d.). Numerous alkaloids can be purified from crude extracts by acid-base extraction. They often have pharmacological effects and are used as medications, recreational drugs, or in entheogenic rituals. Examples are the local anesthetic and stimulant cocaine; the psychedelic psilocin; the stimulant caffeine; and nicotine (Alkaloid, n.d.); the analgesic morphine; the anti-bacterial berberine; the anti-cancer compound vincristine; the anti-hypertension agent reserpine; the cholinomimeric galantamine; the spasmolysis agent atropine; the vasodilator vincamine; the anti-arrhythmia compound quinidine; the anti-asthma therapeutic ephedrine; and the anti-malarial drug quinine. Although alkaloids act on a diversity of metabolic systems in humans and other animals, they almost uniformly invoke a bitter taste (Rhoades, 1979).

Because of the structural diversity of alkaloids, there is no single method of their extraction from natural raw materials (Hesse, 2002). Most methods exploit the property of most alkaloids to be soluble in organic solvents but not in water, and the opposite tendency of their salts. In the acidic extraction, the raw plant material is processed by a weak acidic solution (e.g. acetic acid in water, ethanol, or methanol). A base is then added to convert alkaloids to basic forms that are extracted with organic solvent (if the extraction was performed with alcohol, it is removed first, and the remainder is dissolved in water). Alkaloids are separated from their mixture using their different solubility in certain solvents and different reactivity with certain reagents or by distillation (Grinkevich & Safronich, 1983).

References

Alkaloid. (n.d.). In How stuff works. Retrieved from http://science.howstuffworks.com/alkaloid-info.htm.


Alkaloids. (n.d.). In Chemical encyclopedia. Retrieved from http://www.xumuk.ru/encyklopedia/119.html.


Alkaloids in medicine. (n.d.). In PICSE: Organic Chemistry. Retrieved from http://mv.picse.net/alkoloids/poppies/alkaloids-in-medicine/.


Grinkevich NI & Safronich LN. (1983). The chemical analysis of medicinal plants. (1st ed.). Russia: Moskva, Vysshaia shkola.


Hesse M. (2002). Alkaloids: Nature's curse or blessing?. (1st ed.). Zurich, Switzerland: Wiley-VCH.


Rhoades DF. (1979). Evolution of plant chemical defense against herbivores. In Rosenthal, GA, & Janzen DH (eds.), Herbivores: Their interaction with secondary plant metabolites. NY, New York: Academic Press.

Akt, Alismatis Rhizoma, anti-proliferative, anti-proliferative effect, apoptosis, B16F10, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, Cytostatic, cytotoxic, Gastric cancer or Stomach cancer, Hep3B, HepG2-DR, HT1080, K562-DR, Melanoma, p-Akt, PC3, PI3K, PI3K/Akt, Sarcoma, SGC7901, SKOV3

Alisol B Acetate

Cancer:
Liver, melanoma, ovarian, sarcoma, gastric cancer

Action: Cytostatic, cytotoxic

Four prostane-type triterpenes were isolated from a methanol extract of Alismatis Rhizoma by bioassay-guided isolation using in vitro cytotoxic assay. The compounds were identified as alisol B 23-acetate (1), alisol C 23-acetate (2), alisol B (3), alisol A 24-acetate (4) by spectroscopic methods. Amongst the compounds, alisol B (3) showed significant cytotoxicity against SK-OV3, B16-F10, and HT1080 cancer cell lines with ED50 values of 7.5, 7.5, 4.9 microg/ml, respectively (Lee et al., 2001).

Hepatocellular Carcinoma

Long dan xie gan tang (pinyin) is one of the most commonly used herbal formulas by patients with chronic liver disease in China. Accumulated anecdotal evidence suggests that Long dan tang may have beneficial effects in patients with hepatocellular carcinoma. Long dan tang is comprised of five herbs: Gentiana root, Scutellaria root, Gardenia fruit, Alisma rhizome, and Bupleurum root. The cytotoxic effects of compounds from the five major ingredients isolated from the above plants, i.e. gentiopicroside, baicalein, geniposide, alisol B acetate and saikosaponin-d, respectively, on human hepatoma Hep3B cells, were investigated.

Results suggest that alisol B acetate and saikosaponin-d induced cell apoptosis through the caspase-3-dependent and -independent pathways, respectively. Instead of inducing apoptosis, baicalein inhibits TGF-beta(1)-induced apoptosis via increase in cellular H(2)O(2) formation and NF-kappaB activation in human hepatoma Hep3B cells (Chou, Pan, Teng & Guh, 2003).

Gastric Cancer

The cytotoxic effect of alisol B acetate on SGC7901 cells was measured by MTT assay and phase-contrast and electron microscopy. Cell-cycle and mitochondrial transmembrane potential (Deltapsim) were determined by flow cytometry and Western blotting was used to detect the expression of apoptosis-regulated gene Bcl-2, Bax, Apaf-1, caspase-3, caspase-9, Akt, P-Akt and phosphatidylinositol 3-kinases (PI3K).

Alisol B acetate inhibited the proliferation of SGC7901 cell line in a time- and dose-dependent manner. Alisol B acetate exhibits an anti-proliferative effect in SGC7901 cells by inducing apoptosis. Apoptosis of SGC7901 cells involves mitochondria-caspase and PI3K/Akt dependent pathways (Xu, Zhao & Li, 2009).

References

Chou CC, Pan SL, Teng CM, & Guh JH. (2003). Pharmacological evaluation of several major ingredients of Chinese herbal medicines in human hepatoma Hep3B cells. European Journal of Pharmaceutical Sciences, 19(5), 403-12.

 

 

Lee S, Kho Y, Min B, et al. (2001). Cytotoxic triterpenoides from Alismatis rhizome. Archives of Pharmacal Research. 24(6), 524-526.

 

Xu YH, Zhao LJ, & Li Y. (2009). Alisol B acetate induces apoptosis of SGC7901 cells via mitochondrial and phosphatidylinositol 3-kinases/Akt signaling pathways.

 

World Journal of Gastroenterology, 15(23), 2870-2877.

apoptosis, Breast cancer, Ca Ski, Chapter 7 Isolates and Cancer Research, chemo-preventive, Curcuma zedoaria, HCT-116, MCF-7

Alismol

Cancer: Breast, cervical, colorectal

Action: Inhibits Ca2+ influx

Breast Cancer, Cervical Carcinoma, Colorectal Carcinoma

Bioassay-guided isolation of the active hexane fractions of Curcuma zedoaria led to the identification of five pure compounds, namely, curzerenone (1), neocurdione (2), curdione (3), alismol (4), and zederone (5) and a mixture of sterols, namely, campesterol (6), stigmasterol (7), and β -sitosterol (8).

Curzerenone and alismol significantly inhibited cell proliferation in human cancer cell lines MCF-7 breast cancer, Ca Ski cervical carcinoma, and HCT-116 colorectal carcinoma in a dose-dependent manner. It can be suggested that curzerenone and alismol are modulated by apoptosis via caspase-3 signaling pathway. The findings of the present study support the use of Curcuma zedoaria rhizomes in traditional medicine for the treatment of cancer-related diseases. Thus, two naturally occurring sesquiterpenoids, curzerenone and alismol, hold great promise for use in chemo-preventive and chemotherapeutic strategies (Syed Abdul Rahman, Abdul Wahab, & Abd Malek, 2013).

Ca2+ influx

Alismol inhibited mainly Ca2+ influx through a voltage-dependent Ca2+ channel (Matsuda et al., 1987) and Alismol, a sesquiterpenoid isolated from Alismatis Rhizoma, caused a sustained, though weak, anti-hypertensive action in all the experimental models, but did not significantly affect the plasma renin activity, ACE activity and the level of aldosterone (Yamahara et al., 1989).

References

Matsuda H, Kobayashi G, Yamahara J, et al. (1987). Effects of alismol isolated from Alismatis Rhizoma on calcium-induced contraction in the rabbit thoracic aorta. Life Sci, 41(15):1845-52.


Syed Abdul Rahman SN, Abdul Wahab N, & Abd Malek SN. (2013). In vitro morphological assessment of apoptosis induced by anti-proliferative constituents from the rhizomes of Curcuma zedoaria. Evidence-Based Complementary and Alternative Medicine, 2013(2013), 257108. doi: 10.1155/2013/257108.


Yamahara J, Kobayashi G, Iwamoto M, et al. (1989). The effect of alismol isolated from alismatis rhizoma on experimental hypertensive models in rats. Phytotherapy Research, 3(2):57–60. doi: 10.1002/ptr.2650030205

anti-tumor, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, growth-inhibitory, IL-2, Immune, Immunomodulatory, TNF

Aconitum polysaccharide ACP-a1

Aconitum polysaccharide ACP-a1

Cancer: Liver, leukemia

Action: Chemo-sensitizer

Hepatoma

A polysaccharide (ACP-a1) was successfully purified and identified from the roots of Aconitum coreanum (Lvl.)

The effects of ACP-a1 on the tumor growth and immune function were assessed in hepatoma H22 bearing mice. Results showed that ACP-a1 significantly inhibited the growth of hepatoma H22 transplanted in mice and prolonged the survival time of H22 tumor-bearing mice. As well, the body weight, peripheral white blood cells (WBC), thymus index and spleen index of H22 tumor-bearing were also improved after ACP-a1 treatment.

Furthermore, ACP-a1 could promote the secretion of serum cytokines in H22 tumor-bearing mice, such as IL-2, TNF-α and IFN-γ. Taken together, these results indicate that ACP-a1 inhibits tumor growth in vivo at least partly via improving immune responses of the host organism, and seems to be safe and effective as a novel agent with immunomodulatory activity for the use of anti-tumor therapy (Li et al., 2013).

Chemo-sensitizer; Liver carcinoma

The monkshood polysaccharide (MPS), aconitum, was studied for its combined synergistic effect, with Adriamycin (ADM), versus Adriamycin alone. Both treatments were delivered via long circulating temperature-sensitive liposome (LTSL) in H22, liver carcinoma, tumor-bearing mice. The synergic action of monkshood polysaccharide (MPS) and adriamycin (ADM) long circulating temperature-sensitive liposome (ALTSL) in targeting therapy for H22 tumor-bearing mice was studied

Outcomes assessed included tumor weight, as an index for anti-tumorigenic effect, as well as survival time. Natural killer cell activity of NK cells was higher in the ALTSL group versus the control, but lower than the MPS + ALTSL group. Lymphocyte transformation in the MPS + ALTSL group was markedly improved (P < 0.01) relative to the ALTSL.

Results of RT-PCR indicated that the expression of IL-2 mRNA and IL-12 mRNA, in lymphocytes, in ALTSL group were significantly higher than those in the control. However, expression of IL-2 mRNA and IL-12 mRNA was much higher in the MPS + ALTSL versus the ALTSL group.

LTSL can increase the anti-tumor effect and decrease the
side-effects, such as cytotoxicity, of ADM. MPS combined with ALTSL can enhance natural killer cell activity and transformation of T cells, creating a synergistic anti-tumorigenic effect (Dong et al., 2006).

Leukemia

Two amide alkaloids, named 3-isopropyl-tetrahydropyrrolo [1,2-a]
pyrimidine-2,4(1H,3H)-dione (1) and 1-acetyl-2,3,6-triisopropyl-tetrahydropyrimidin-4(1H)-one (2), were isolated from the roots of Aconitum taipeicum. These compounds exhibited more significant cell growth-inhibitory activities against human promyelocytic leukemia (HL-60) cells than adriamycin, with the IC(50) of 1.1 ± 0.03 µg/mL and 1.6 ± 0.07 µg/mL respectively. In addition, two compounds showed anti-tumor activities against K562 cells as well (Xu, Guo & Wu, 2010).

References

Dong LF, Zhang YJ, Liu JS, et al. (2006). Anti-tumor effect of monkshood polysaccharide with Adriamycin long circulating temperature-sensitive liposome and its mechanism. Chinese Journal of Cellular and Molecular Immunology, 22(4), 458-462.

Li H, Sun M, Xu J, et al. (2013). Immunological response in H22 transplanted mice undergoing Aconitum coreanum polysaccharide treatment. Int J Biol Macromol, 55:295-300. doi:10.1016/j.ijbiomac.2013.01.011.

Xu Y, Guo ZJ, Wu N. (2010). Two new amide alkaloids with anti-leukaemia activities from Aconitum taipeicum. Fitoterapia, 81(8):1091-3. doi: 10.1016/j.fitote.2010.07.005.

Anti-cancer, apoptosis, apoptosis induction, Apoptotic, BAX, Bcl-2, Boswellia carterri Birdw, Boswellia serrata, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, DR5, G1, Gastric cancer or Stomach cancer, HT-29, induces apoptosis, LNCaP, PC-3, p21, p53, PARP, Prostate cancer, SGC-7901, MKN-45

Acetyl-keto-beta-boswellic acid (AKBA)

Cancer: Colorectal, prostate, gastric

Action: Anti-cancer

Apoptotic

Acetyl-keto-beta-boswellic acid (AKBA), a triterpenoid isolated from Boswellia carterri Birdw and Boswellia serrata, has been found to inhibit tumor cell growth and to induce apoptosis. Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation, and independent of Fas/Fas ligand interaction in colon cancer HT-29 cells (Liu et al., 2002).

Colon Cancer

Although there is increasing evidence showing that boswellic acid might be a potential anti-cancer agent, the mechanisms involved in its action are unclear. It has been shown that acetyl-keto-beta-boswellic acid (AKBA) inhibits cellular growth in several colon cancer cell lines. Cell cycle analysis by flow cytometry showed that cells were arrested at the G1 phase after AKBA treatment.

These results demonstrate that AKBA inhibits cellular growth in colon cancer cells. These findings may have implications for the use of boswellic acids as potential anti-cancer agents in colon cancer (Liu et al., 2006).

AKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell-cycle in G1-phase and induction of apoptosis. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity (Yuan et al., 2013).

Gastric Cancer

AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited gastric cancer cells line SGC-7901 and MKN-45 xenografts without toxicity.

This effect might be associated with its roles in cell-cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Upon AKBA treatment, β-catenin expression in nuclei was inhibited, and membrane β-catenin was activated (Zhang et al., 2013).

Prostate

The apoptotic effects and the mechanisms of action of AKBA were studied in LNCaP and PC-3 human prostate cancer cells. AKBA induced apoptosis in both cell lines at concentrations above 10 microg/mL. AKBA-induced apoptosis was correlated with the activation of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase (PARP) cleavage.

AKBA treatment increased the levels of CAAT/enhancer binding protein homologous protein (CHOP) and activated a DR5 promoter reporter but did not activate a DR5 promoter reporter with the mutant CHOP binding site. These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP (Lu et al., 2008).

References

Liu J-J, Nilsson A, Oredsson S, et al. (2002). Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. Carcinogenesis. 23(12): 2087–2093. doi:10.1093/carcin/23.12.2087.

 

 

Liu JJ, Huang B, Hooi SC. (2006). Acetyl-keto-beta-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells. Br J Pharmacol, 148(8):1099-107.

 

Lu M, Xia L, Hua H, Jing Y. (2008). Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells. Cancer Res, 68(4):1180-6. doi: 10.1158/0008-5472.CAN-07-2978.

 

Yuan Y, Cui SX, Wang Y, et al. (2013). Acetyl-11-keto-beta-boswellic acid (AKBA) prevents human colonic adenocarcinoma growth through modulation of multiple signaling pathways. Biochim Biophys Acta, 1830(10):4907-16. doi: 10.1016/j.bbagen.2013.06.039.

 

Zhang YS, Xie JZ, Zhong JL, et al. (2013) Acetyl-11-keto-β-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/β -catenin signaling pathway. Biochim Biophys Acta, 1830(6):3604-15. doi: 10.1016/j.bbagen.2013.03.003.

Anti-metastatic, anti-metastatic effect, anti-oxidant, Arctostaphylos uva-ursi [(L.) Spreng, B16 (lung metastasis), B16F10, Chapter 7 Isolates and Cancer Research, Cistanche deserticola (Ma), ERK, Lung cancer, Melanoma, metastasis, Stachys sieboldii (Miq)

Acetoside

Cancer: Lung cancer, melanoma

Action: Anti-metastatic

Acetoside is isolated from Stachys sieboldii (Miq), Arctostaphylos uva-ursi [(L.) Spreng, Cistanche deserticola (Ma).

Anti-metastatic; Lung Cancer

The anti-metastatic effect of acteoside, a phenylethanoid glycoside widely distributed in the plant kingdom, was examined with respect to lung metastasis using a mouse model injected with B16 melanoma cells intravenously. Administration of acteoside prolonged survival time significantly and the average survival time was 63.3 +/- 3.4d compared with 52.1 +/- 2.5d in control mice. This result suggests that acteoside showed suppressive effect on lung metastasis of B16 melanoma cells (Ohno et al., 2009).

Melanoma

Acteoside showed an inhibitory effect on tyrosinase activity and melanin synthesis in both cell-free assay systems and cultured B16F10 melanoma cells. Acteoside decreased levels of tyrosinase, tyrosinase-related protein-1 (TRP-1) and microphthalmia-associated transcription factor (MITF) proteins, whereas it increased ERK phosphorylation. Acteoside suppressed melanogenesis induced by α-melanocyte-stimulating hormone and showed UV-absorbing effects (Son et al., 2011). Acteoside also inhibited production of both melanin and cyclic AMP in cells stimulated by 1 micromol/l forskolin, an adenyl cyclase activator. Acteoside showed anti-oxidant activity in a cell-free DPPH (1-diphenyl-2-picrylhydroazyl) assay and inhibited generation of intracellular reactive oxygen species (Song & Sim., 2009).

References

Ohno T, Inoue M, Ogihara Y, Saracoglu I. (2012). Anti-metastatic activity of acteoside, a phenylethanoid glycoside. Biological & Pharmaceutical Bulletin, 25(5):666-8. doi: 10.1248/bpb.25.666


Song HS, Sim SS. (2009). Acteoside inhibits alpha-MSH-induced melanin production in B16 melanoma cells by inactivation of adenyl cyclase. J Pharm Pharmacol, 61(10):1347-51. doi: 10.1211/jpp/61.10.0011.


Son YO, Lee SA, Kim SS, et al. (2011). Acteoside inhibits melanogenesis in B16F10 cells through ERK activation and tyrosinase down-regulation. J Pharm Pharmacol, 63(10):1309-19. doi: 10.1111/j.2042-7158.2011.01335.x.

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.

Anti-cancer, anti-oxidative, Breast cancer, Chapter 7 Isolates and Cancer Research

β Sitosterol

Cancer: Breast, multiple myeloma

Action: Anti-oxidative

Breast Cancer

While many factors are involved in the etiology of cancer, it has been clearly established that diet significantly impacts one's risk for this disease. More recently, specific food components have been identified which are uniquely beneficial in mitigating the risk of specific cancer subtypes. Plant sterols are well known for their effects on blood cholesterol levels, however research into their potential role in mitigating cancer risk remains in its infancy. The cholesterol modulating actions of plant sterols may overlap with their anti-cancer actions.

Breast cancer is the most common malignancy affecting women and there remains a need for effective adjuvant therapies for this disease, for which plant sterols may play a distinctive role (Grattan, 2013).

Porphyra dentata, an edible red macroalgae, is used as a folk medicine in Asia. The in vitro and in vivo protective effects of a sterol fraction from P. dentata against breast cancer, linked to tumor-induced myeloid derived-suppressor cells (MDSCs), was investigated.

A sterol fraction containing cholesterol, β-sitosterol, and campesterol was prepared by solvent fractionation of methanol extract of P. dentata    in silica gel column chromatography. This sterol fraction in vitro significantly inhibited cell growth and induced apoptosis in 4T1 cancer cells.

The sterol fraction from P. dentata showed potential for protecting an organism from 4T1 cell-based tumor genesis. The anti-cancer effects potentially are a result of the presence of beta-sitosterol and campesterol. This sterol-containing fraction reduced tumorgenesis and increased the survival rate of 4T1-engrafted mice. This inhibition would be consistent with the use of Porphyra dentata as a folk medicine to treat inflammatory disorders and also for breast cancer (Kazlowska et al., 2013).

The role of reactive oxygen species (ROS) in association with AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) pathways was demonstrated in beta-sitosterol-treated multiple myeloma U266 cells. Beta-sitosterol exerted cytotoxicity, increased sub-G1 apoptotic population and activated caspase-9 and -3, cleaved poly (ADP-ribose) polymerase (PARP) followed by decrease in mitochondrial potential in U266 cells. Beta-sitosterol promoted ROS production, activated AMPK, acetyl-CoA carboxylase (ACC) and JNK in U266 cells. Also, beta-sitosterol attenuated the phosphorylation of AKT, mammalian target of rapamycin and S6K, and the expression of cyclooxygenase-2 and VEGF in U266 cells (Sook et al., 2013).

Cancer: Breast, skin epidermoid carcinoma, lung epithelial carcinoma

Action: Promotes apoptosis, antioxidant activity

Among many cancers, breast cancer in females and lung cancer in males are the most frequently diagnosed cancers and the leading cause of cancer death for each sex in both economically developed and developing countries [1]. Lung cancer accounted for 13% of the total cases and 18% of the deaths due to cancer occurred in 2008 [1]. Skin cancer is the major cutaneous malignancy and about 76,250 people are estimated to be diagnosed for skin cancer in 2013 [2]. Incidence rate for melanoma has been rising from past three decades. Breast cancer is by far the most frequent cancer among women with an estimated 23% of all cancers and is the most frequent cause of cancer death in women [1].

The use of natural, synthetic or biological agents to prevent, reverse or suppress the growth and progression of cancer is referred as chemoprevention of cancer [3]. It is one of the most promising strategies for cancer control, and is accomplished by various means including chemoprevention by phytochemicals from vegetables, fruits, spices, teas, herbs and medicinal plants thus making it as one of the most feasible means of cancer control [4]. Phytochemicals are secondary plant metabolites and have been used for centuries throughout the world in traditional cures and herbal remedies, and as ayurvedic and homeopathic medicines in India. More recently, there has been a considerable interest in secondary plant metabolites because of their potential preventative effects on chronic diseases including cancer.

Many studies have demonstrated that phytochemicals in common fruits and vegetables can have complementary and overlapping mechanisms of action, including antioxidant activity, scavenging free radicals and regulation of gene expression, including oncogenes and tumor suppressor genes, in cell proliferation and cell differentiation; induction of cell-cycle arrest and apoptosis; modulation of enzyme activities in detoxification, oxidation and reduction; stimulation of the immune system; regulation of hormone metabolism; and antibacterial and antiviral effects [5-7]. Phytosterols (PS) are triterpenes that are important structural components of plant membranes. More than 200 different types of phytosterols have been reported in plant species. The richest sources of phytosterols are vegetable oils, nuts, cereal products, fruits and berries [8]. Structural resemblance of PS with cholesterol enables them to displace low-density lipoprotein (LDL) cholesterol in the human intestine [9]. Protective effects of PS against cardiovascular diseases (CVD), colon and breast cancer developments have been widely documented. The most common dietary phytosterols are β-sitosterol, campesterol and stigmasterol. Among these, the most abundant phytosterol is β-sitosterol. Studies have shown that β-sitosterol exhibits anti-inflammatory, angiogenic and immune-modulating properties [10]. β-sitosterol is reported to activate Fas signaling in breast cancer cells [11], and induce cell cycle arrest and apoptotic cell death in prostate cancer cells [12,13].

Herein, we evaluated the efficacy of β-sitosterol on three different cancer cell lines including human skin epidermoid carcinoma cell line (A431), human lung epithelial carcinoma cell line (A549) and human breast adenocarcinoma cell line (MDA-MB-231). It was observed that as compared to A431 and A549 cells, β-sitosterol showed prominent growth inhibitory and pro-apoptotic activity in MDA-MB-231 cells. Further, study provides valuable insight into the chemopreventive efficacy and associated molecular alterations of β-sitosterol in breast cancer cells in culture.

The current study shows that β-Sitosterol (ST), a dietary phytosterol has stronger anticancer activity against breast cancer cells compared to lung and skin cancer cells which may be attributed to the differential expression of genes including hormones, receptors and tissue specific proteins. Along with anti-proliferative and growth inhibitory effect, ST induced G0/G1 cell cycle arrest via modulation of cell cycle regulators CDK4, cyclin D1, p21/Cip1and p27/Kip1 breast cancer cells. Further ST caused cell death involves the induction of apoptosis in breast cancer cells via mitochondrial membrane depolarization and increase in Bax/Bcl-2 ratio. This study provides valuable insight into the chemopreventive efficacy and associated molecular alterations of ST in breast cancer cells. However, further studies are needed to understand and assess the potential clinical utility of ST as a chemopreventive agent against breast cancer.

References

Grattan BJ Jr. (2013). Plant sterols as anti-cancer nutrients: evidence for their role in breast cancer. Nutrients, 5(2):359-87. doi: 10.3390/nu5020359.


Kazlowska K, Lin HTV, Chang SH, Tsai GJ. Evidence-Based Complementary and Alternative Medicine. (2013). In vitro and in vivo anti-cancer effects of sterol fraction from red algae porphyra. Evidence-Based Complementary and Alternative Medicine, 2013(2013), 493869. http://dx.doi.org/10.1155/2013/493869.


Sook SH, Lee HJ, Kim JH, et al. (2013). Reactive Oxygen Species-Mediated Activation of AMP-Activated Protein Kinase and c-Jun N-terminal Kinase Plays a Critical Role in Beta-Sitosterol-Induced Apoptosis in Multiple Myeloma U266 cells. Phytother Res. doi: 10.1002/ptr.4999.

1.Ferlay J, Shin H, Bray F, Forman D, Mathers C, Parkin D. Estimates of worldwide burden of cancer in 2008. Int J Cancer 2010, 127:2893-2917.


2.American Cancer Society: Cancer Facts and Figures: 2010. Atlanta: American Cancer Society; 2010::1-62.


3.Anne S, Tsao M, Edward S, Kim M, Waun Ki Hong M. Chemoprevention of cancer. Am Cancer J Clin 2004, 54:150-180.


4.Nishino H, Tokuda H, Satomi Y, Masuda M, Onozuka M, Yamaguchi S, Takayasu J: Cancer chemoprevention by phytochemicals and their related compounds. Asian Pacific J Cancer 2000, 1:49-55.


5.Dragsted L, Strube M, Larsen J: Cancer-protective factors in fruits and vegetables: biochemical and biological background. Pharmacol Toxicol 1993, 72:116-135.

6.Demirkol O, Adams C, Ercal N: Biologically important thiols in various vegetables and fruits. J Agric Food Chem 2004, 52:8151-8154.

7.Chandra S, Sah K, Bagewadi A, Keluskar V, Shetty A: Additive and synergistic effect of phytochemicals in prevention of oral cancer. Eur J Gen Dent 2012, 1:142-147.

8.Valsta L, Lemström A, Ovaskainen M, Lampi A, Toivo J, Korhonen T, Piironen V: Estimation of plant sterol and cholesterol intake in Finland: quality of new values and their effect on intake. Br J Nutr 2007, 92:671-678.


9.Trautwein E, Lin Y, Mel S, Molhuizen H, Ntanios F: Proposed mechanisms of cholesterol-lowering action of plant sterols. Eur J Lipid Sci Technol 2003, 105:171-185.


10.Bouic P, Lamprecht J: Plant Sterols and Sterolins: A review of their Immune-modulating properties sterols & sterolins. Altern Med Rev 1999, 4:170-177.


11.Awad A, Chinnam M, Fink C, Bradford P: Beta-Sitosterol activates Fas signaling in human breast cancer cells. Phytomedicine 2007, 14:747-754.


12.Awad A, Burr A, Fink C: Effect of resveratrol and beta-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells. Prostaglandins Leukot Essent Fat Acids 2005, 72:219-226.

13.Von Holtz R, Fink C, Awad A: Beta-Sitosterol activates the sphingomyelin cycle and induces apoptosis in LNCaP human prostate cancer cells. Nutr Cancer 1998, 32:8-12.

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.

anti-tumor, anti-tumor activity, Chapter 7 Isolates and Cancer Research, cytotoxic, Enhances phagocytic activity, Immunomodulatory

Pseudostellaria heterophylla

Cancer: none noted

Action: Enhances phagocytic activity

A mitogenic fraction (PH-I) separated from Pseudostellaria heterophylla exhibits both immunomodulatory and anti-tumor activities. PH-I was further purified by gel filtration chromatography and the resulting three fractions (PH-I A, PH-I B and PH-I C) were assessed for their anti-tumor activity in vivo. It was found that fraction PH-I C from P. heterophylla could markedly suppress the growth of EAT cells in vivo. Mechanistic studies have shown that i.p. injection of PH-I C into mice could enhance the phagocytic activity of thioglycollate-elicited peritoneal macrophages.

Moreover, PH-I C showed a potent activating effect on the cytotoxic activity of natural killer (NK) cells and alloreactive cytotoxic T cells (Tc) as well as increased the MurIL-2-induced lymphokine activated killer cell (LAK) activity in vitro. In addition, PH-I C could increase the number of tumor infiltrating lymphocytes (TILs) in the tumor site of WEHI-164-bearing mice. Finally, i.v. injection of PH-I C significantly elevated the levels of IFN-gamma and IL-4 in sera of EAT-bearing mice (Wong et al., 1994).

Reference

Wong CK, Leung KN, Fung KP, Choy YM. (1994). The immunostimulating activities of anti-tumor polysaccharides from Pseudostellaria heterophylla. Immunopharmacology, 28(1):47-54.

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.

Anti-tumoral, Chapter 7 Isolates and Cancer Research, Chemotherapy, chemotherapy support, Lung cancer

β-Elemene

Cancer: Lung

Action: Anti-tumoral., chemotherapy support

Lung Cancer

Randomized controlled clinical trials related to the use of β-elemene injection, as an adjunctive treatment for lung cancer, were retrieved from the Chinese Biomedical (CBMweb), Chinese Medical Current Content (CMCC), China National Knowledge Infrastructure (CNKI), ChinaInfo, Cochrane Central Register of Controlled Trials; MEDLINE, EMBASE, OVID and TCMLARS databases.

A total of 21 source documents (1,467 patients) matched pre-specified criteria for determining the effectiveness and safety of β-elemene injection as an adjunctive treatment for lung cancer. Five studies involving 285 NSCLC patients reported a higher 24-month survival rate (39.09%) with the adjunctive treatment than with chemotherapy alone. Four studies involving 445 patients reported that the increased probability for improved performance status for patients treated with elemene-based combinations was higher than that of patients treated with chemotherapy alone. The results from a subgroup analysis on 12 studies involving 974 NSCLC patients and 9 studies involving 593 patients with both SCLC and NSCLC showed that the tumor control rate for NSCLC improved more in the elemene-based combinations treatment group than in the chemotherapy alone control group. The tumor response rate for NSCLC also improved more among patients treated with elemene based combinations (50.71%) than among patients treated with chemotherapy alone.

The effectiveness of chemotherapy for the treatment of lung cancer may improve when combined with β-elemene injection as an adjunctive treatment. The combined treatment can result in an improved quality of life and prolonged survival (Wang et al., 2012).

Reference

Wang B, Peng XX, Sun R, Li J, Zhan XR, Wu LJ, Wang SL, Xie T. (2012). Systematic review of β-elemene injection as adjunctive treatment for lung cancer. Chinese Journal of Integrative Medicine, 18(11), 8313-823.