Category Archives: SGC7901

AKR1C1/1C2, Akt, anti-inflammatory, anti-oxidant, apoptosis, attenuation of immune suppression, Breast cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemoprevention, Colon Cancer or Colorectal cancer, Gastric cancer or Stomach cancer, HIF, hNSC, honey, HT-29, Immune, Immunomodulatory, induces apoptosis, Lung cancer, MAPK, MDR, p21, p38, Passiflora caerulea, Passiflora incarnate, Scutellaria baicalensis, SGC7901, VEGF, VEGF

Chrysin

Cancer:
Lung cancer, breast cancer, leukemia, gastric, colon

Action: Anti-inflammatory, induces apoptosis, inhibits HIF-1 α, immunomodulatory

Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound extracted from many plants (including Scutellaria baicalensis (Georgi), Passiflora caerulea (L.), Passiflora incarnate (L.))., honey, and propolis. It possesses potent anti-inflammatory, anti-oxidant properties, promotes cell death, and perturbs cell-cycle progression. Chrysin induced p38-MAPK activation, and using a specific p38-MAPK inhibitor, SB203580, attenuated chrysin-induced p21 (Waf1/Cip1) expression (Weng et al., 2005).

MDR; NSCLC

Chrysin is a major flavonoid in Scutellaria baicalensis, a widely used traditional Chinese and Japanese medicine. Novel links of pro-inflammatory signals, AKR1C1/1C2 expression and drug resistance in human non-small lung cancer have been demonstrated, and the protein kinase C pathway may play an important role in this process. It is thought that chrysin may act as a potential adjuvant therapy for drug-resistant non-small lung cancer, especially for those with AKR1C1/1C2 overexpression (Wang et al., 2007).

Gastric Cancer, Colon Cancer

Additionally, derivatives of chrysin have been shown to have strong activities against SGC-7901 human gastric cell line and HT-29 human colon cancer cell lines (Zheng et al., 2003).

Breast Cancer

While Chrysin is a potent breast cancer resistance protein inhibitor, it was found to have no significant effect on toptecan pharmacokinetics in rats (Zhang et al., 2005).

VEGF, HIF-1

Chrysin was found to inhibit hypoxia-inducible factor-1α (HIF-1α) expression through AKT signaling. Inhibition of HIF-1α by chrysin resulted in abrogation of vascular endothelial growth factor expression (Fu et al., 2007).

Leukemia

Chrysin has been shown to inhibit proliferation and induce apoptosis, and is more potent than other tested flavonoids in leukemia cells, where chrysin is likely to act via activation of caspases and inactivation of Akt signaling in the cells (Khoo et al., 2010).

Immune

The chemo-preventive action of chrysin has been found to specifically inhibit the enzymatic activity of IDO-1 but not mRNA expression in human neuronal stem cells (hNSC), confirmed by cell-based assay and qRT-PCR. These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy (Chen et al., 2012).

References

Chen SS, Corteling R, Stevanato L, Sinden J. (2012). Polyphenols Inhibit Indoleamine 3,5-Dioxygenase-1 Enzymatic Activity — A Role of Immunomodulation in Chemoprevention. Discovery Medicine.


Fu B, Xue J, Li Z, et al. (2007). Chrysin inhibits expression of hypoxia-inducible factor-1 α through reducing hypoxia-inducible factor-1 α stability and inhibiting its protein synthesis. Mol Cancer Ther, 6:220. doi: 10.1158/1535-7163.MCT-06-0526


Khoo BY, Chua SL, Balaram P. (2010). Apoptotic Effects of Chrysin in Human Cancer Cell Lines. Int. J. Mol. Sci, 11(5), 2188-2199. doi:10.3390/ijms11052188


Wang HW, Lin CP, Chiu JH, et al. (2007). Reversal of inflammation-associated dihydrodiol dehydrogenases (AKR1C1 and AKR1C2) overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin. International Journal of Cancer, 120(9), 2019-2027.


Weng MS, Ho YS, Lin JK. (2005). Chrysin induces G1 phase cell-cycle arrest in C6 glioma cells through inducing p21Waf1/Cip1 expression: involvement of p38 mitogen-activated protein kinase. Biochem Pharmacol, 69(12):1815-27.


Zhang S, Wang X, Sagawa K, Morris ME. (2005). Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (,äì/,äì) mice. Drug Metabolism and Disposition, 33(3), 341-348.


Zheng X, Meng WD, Xu YY, Cao JG, & Qing FL. (2003). Synthesis and anti-cancer effect of chrysin derivatives. Bioorganic & Medicinal Chemistry Letters, 13(5), 881-884.

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, 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.

AMPK, angiogenesis, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-proliferative, anti-proliferative effect, anti-tumor, apoptosis, apoptosis-inducing, Apoptotic, autophagic cell death, Autophagy, BAD, BAX, Bcl-2, Breast cancer, Breast cancer cell lines, c-Myc, cancer stem cells, cardio-protective, CCAAT, CDK, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, Chemotherapy, CNE, Colon Cancer or Colorectal cancer, COX-2, CSC, CSCs, Cytostatic, cytotoxic, ER, ERK, G0/G1, G1, GADD153, growth-inhibitory, HepG2, SMMC-7721, ICAM-1, IL-6, inflammation, K562, KBM-5, LNCaP, MTOR, p16, p21, p27, PC3 and LNCaP, Pro-apoptotic, Prostate cancer, Rectal cancer, RSK, S, SGC7901, STAT3, T47D, MDA-MB-231, TNF, U937, MDA-MB-231, VCAM-1, VEGF, VEGF

Tanshinone II A & Tanshinone A (See also Cryptotanshinone)

Cancer:
Leukemia, prostate, breast, gastric, colorectal, nasopharyngeal carcinoma

Action: Chemo-sensitizer, cytostatic, cancer stem cells, anti-cancer, autophagic cell death, cell-cycle arrest

Anti-cancer

Tanshinone IIA and cryptotanshinone could induce CYP3A4 activity (Qiu et al., 2103).

Tanshinone II-A (Tan IIA) is the most abundant diterpene quinone isolated from Danshen (Salvia miltiorrhiza), which has been used in treating cardiovascular diseases for more than 2,000 years in China. Interest in its versatile protective effects in cardiovascular, metabolic, neurodegenerative diseases, and cancers has been growing over the last decade.

Tan IIA is a multi-target drug, whose molecular targets include transcription factors, scavenger receptors, ion channels, kinases, pro- and anti-apoptotic proteins, growth factors, inflammatory mediators, microRNA, and others. More recently, enhanced or synergistic effects can be observed when Tan IIA is used in combination therapy with cardio-protective and anti-cancer drugs (Xu & Liu, 2013).

Leukemia

The in vitro anti-proliferation and apoptosis-inducing effects of Tanshinone IIA on leukemia THP-1 cell lines and its mechanisms of action were investigated. MTT assay was used to detect the cell growth-inhibitory rate; cell apoptotic rate and the mitochondrial membrane potential (Deltapsim) were investigated by flow cytometry (FCM); apoptotic morphology was observed by Hoechst 33258 staining and DNA fragmentation analysis.

It was therefore concluded that Tanshinone IIA has significant growth inhibition effects on THP-1 cells by induction of apoptosis, and that Tanshinone IIA-induced apoptosis on THP-1 cells is mainly related to the disruption of Deltapsim and activation of caspase-3 as well as down-regulation of anti-apoptotic protein Bcl-2, survivin and up-regulation of pro-apoptotic protein Bax. The results indicate that Tanshinone IIA may serve as a potential anti-leukemia agent (Liu et al., 2009).

Prostate Cancer

Chiu et al. (2013) explored the mechanisms of cell death induced by Tan-IIA treatment in prostate cancer cells in vitro and in vivo. Results showed that Tan-IIA caused prostate cancer cell death in a dose-dependent manner, and cell-cycle arrest at G0/G1 phase was noted, in LNCaP cells. The G0/G1 phase arrest correlated with increased levels of CDK inhibitors (p16, p21 and p27) and decrease of the checkpoint proteins. Tan-IIA also induced ER stress in prostate cancer cells: activation and nuclear translocation of GADD153/CCAAT/enhancer-binding protein-homologous protein (CHOP) were identified, and increased expression of the downstream molecules GRP78/BiP, inositol-requiring protein-1α and GADD153/CHOP were evidenced. Blockage of GADD153/CHOP expression by siRNA reduced Tan-IIA-induced cell death in LNCaP cells.

Gastric Cancer

Tan IIA can reverse the malignant phenotype of SGC7901 gastric cancer cells, indicating that it may be a promising therapeutic agent.

Tan IIA (1, 5, 10 µg/ml) exerted powerful inhibitory effects on cell proliferation (P < 0.05, and P < 0.01), and this effect was time- and dose-dependent. FCM results showed that Tan IIA induced apoptosis of SGC7901 cells, reduced the number of cells in S phase and increased those in G0/G1 phase. Tan IIA also significantly increased the sensitivity of SGC7901 gastric cancer cells to ADR and Fu. Moreover, wound-healing and transwell assays showed that Tan IIA markedly decreased migratory and invasive abilities of SGC7901 cells (Xu et al., 2013).

Cell-cycle Arrest

MTT and SRB assays were applied to measure the effects of tanshinone A on cell viability. Cell-cycle distribution and apoptosis were assessed via flow cytometry using PI staining and the Annexin V/PI double staining method respectively. Changes to mitochondrial membrane potential was also detected by flow cytometry. The spectrophotometric method was utilized to detect changes of caspase-3 activity. Western blotting assay was used to evaluate the expression of Bcl-2, Bax and c-Myc proteins.

Results indicated that Tan-IIA displayed significant inhibitory effect on the growth of K562 cells in a dose- and time- dependent manner, and displayed only minimal damage to hepatic LO2 cells.

Tan-IIA could arrest K562 cells in the G0/G1 phase and induce apoptosis, decrease mitochondrial transmembrane potential, and the expressions of Bcl-2 and c-Myc proteins, increase the expression of Bax protein and activity of caspase-3. Accordingly, it was presumed that the induction of apoptosis may be through the endogenous pathway. Subsequently, tanshinone A could be a promising candidate in the development of a novel anti-tumor agent (Zhen et al., 2011).

Prostate Cancer, Chemo-sensitizer

Treatment with a combination of Chinese herbs and cytotoxic chemotherapies has shown a higher survival rate in clinical trials.

Tan-IIA displayed synergistic anti-tumor effects on human prostate cancer PC3 cells and LNCaP cells, when combined with cisplatin in vitro. Anti-proliferative effects were detected via MTT assay. Cell-cycle distribution and apoptosis were detected by flow cytometer. Protein expression was detected by Western blotting. The intracellular concentration of cisplatin was detected by high performance liquid chromatography (HPLC).

Results demonstrated that tanshinone II A significantly enhanced the anti-proliferative effects of cisplatin on human prostate cancer PC3 cells and LNCaP cells with an increase in the intracellular concentration of cisplatin. These effects were correlated with cell-cycle arrest at the S phase and induction of cell apoptosis. Apoptosis could potentially be achieved through the death receptor and mitochondrial pathways, decreased expression of Bcl-2.

Collectively, results indicated that the combination of tanshinone II A and cisplatin had a better treatment effect, in vitro, not only on androgen-dependent LNCaP cells but also on androgen-independent PC3 cells (Hou, Xu, Hu, & Xie, 2013).

Autophagic Cell Death, CSCs

Tan IIA significantly increased the expression of microtubule-associated protein light chain 3 (LC3) II as a hallmark of autophagy in Western blotting and immunofluorescence staining. Tan IIA augmented the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and attenuated the phosphorylation of mammalian target of rapamycin (mTOR) and p70 S6K in a dose-dependent manner.Tan IIA dramatically activated the extracellular signal regulated kinase (ERK) signaling pathway including Raf, ERK and p90 RSK in a dose-dependent and time-dependent manner. Consistently, ERK inhibitor PD184352 suppressed LC3-II activation induced by Tan IIA, whereas PD184352 and PD98059 did not affect poly (ADP-ribose) polymerase cleavage and sub-G1 accumulation induced by Tan IIA in KBM-5 leukemia cells.

Tan IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 cells as a potent natural compound for leukemia treatment (Yun et al., 2013).

Cancer stem cells (CSCs) are maintained by inflammatory cytokines and signaling pathways. Tanshinone IIA (Tan-IIA) possesses anti-cancer and anti-inflammatory activities. The purpose of this study is to confirm the growth inhibition effect of Tan-IIA on human breast CSCs growth in vitro and in vivo and to explore the possible mechanism of its activity. After Tan-IIA treatment, cell proliferation and mammosphere formation of CSCs were decreased significantly; the expression levels of IL-6, STAT3, phospho-STAT3 (Tyr705), NF-κBp65 in nucleus and cyclin D1 proteins were decreased significantly; the tumor growth and mean tumor weight were reduced significantly.

Tan-IIA has the potential to target and kill CSCs, and can inhibit human breast CSCs growth both in vitro and in vivo through attenuation of IL-6/STAT3/NF-kB signaling pathways (Lin et al., 2013).

Colorectal Cancer

Tan II-A can effectively inhibit tumor growth and angiogenesis of human colorectal cancer via inhibiting the expression level of COX-2 and VEGF. Angiogenesis plays a significant role in colorectal cancer (CRC) and cyclooxygenase-2 (COX-2) appears to be involved with multiple aspects of CRC angiogenesis (Zhou et al., 2012). The results showed that Tan IIA inhibited the proliferation of inflammation-related colon cancer cells HCT116 and HT-29 by decreasing the production of inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), which are generated by macrophage RAW264.7 cell line.

Treatment with TanshinoneIIA prevented increased PU.1, a transcriptional activator of miR-155, and hence increased miR-155, whereas aspirin could not. These findings support that the interruption of signal conduction between activated macrophages and colon cancer cells could be considered as a new therapeutic strategy and miR-155 could be a potential target for the prevention of inflammation-related cancer (Tu et al., 2012).

Breast Cancer

The proliferation rate of T47D and MDA-MB-231 cells influenced by 1×10-6 mol·L-1 and 1×10-7 mol·L-1 Tanshinone IIA was analyzed by MTT assay. Estrogen receptor antagonist ICI182, 780 was employed as a tool. Level of ERα and ERβ mRNA in T47D cells was quantified by Real-time RT-PCR assay. Expression of ERα and ERβ protein was measured by flow cytometry. The proliferation rates of T47D cells treated with Tanshinone IIA decreased significantly. Such effects could be partly blocked by ICI182, 780.

Meanwhile, the proliferation rates of MDA-MB-231 cells treated with Tanshinone IIA decreased much more dramatically. Real-time RT-PCR and flow cytometry results showed that Tanshinone IIA could induce elevation of ERα and ERβ, especially ERα mRNA, and protein expression level in T47D cells. Tanshinone IIA shows inhibitory effects on proliferation of breast cancer cell lines (Zhao et al., 2010).

The role of cell adhesion molecules in the process of inflammation has been studied extensively, and these molecules are critical components of carcinogenesis and cancer metastasis. This study investigated the effect of tanshinone I on cancer growth, invasion and angiogenesis on human breast cancer cells MDA-MB-231, both in vitro and in vivo. Tanshinone I dose-dependently inhibited ICAM-1 and VCAM-1 expressions in human umbilical vein endothelial cells (HUVECs) that were stimulated with TNF-α for 6 h.

Additionally, reduction of tumor mass volume and decrease of metastasis incidents by tanshinone I were observed in vivo. In conclusion, this study provides a potential mechanism for the anti-cancer effect of tanshinone I on breast cancer cells, suggesting that tanshinone I may serve as an effective drug for the treatment of breast cancer (Nizamutdinova et al., 2008).

Nasopharyngeal Carcinoma

To investigate anti-cancer effect and potential mechanism of tanshinone II(A) (Tan II(A)) on human nasopharyngeal carcinoma cell line CNE cells, the anti-proliferative effect of Tan II(A) on CNE cells was evaluated by morphological examination, cell growth curves, colonial assay and MTT assay. Tan II(A) could inhibit CNE cell proliferation in dose- and time-dependent manner. After treatment with Tan II(A), intracellular Ca2+ concentration of CNE cells was increased, mitochondria membrane potential of the cells was decreased, relative mRNA level of Bad and MT-1A was up-regulated. Tan II(A) had an anti-cancer effect on CNE cells through apoptosis via a calcineurin-dependent pathway and MT-1A down-regulation, and may be the next generation of chemotherapy (Dai et al., 2011).

References

Chiu SC, Huang SY, Chen SP, et al. (2013). Tanshinone IIA inhibits human prostate cancer cells growth by induction of endoplasmic reticulum stress in vitro and in vivo. Prostate Cancer Prostatic Dis. doi: 10.1038/pcan.2013.38.


Dai Z, Huang D, Shi J, Yu L, Wu Q, Xu Q. (2011). Apoptosis inducing effect of tanshinone II(A) on human nasopharyngeal carcinoma CNE cells. Zhongguo Zhong Yao Za Zhi, 36(15):2129-33.


Hou LL, Xu QJ, Hu GQ, Xie SQ. (2013). Synergistic anti-tumor effects of tanshinone II A in combination with cisplatin via apoptosis in the prostate cancer cells. Acta Pharmaceutica Sinica, 48(5), 675-679.


Lin C, Wang L, Wang H, et al. (2013). Tanshinone IIA inhibits breast cancer stem cells growth in vitro and in vivo through attenuation of IL-6/STAT3/NF-kB signaling pathways. J Cell Biochem, 114(9):2061-70. doi: 10.1002/jcb.24553.


Liu JJ, Zhang Y, Lin DJ, Xiao RZ. (2009). Tanshinone IIA inhibits leukemia THP-1 cell growth by induction of apoptosis. Oncol Rep, 21(4):1075-81.


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


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


Tu J, Xing Y, Guo Y, et al. (2012). TanshinoneIIA ameliorates inflammatory microenvironment of colon cancer cells via repression of microRNA-155. Int Immunopharmacol, 14(4):353-61. doi: 10.1016/j.intimp.2012.08.015.


Xu M, Cao FL, Li NY, et al. (2013). Tanshinone IIA reverses the malignant phenotype of SGC7901 gastric cancer cells. Asian Pac J Cancer Prev, 14(1):173-7.


Xu S, Liu P. (2013). Tanshinone II-A: new perspectives for old remedies. Expert Opin Ther Pat, 23(2):149-53. doi: 10.1517/13543776.2013.743995.


Yun SM, Jung JH, Jeong SJ, et al. (2013). Tanshinone IIA Induces Autophagic Cell Death via Activation of AMPK and ERK and Inhibition of mTOR and p70 S6K in KBM-5 Leukemia Cells. Phytother Res. doi: 10.1002/ptr.5015.


Zhen X, Cen J, Li YM, Yan F, Guan T, Tang, XZ. (2011). Cytotoxic effect and apoptotic mechanism of tanshinone A, a novel tanshinone derivative, on human erythroleukemic K562 cells. European Journal of Pharmacology, 667(1-3), 129-135. doi: 10.1016/j.ejphar.2011.06.004.


Zhao PW, Niu JZ, Wang JF, Hao QX, Yu J, et al. (2010). Research on the inhibitory effect of Tanshinone IIA on breast cancer cell proliferation. Zhong Guo Yao Li Xue Tong Bao, 26(7):903-906.


Zhou LH, Hu Q, Sui H, et al. (2012). Tanshinone II–a inhibits angiogenesis through down regulation of COX-2 in human colorectal cancer. Asian Pac J Cancer Prev, 13(9):4453-8.

Akt, angiogenesis, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-proliferative, apoptosis, Apoptotic, ARO, Autophagy, Autophagy inhibitor, BAX, Bcl-2, Breast cancer, Breast cancer cell lines, CDK6, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, cytotoxic, Depression or Anxiety, Down-regulates, DU145 and PC3, ER, ER-negative, Evodia rutaecarpa, G0/G1, G1, G2/M, IKK, increases intracellular ROS, inflammation, inhibits metastasis, inhibits NF-κB, Lung cancer, MCF-7 and MDA-MB-231, MDR, MTOR, Nitric Oxide, Pancreatic cancer, PI3K, PI3K/Akt, PTEN, ROS, SGC7901, TNF

Evodiamine

Cancer: Pancreatic, gastric, breast; ER+, ER-, lung

Action: Inhibits NF- κB, inhibits metastasis, increases intracellular ROS, apoptosis, cell-cycle arrest, anti-cancer, MDR

Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodia rutaecarpa [(Juss.) Benth.] (alkaloidal component of the extract). With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and thermo-regulative effects. Evodiamine has evolved a superior ability to bind various proteins (Yu et al., 2013). Evodiamine exhibits anti-proliferative, anti-metastatic, and apoptotic activities.

Anti-cancer, MDR

Evodiamine possesses anti-anxiety, anti-obesity, anti-nociceptive, anti-inflammatory, anti-allergic, and anti-cancer effects. As well, it has thermoregulation, protection of myocardial ischemia-reperfusion injury and vessel-relaxing activities (Kobayashi, 2003; Shin et al., 2007; Ko et al., 2007; Ji, 2011). Evodiamine exhibits anti-cancer activities both in vitro and in vivo by inducing cell-cycle arrest or apoptosis, and inhibiting angiogenesis, invasion, and metastasis in a variety of cancer cell lines (Ogasawara et al., 2001; Ogasawara et al., 2002; Fei et al., 2003; Shyu et al., 2006). It presents anti-cancer potentials at micromolar concentrations and even at the nanomolar level in some cell lines in vitro (Lee et al., 2006; Wang, Li, & Wang, 2010). Evodiamine also stimulates autophagy, which serves as a survival function (Yang et al., 2008). Compared with other compounds, evodiamine is less toxic to normal human cells, such as human peripheral blood mononuclear cells (Fei et al., 2003; Zhang et al., 2004). It also inhibits the proliferation of adriamycin-resistant human breast cancer NCI/ADR-RES cells both in vitro and in Balb-c/nude mice (Liao et al., 2005).

Lung Cancer, Cell-cycle Arrest

Evodiamine (10  mg/kg) administrated orally twice daily significantly inhibits   tumor growth (Liao et al., 2005). Moreover, treatment with 10 mg/kg evodiamine from the 6th day after tumor inoculation into mice reduces lung metastasis and does not affect the body weight of mice during the experimental period (Ogasawara et al., 2001).

Cell-cycle Arrest

Evodiamine inhibits TopI enzyme, forms the DNA covalent complex with a similar concentration to that of irinotecan, and induces DNA damage (Chan et al., 2009; Tsai et al., 2010; Dong et al., 2010). However, TopI may not be the main target of this compound. Cancer cells treated with evodiamine exhibit G 2 / M phase arrest (Kan et al., 2004; Huang et al., 2004; Liao et al., 2005) rather than S phase arrest, which is not consistent with the mechanism of classic TopI inhibitors, such as irinotecan. Therefore, other targets aside from TopI may also be important for realizing the anti-cancer potentials of evodiamine. This statement is supported by the fact that evodiamine has effects on tubulin polymerization (Huang et al., 2004).

Increases Intracellular ROS, Apoptosis

Exposure to evodiamine rapidly increases intracellular ROS followed by an onset of mitochondrial depolarization (Yang et al., 2007). The generation of ROS and nitric oxide acts in synergy and triggers mitochondria-dependent apoptosis (Yang et al., 2008). Evodiamine also induces caspase-dependent and caspase-independent apoptosis, down-regulates Bcl-2 expression, and up-regulates Bax expression in some cancer cells (Zhang et al., 2003; Lee et al., 2006). The phosphatidylinositol 3-kinase/Akt/caspase and Fas ligand (Fas-L)/NF-κB signaling pathways might account for evodiamine-induced cell death. Moreover, these signals could be increased by the ubiquitin-proteasome pathway (Wang, Li, & Wang, 2010).

Inhibits Metastasis

Evodiamine has a marked inhibitory activity on tumor cell migration in vitro. When evodiamine at 10 mg/kg was administered into mice from the 6th day after tumor inoculation, the number of tumor nodules in lungs was decreased by 48% as compared to control. The inhibition rate was equivalent to that produced by cisplatin. Results suggest that evodiamine may be regarded as a promising agent in tumor metastasis therapy (Ogasawara et al., 2005).

Inhibits NF-κB

Evodiamine inhibited tumor necrosis factor (TNF)-induced Akt activation and its association with IKK. This down-regulation potentiated the apoptosis induced by cytokines and chemotherapeutic agents and suppressed TNF-induced invasive activity. Overall, these results indicate that evodiamine inhibits both constitutive and induced NF-κB activation and NF-κB-regulated gene expression (Takada et al., 2005).

Breast Cancer

Endocrine sensitivity, assessed by the expression of estrogen receptor (ER), has long been the predict factor to guide therapeutic decisions. Tamoxifen has been the most successful hormonal treatment in endocrine-sensitive breast cancer. However, in estrogen-insensitive cancer tamoxifen showed less effectiveness than in estrogen-sensitive cancer. It is interesting to develop new drugs against both hormone-sensitive and insensitive tumor. In this present study Wang et al. (2013) examined anti-cancer effects of evodiamine extracted from the Chinese herb, Evodiae fructus, in estrogen-dependent and -independent human breast cancer cells, MCF-7 and MDA-MB-231 cells, respectively.

Breast Cancer; ER+, ER-

The expression of ER α and β in protein and mRNA levels was down-regulated by evodiamine according to data from immunoblotting and RT-PCR analysis. Overall, results indicate that evodiamine mediates degradation of ER and induces caspase-dependent pathway leading to inhibition of proliferation of breast cancer cell lines. It suggests that evodiamine may in part mediate through ER-inhibitory pathway to inhibit breast cancer cell proliferation.

Evodiamine (10 mg/kg) significantly reduced tumor growth and pulmonary metastasis. In vitro, evodiamine inhibited cell migration and invasion abilities through down-regulation of MMP-9, urokinase-type plasminogen activator (uPA) and uPAR expression. Evodiamine-induced G0/G1 arrest and apoptosis were associated with a decrease in Bcl-2, cyclin D1 and cyclin-dependent kinase 6 (CDK6) expression and an increase in Bax and p27Kip1 expression (Du et al., 201).

Gastric Cancer

A study by Rasul et al. (2012) was conducted to investigate the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity on SGC-7901 human gastric adenocarcinoma cells and further to elucidate the underlying molecular mechanisms. Evodiamine significantly inhibited the proliferation of SGC-7901 cells and induced G2/M phase cell-cycle arrest.

Evodiamine-induced autophagy is partially involved in the death of SGC-7901 cells which was confirmed by using the autophagy inhibitor 3-methyladenine (3-MA). Evodiamine has therapeutic potential against cancers.

Pancreatic Cancer

In vitro application of the combination therapy triggered significantly higher frequency of pancreatic cancer cells apoptosis, inhibited the activities of PI3K, Akt, PKA, mTOR and PTEN, and decreased the activation of NF-κB and expression of NF- κB-regulated products. Evodiamine can augment the therapeutic effect of gemcitabine in pancreatic cancer through direct or indirect negative regulation of the PI3K/Akt pathway (Wei et al., 2012).

References

Chan ALF, Chang WS, Chen LM et al. (2009). Evodiamine stabilizes topoisomerase I-DNA cleavable complex to inhibit topoisomerase I activity. Molecules, (14):4:1342–1352.


Dong G, Sheng C, Wang CS, et al. (2010). Selection of evodiamine as a novel topoisomerase i inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as anti-tumor agents. Journal of Medicinal Chemistry, 53(21):7521–7531.


Du J, Wang XF, Zhou QM, et al. (2013). Evodiamine induces apoptosis and inhibits metastasis in MDA “American Typewriter”; “American Typewriter”;‑ MB-231 human breast cancer cells in vitro and in vivo. Oncol Rep, 30(2):685-94. doi: 10.3892/or.2013.2498.


Fei XF, Wang BX, T. Li TJ et al. (2003). Evodiamine, a constituent of Evodiae Fructus, induces anti-proliferating effects in tumor cells. Cancer Science, 94(1):92–98.


Huang YC, Guh JH, Teng CM. (2004). Induction of mitotic arrest and apoptosis by evodiamine in human leukemic T-lymphocytes. Life Sciences, 75(1):35–49.


Ji YB. (2011). Active Ingredients of Traditional Chinese Medicine: Pharmacology and Application. People's Medical Publishing House Co., LTD. Connecticut USA


Kan SF, Huang WJ, Lin LC, Wang PS. (2004). Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP. International Journal of Cancer, 110(5):641–651.


Ko HC, Wang YH, Liou KT et al. (2007). Anti-inflammatory effects and mechanisms of the ethanol extract of Evodia rutaecarpa and its bioactive components on neutrophils and microglial cells. European Journal of Pharmacology, 555(2-3):211–217.


Kobayashi Y. (2003). The nociceptive and anti-nociceptive effects of evodiamine from fruits of Evodia rutaecarpa in mice. Planta Medica, 69(5):425–428.


Lee TJ, Kim EJ, Kim S et al. (2006). Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells. Molecular Cancer Therapeutics, 5(9):2398–2407.


Liao CH, Pan SL, Guh JH et al. (2005). Anti-tumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus, in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo. Carcinogenesis, 26(5):968–975.


Ogasawara M, Matsubara T, Suzuki H. (2001). Inhibitory effects of evodiamine on in vitro invasion and experimental lung metastasis of murine colon cancer cells. Biological and Pharmaceutical Bulletin, 24(8):917–920.


Ogasawara M, Matsunaga T, Takahashi S, Saiki I, Suzuki H. (2002). Anti-invasive and metastatic activities of evodiamine. Biological and Pharmaceutical Bulletin, 25(11):1491–1493.


Rasul A, Yu B, Zhong L, et al. (2012). Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy. Oncol Rep, 27(5):1481-7. doi: 10.3892/or.2012.1694


Shin YW, Bae EA, Cai XF, Lee JJ, and Kim DH. (2007). In vitro and in vivo antiallergic effect of the fructus of Evodia rutaecarpa and its constituents, Biological and Pharmaceutical Bulletin, 30(1):197–199, 2007.


Shyu KG, Lin S, Lee CC et al. (2006). Evodiamine inhibits in vitro angiogenesis: implication for anti-tumorgenicity. Life Sciences, 78(19):2234–2243.


Takada Y, Kobayashi Y, Aggarwal BB. (2005). Evodiamine Abolishes Constitutive and Inducible NF- κB Activation by Inhibiting IκBα Kinase Activation, Thereby Suppressing NF-κ B-regulated Antiapoptotic and Metastatic Gene Expression, Up-regulating Apoptosis, and Inhibiting Invasion. The Journal of Biological Chemistry, 280:17203-17212. doi: 10.1074/jbc.M500077200.


Tsai HP, Lin LW, Lai ZY et al. (2010). Immobilizing topoisomerase I on a surface plasmon resonance biosensor chip to screen for inhibitors. Journal of Biomedical Science, 17(1):49.


Wang C, Li S, Wang MW. (2010). Evodiamine-induced human melanoma A375-S2 cell death was mediated by PI3K/Akt/caspase and Fas-L/NF- κ B signaling pathways and augmented by ubiquitin-proteasome inhibition. Toxicology in Vitro, 24(3):898–904.


Wang KL, Hsia SM, Yeh JY, et al. (2013). Anti-Proliferative Effects of Evodiamine on Human Breast Cancer Cells. PLoS One, 8(6):e67297.


Wei WT, Chen H, Wang ZH, et al. (2012). Enhanced anti-tumor efficacy of gemcitabine by evodiamine on pancreatic cancer via regulating PI3K/Akt pathway. Int J Biol Sci, 8(1):1-14.


Yu H, Jin H, Gong W, Wang Z, Liang H. (2013). Pharmacological actions of multi-target-directed evodiamine. Molecules, 18(2):1826-43. doi: 10.3390/molecules18021826.


Yang J, Wu LJ, Tashino SI, et al. (2007). Critical roles of reactive oxygen species in mitochondrial permeability transition in mediating evodiamine-induced human melanoma A375-S2 cell apoptosis. Free Radical Research, 41(10):1099–1108.


Zhang Y, Wu LJ, Tashiro SI, Onodera S, Ikejima T. (2003). Intracellular regulation of evodiamine-induced A375-S2 cell death. Biological and Pharmaceutical Bulletin, 26(11):1543–1547.


Zhang Y, Zhang QH, Wu LJ, et al. (2004). Atypical apoptosis in L929 cells induced by evodiamine isolated from Evodia rutaecarpa. Journal of Asian Natural Products Research, 6(1):19–27.