Antitumor mechanisms of S-allyl mercaptocysteine for breast cancer therapy

BMC Complementary and Alternative Medicine

Zhongxi Zhao¹  Guimei Lin¹  Kaiming Wang¹  Hong Zhang¹ 

[1] School of Pharmaceutical Sciences and Center for Pharmaceutical Research & DDS, Shandong University, Jinan, Shandong 250012, China

关键词: Cell cycle arrest;    Apoptosis;    Breast cancer;    S-allyl mercaptocysteine;   

Others  :  1087161
DOI  :  10.1186/1472-6882-14-270

 received in 2013-10-31, accepted in 2014-07-22,  发布年份 2014

【 摘 要 】

Background

S-allyl mercaptocysteine (SAMC), a water-soluble component derived from garlic, has been found to exert multi-antitumor activities. This study was to investigate the responsible molecular mechanisms of SAMC in human breast cancer cell lines.

Methods

Sulforhodamine B assay was used to determine cell viability, flow cytometry was applied for the analysis of cell cycle and cell apoptosis, the change of protein was detected by Western blot.

Results

It was found that SAMC exhibited an effective cell growth inhibition of human breast cancer cell lines MCF-7 (ER positive) and MDA-MB-231 (ER negative) in a dose- and time-dependent manner by inducing cell cycle arrested in G0/G1 phase, the block of cell cycle was associated with the up-regulation of p53 and p21. Furthermore, the SAMC-mediated cell cycle arrest was accompanied with promotion of apoptosis, as indicated by the changes in the nuclear morphology and expressions of apoptosis-related proteins. SAMC clearly triggered the mitochondrial apoptotic pathway as indicated by activation of Bax, decreased expression of Bcl-2 and Bcl-X_L, and subsequent activation of caspase-9 and caspase-3.

Conclusion

These results highlight the value of a continued investigation into the use of SAMC as a potential antitumor candidate for breast cancer.

【 授权许可】

   
2014 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 5.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Saad ED: Endpoints in advanced breast cancer: methodological aspects & clinical implications. Indian J Med Res 2011, 134:413-418.
• [2]Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 2013, 63(1):11-30.
• [3]Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L: Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005, 11(16):5678-5685.
• [4]Badve S, Nakshatri H: Oestrogen-receptor-positive breast cancer: towards bridging histopathological and molecular classifications. J Clin Pathol 2009, 62(1):6-12.
• [5]Shen K, Rice SD, Gingrich DA, Wang D, Mi Z, Tian C, Ding Z, Brower SL, Ervin PR Jr, Gabrin MJ, Tseng G, Song N: Distinct genes related to drug response identified in ER positive and ER negative breast cancer cell lines. PloS one 2012, 7(7):e40900.
• [6]Andre F, Broglio K, Roche H, Martin M, Mackey JR, Penault-Llorca F, Hortobagyi GN, Pusztai L: Estrogen receptor expression and efficacy of docetaxel-containing adjuvant chemotherapy in patients with node-positive breast cancer: results from a pooled analysis. J Clin Oncol 2008, 26(16):2636-2643.
• [7]Cazzaniga M, Bonanni B: Breast cancer chemoprevention: old and new approaches. J Biomed Biotechnol 2012, 2012:985620.
• [8]Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y, Early Breast Cancer Trialists’ Collaborative G: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 366(9503):2087-2106.
• [9]Maughan KL, Lutterbie MA, Ham PS: Treatment of breast cancer. Am Fam Physician 2010, 81(11):1339-1346.
• [10]Fleischauer AT, Arab L: Garlic and cancer: a critical review of the epidemiologic literature. J Nutr 2001, 131(3s):1032S-1040S.
• [11]Chiu TH, Lan KY, Yang MD, Lin JJ, Hsia TC, Wu CT, Yang JS, Chueh FS, Chung JG: Diallyl sulfide promotes cell-cycle arrest through the p53 expression and triggers induction of apoptosis via caspase- and mitochondria-dependent signaling pathways in human cervical cancer Ca Ski cells. Nutr Cancer 2013, 65(3):505-514.
• [12]Lai KC, Kuo CL, Ho HC, Yang JS, Ma CY, Lu HF, Huang HY, Chueh FS, Yu CC, Chung JG: Diallyl sulfide, diallyl disulfide and diallyl trisulfide affect drug resistant gene expression in colo 205 human colon cancer cells in vitro and in vivo. Phytomedicine 2012, 19(7):625-630.
• [13]Miroddi M, Calapai F, Calapai G: Potential beneficial effects of garlic in oncohematology. Mini Rev Med Chem 2011, 11(6):461-472.
• [14]Wallace GC, Haar CP, Vandergrift WA 3rd, Giglio P, Dixon-Mah YN, Varma AK, Ray SK, Patel SJ, Banik NL, Das A: ulti-targeted DATS prevents tumor progression and promotes apoptosis in ectopic glioblastoma xenografts in SCID mice via HDAC inhibition. J Neurooncol 2013, 114(1):43-50.
• [15]Wu PP, Chung HW, Liu KC, Wu RS, Yang JS, Tang NY, Lo C, Hsia TC, Yu CC, Chueh FS, Lin SS, Chung JG: Diallyl sulfide induces cell cycle arrest and apoptosis in HeLa human cervical cancer cells through the p53, caspase- and mitochondria-dependent pathways. Inter J Oncol 2011, 38(6):1605-1613.
• [16]Howard EW, Ling MT, Chua CW, Cheung HW, Wang X, Wong YC: Garlic-derived S-allylmercaptocysteine is a novel in vivo antimetastatic agent for androgen-independent prostate cancer. Clin Cancer Res 2007, 13(6):1847-1856.
• [17]Hu H, Zhang XP, Wang YL, Chua CW, Luk SU, Wong YC, Ling MT, Wang XF, Xu KX: Identification of a novel function of Id-1 in mediating the anticancer responses of SAMC, a water-soluble garlic derivative, in human bladder cancer cells. Mol Med Rep 2011, 4(1):9-16.
• [18]Liang D, Qin Y, Zhao W, Zhai X, Guo Z, Wang R, Tong L, Lin L, Chen H, Wong YC, Zhong Z: S-allylmercaptocysteine effectively inhibits the proliferation of colorectal cancer cells under in vitro and in vivo conditions. Cancer lett 2011, 310(1):69-76.
• [19]Sigounas G, Hooker J, Anagnostou A, Steiner M: S-allylmercaptocysteine inhibits cell proliferation and reduces the viability of erythroleukemia, breast, and prostate cancer cell lines. Nutr Cancer 1997, 27(2):186-191.
• [20]Yan JY, Tian FM, Hu WN, Zhang JH, Cai HF, Li N: Apoptosis of human gastric cancer cells line SGC 7901 induced by garlic-derived compound S-allylmercaptocysteine (SAMC). Eur Rev Med Pharmacol Sci 2013, 17(6):745-751.
• [21]Li G, Qiao C, Lin R, Pinto J, Osborne M, Tiwari R: Antiproliferative effects of garlic constituents in cultured human breast-cancer cells. Oncol Rep 1995, 2(5):787-791.
• [22]Christian Starkenmann YN, Myriam T: Nonvolatile S-Alk(en)ylthio-L -cysteine Derivatives in Fresh Onion(Allium cepa L. Cultivar). J Agric Food Chem 2011, 59:9457-9465.
• [23]Rietman BH, Tesser GI, PRFR: A facile method for the preparation of S-(alkylsulfenyl) cysteines. Synth Commun 1994, 24(9):1323-1332.
• [24]Houghton P, Fang R, Techatanawat I, Steventon G, Hylands PJ, Lee CC: The sulphorhodamine (SRB) assay and other approaches to testing plant extracts and derived compounds for activities related to reputed anticancer activity. Methods 2007, 42(4):377-387.
• [25]Vermeulen K, Van Bockstaele DR, Berneman ZN: The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell prolif 2003, 36(3):131-149.
• [26]Schafer KA: The cell cycle: a review. Vet Pathol 1998, 35(6):461-478.
• [27]Gasco M, Shami S, Crook T: The p53 pathway in breast cancer. Breast Cancer Res 2002, 4(2):70-76. BioMed Central Full Text
• [28]Maga G, Hubscher U: Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci 2003, 116(Pt 15):3051-3060.
• [29]Kelman Z, O’Donnell M: Structural and functional similarities of prokaryotic and eukaryotic DNA polymerase sliding clamps. Nucleic Acids Res 1995, 23(18):3613-3620.
• [30]Wyman C, Botchan M: DNA replication. A familiar ring to DNA polymerase processivity. Curr Biol 1995, 5(4):334-337.
• [31]Mareel M, Leroy A: Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev 2003, 83(2):337-376.
• [32]Cohen GM: Caspases: the executioners of apoptosis. Biochem J 1997, 326(Pt 1):1-16.
• [33]Hengartner M: Apoptosis. Death by crowd control. Science 1998, 281(5381):1298-1299.
• [34]Newman DJ, Cragg GM: Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007, 70(3):461-477.
• [35]Fulda S, Debatin KM: Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 2006, 25(34):4798-4811.
• [36]Kroemer G, Reed JC: Mitochondrial control of cell death. Nat Med 2000, 6(5):513-519.
• [37]Gross A, McDonnell JM, Korsmeyer SJ: BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999, 13(15):1899-1911.
• [38]Nagata S: Apoptosis by death factor. Cell 1997, 88(3):355-365.
• [39]Wells A, Yates C, Shepard CR: E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 2008, 25(6):621-628.
• [40]Nass SJ, Herman JG, Gabrielson E, Iversen PW, Parl FF, Davidson NE, Graff JR: Aberrant methylation of the estrogen receptor and E-cadherin 5′ CpG islands increases with malignant progression in human breast cancer. Cancer Res 2000, 60(16):4346-4348.