Naciye Dilara ZEYBEK, Sevda MÜFTÜOĞLU, Tuğba ALARCON MARTİNEZ

Evaluation of the Cytotoxic and Autophagic Effects of Atorvastatin on MCF-7 Breast Cancer Cells

Background: Recently, cytotoxic effects of statins on breastcancer cells have been reported. However, the mechanism of antiproliferativeeffects is currently unknown. Autophagy is non-apoptoticprogrammed cell death, which is characterized by degradation ofcytoplasmic components and as having a role in cancer pathogenesis.Aims: To investigate the anti-proliferative effects of atorvastatinon MCF-7 human breast adenocarcinoma cells with respect to bothautophagy and apoptosis.Study Design: Cell culture study.Methods: Cell viability was analyzed using WST-1 cell proliferationassay. Apoptosis was determined by the TUNEL method, whereasautophagy was assessed by Beclin-1 and LC3B immunofluorescencestaining. Ultrastructural analysis of cells was performed by electronmicroscopy.Results: Atorvastatin reduced MCF-7 cell proliferation in a dose- andtime-dependent manner inducing TUNEL-, Beclin-1-, and LC3Bpositivecells. Moreover, ultrastructural analysis showed apoptotic,autophagic, and necrotic morphological changes in treatment groups.A statistically significant increase in the apoptotic index was detectedwith higher concentrations of atorvastatin at 24 h and 48 h (p

PDF

___

Bjarnadottir O, Kimbung S, Johansson I, Veerla S, Jönsson M, Bendahl PO, et al. Global Transcriptional Changes Following Statin Treatment in Breast Cancer. Clin Cancer Res 2015;21:3402-11
Denoyelle C, Vasse M, Körner M, Mishal Z, Ganné F, Vannier JP, et al. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis 2001;22:1139-48.
Sane KM, Mynderse M, Lalonde DT, Dean IS, Wojtkowiak JW, Fouad F, et al. A novel geranylgeranyl transferase inhibitor in combination with lovastatin inhibits proliferation and induces autophagy in STS-26T MPNST cells. J Pharmacol Exp Ther 2010;333:23-33.
Campbell MJ, Esserman LJ, Zhou Y, Shoemaker M, Lobo M, Borman E, et al. Breast cancer growth prevention by statins. Cancer Res 2006;66:8707-14.
Kang S, Kim ES, Moon A. Simvastatin and lovastatin inhibit breast cell invasion induced by H-Ras. Oncol Rep 2009;21:1317-22.
Ji Y, Rounds T, Crocker A, Sussman B, Hovey RC, Kingsley F, et al. The Effect of Atorvastatin on Breast Cancer Biomarkers in High-Risk Women. Cancer Prev Res (Phila) 2016;9:379-84.
Cardwell CR, Hicks BM, Hughes C, Murray LJ. Statin use after diagnosis of breast cancer and survival: a population-based cohort study. Epidemiol 2015;26:68-78.
Boudreau DM, Yu O, Miglioretti DL, Buist DS, Heckbert SR, Daling JR. Statin use and breast cancer risk in a large population-based setting. Cancer Epidemiol Biomarkers Prev 2007;16:416-21.
Hawk MA, Cesen KT, Siglin JC, Stoner GD, Ruch RJ. Inhibition of lung tumor cell growth in vitro and mouse lung tumor formation by lovastatin. Cancer Lett 1996;109:217-22.
Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo H, et al. 3-hydroxy3-methylglutaryl-coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis. Gastroenterology 2002;122:308-17.
Park YH, Jung HH, Ahn JS, Im YH. Statin induces inhibition of triple negative breast cancer (TNBC) cells via PI3K pathway. Biochem Biophys Res Commun 2013;439:275-9.
Zeybek ND, Inan S, Ekerbicer N, Vatansever HS, Karakaya J, Muftuoglu SF. The effects of Gemcitabine and Vinorelbine on inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) distribution of MCF-7 breast cancer cells. Acta Histochem 2011;113:62-7.
Küçükkaya S, Görduysus MÖ, Zeybek ND, Müftüoğlu SF. In Vitro Cytotoxicity of Calcium Silicate-Based Endodontic Cement as Root-End Filling Materials. Scientifica (Cairo) 2016;2016:9203932.
Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res 2010;70:7699-709.
Parikh A, Childress C, Deitrick K, Lin Q, Rukstalis D, Yang W. Statin-induced autophagy by inhibition of geranylgeranyl biosynthesis in prostate cancer PC3 cells. Prostate 2010;70:971-81.
Hippert MM, O’Toole PS, Thorburn A. Autophagy in cancer: good, bad, or both? Cancer Res 2006;66: 9349-51.
Qi P, He Z, Zhang L, Fan Y, Wang Z Rottlerin-induced autophagy leads to apoptosis in bladder cancer cells. Oncol Lett 2016;12:4577-83.
He Z, Yuan J, Qi P, Zhang L, Wang Z. Atorvastatin induces autophagic cell death in prostate cancer cells in vitro. Mol Med Rep 2015;11:4403-8.
Gozuacik D, Kimchi A. Autophagy and cell death. Curr Top Dev Biol 2007;78:217- 45.
Gao Y, Lu XC, Yang HY, Liu XF, Cao J, Fan L. The molecular mechanism of the anticancer effect of atorvastatin: DNA microarray and bioinformatic analyses. Int J Mol Med 2012;30:765-74.
Sánchez CA, Rodríguez E, Varela E, Zapata E, Páez A, Massó FA, et al. Statininduced inhibition of MCF-7 breast cancer cell proliferation is related to cell cycle arrest and apoptotic and necrotic cell death mediated by an enhanced oxidative stress. Cancer Invest 2008;26:698-707.
Chan KK, Oza AM, Siu LL. The statins as anticancer agents. Clin Cancer Res 2003;9:10-9.
Pisanti S, Picardi P, Ciaglia E, D’Alessandro A, Bifulco M. Novel prospects of statins as therapeutic agents in cancer. Pharmacol Res 2014;88:84-98.
Alegret M, Silvestre JS. Pleiotropic effects of statins and related pharmacological experimental approaches. Methods Find Exp Clin Pharmacol 2006;28:627-56.
Zeybek ND, Gulcelik NE, Kaymaz FF, Sarisozen C, Vural I, Bodur E, et al. Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells. J Endocrinol 2011;210:105-15.
Austreid E, Lonning PE, Eikesdal HP. The emergence of targeted drugs in breast cancer to prevent resistance to endocrine treatment and chemotherapy. Expert Opin Pharmacother 2014;15:681-700.
World Health Organization. Breast Cancer. http://www.who.int/cancer/prevention/ diagnosis-screening/breast-cancer/en/.