A potential estrogen receptor inhibitor compound 34 induces apoptosis via ROS-independent intrinsic apoptosis in MCF-7 cells
This study aimed to investigate the anti-tumor effects of compound 34 on MCF-7 cells in vitro, and explore its mechanisms. MTT results showed that compound 34 selectively inhibited estrogen receptor-positive cells proliferation. Hoechst 33342 staining showed nuclear pyknosis, nuclear debris associated with apoptotic bodies. JC-1 staining showed the loss of mitochondrial membrane potential. Although compound 34 increased intracellular reactive oxygen species (ROS), compound 34-induced apoptosis was not prevented by pretreatment with ROS scavengers. Western blotting showed apoptosis-related protein like cytochrome c and cleaved PARP protein increased. Furthermore, docking studies exhibited that compound 34 could bind into ERα. In summary, compound 34 selectively inhibited estrogen receptor positive cells proliferation and induced apoptosis in MCF-7 cells via ROS-independent intrinsic apoptosis in MCF-7 cells. It may be a potential targeted drug of estrogen receptor for therapeutic application of breast cancer.
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Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the surveillance, epidemiology, and end results database. Breast Cancer Res Tr. 2002; 76: 27-36.
Ariazi EA, Jordan VC. Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem. 2006; 6: 181-202.
Ascenzi P, Bocedi A, Marino M. Structure-function relationship of estrogen receptor α and β: Impact on human health. Mol Aspects Med. 2006; 27: 299-402.
Bahuguna A, Khan I, Bajpai V, Kang S. MTT assay to evaluate the cytotoxic potential of a drug. Bangladesh J Pharma-col. 2017; 12: 115-18.
Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS. Phenol red in tissue culture media is a weak estrogen: Implications concerning the study of estrogen-responsive cells in culture. P Natl Acad Sci USA. 1986; 83: 2496-500.
Bolton JL, Dunlap T. Formation and biological targets of quinones: Cytotoxic versus cytoprotective effects. Chem Res Toxicol. 2017; 30: 13-37.
Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev. 2014; 40: 862-71.
Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metast Rev. 2006; 25: 9-34.
Dowers TS, Qin ZH, Thatcher GRJ, Bolton JL. Bioactivation of Selective Estrogen Receptor Modulators (SERMs). Chem Res Toxicol. 2006; 19: 1125-37.
Helguero LA, Faulds MH, Gustafsson JA, Haldosen LA. Estrogen receptors alfa (ERalpha) and beta (ERbeta) differen-tially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11. Oncogene 2005; 24: 6605-16.
Hsin KY, Matsuoka Y, Asai Y, Kamiyoshi K, Watanabe T, Kawaoka Y, Kitano H. systemsDock: A web server for network pharmacology-based prediction and analysis. Nucleic Acids Res. 2016; 44: W507-13.
Jordan VC. Third annual William L. McGuire Memorial Lecture. "Studies on the estrogen receptor in breast cancer"--20 years as a target for the treatment and prevention of cancer. Breast Cancer Res Tr. 1995; 36: 267-85.
Jordan VC. Tamoxifen: A most unlikely pioneering medicine. Nat Rev Drug Discov. 2003; 2: 205-13.
Kou N, Cho H, Kim HE, Sun Q, Ahn K, Ji H, Choi H, Kim O. Anti-cancer effect of Atractylodes macrocephala extract by double induction of apoptotic and autophagic cell death in head and neck cancer cells. Bangladesh J Pharmacol. 2017; 12: 140-146.
Li K, Wang B, Zheng L, Yang K, Li Y, Hu M, He D. Target ROS to induce apoptosis and cell cycle arrest by 5,7-dimethoxy-1,4-naphthoquinone derivative. Bioorg Med Chem Lett. 2017; 28: 273-77.
Li Q, Zhao XL, Sun J, Jiang SG, Gong XF. Anti-proliferative and apoptosis-inducing activities of juglone in LS-174T cells. Bangladesh J Pharmacol. 2013; 8: 65-72.
Liu C, Shen GN, Luo YH, Piao XJ, Jiang XY, Meng LQ, Wang Y, Zhang Y, Wang JR, Wang H, Xu WT, Li JQ, Liu Y, Wu YQ, Sun HN, Han YH, Jin MH, Cui YD, Fang NZ, Jin CH. Novel 1,4-naphthoquinone derivatives induce apoptosis via ROS-mediated p38/MAPK, Akt and STAT3 signaling in human hepatoma Hep3B cells. Int J Biochem Cell Biol. 2018; 96: 9-19.
Liu J, Liu H, Breemen RBV, Thatcher GRJ, Bolton JL. Bio-activation of the selective estrogen receptor modulator acolbifene to quinone methides. Chem Res Toxicol. 2005; 18: 174-82.
Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, Yelensky R, Brown M, Miller VA, Sarid D, Rizel S, Klein B, Rubinek T, Wolf I. D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013; 73: 6856-64.
Novais JS, Moreira CS, Silva ACJA, Loureiro RS, Figueiredo AMS, Ferreira VF, Castro HC, da Rocha DR. Antibacterial naphthoquinone derivatives targeting resistant strain Gram-negative bacteria in biofilms. Microb Pathogenesis. 2018; 118: 105-14.
Rasul A, Bao R, Malhi M, Zhao B, Tsuji I, Li J, Li X. Induction of apoptosis by costunolide in bladder cancer cells is mediated through ROS generation and mitochondrial dysfunction. Molecules 2013; 18: 1418-33.
Rasul A, Ding C, Li X, Khan M, Yi F, Ali M, Ma T. Dracorhodin perchlorate inhibits PI3K/Akt and NF-kappaB activation, up-regulates the expression of p53, and enhances apoptosis. Apoptosis 2012a; 17: 1104-19.
Renoir JM, Marsaud V, Lazennec G. Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem Pharmacol. 2013; 85: 449-65.
Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L, Gursky A, Siddiqui J, Tomlins SA, Roychowdhury S, Pienta KJ, Kim SY, Roberts JS, Rae JM, Poznak CHV, Hayes DF, Chugh R, Kunju LP, Talpaz M, Schott AF, Chinnaiyan AM. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013; 45: 1446.
Si L, Yan X, Hao W, Ma X, Ren H, Ren B, Li D, Dong Z, Zheng Q. Licochalcone D induces apoptosis and inhibits migration and invasion in human melanoma A375 cells. Oncol Rep. 2018; 39: 2160-70.
Skulachev VP. Bioenergetic aspects of apoptosis, necrosis and mitoptosis. Apoptosis 2006; 11: 473-85.
Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA, Hudis C, Chen D, Taran T, Hortobagyi G, Greene G, Berger M, Baselga J, Chandarlapaty S. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013; 45: 1439.
Welshons WV, Jordan VC. Adaptation of estrogen-dependent MCF-7 cells to low estrogen (phenol red-free) culture. Eur J Cancer Clin Oncol. 1987; 23: 1935-39.
Yee C, Yang W, Hekimi S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell. 2014; 157: 897-909.
Yu L, Liu H, Li W, Zhang F, Luckie C, van Breemen RB, Thatcher GRJ, Bolton JL. Oxidation of raloxifene to quinoids: Potential toxic pathways via a diquinone methide and o-quinones. Chem Res Toxicol. 2004; 17: 879-88.
Zhivetyeva SI, Zakharova OD, Ovchinnikova LP, Baev DS, Bagryanskaya IY, Shteingarts VD, Tolstikova TG, Nevinsky GA, Tretyakov EV. Phosphonium betaines derived from hexafluoro-1,4-naphthoquinone: Synthesis and cytotoxic and anti-oxidant activities. J Fluorine Chem. 2016; 192: 68-77.
Zhong S, Mackerell AD. Binding response: A descriptor for selecting ligand binding site on protein surfaces. J Chem Inf Model. 2007; 47: 2303-15.
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