Synergistic cytotoxic effect of genistein and doxorubicin on drug-resistant human breast cancer MCF-7/Adr cells

Xue,Jia-Peng; Wang,Geng; Zhao,Zong-Bin; Wang,Qun; Shi,Yun

doi:10.3892/or.2014.3365

Synergistic cytotoxic effect of genistein and doxorubicin on drug-resistant human breast cancer MCF-7/Adr cells

Authors:
- Jia-Peng Xue
- Geng Wang
- Zong-Bin Zhao
- Qun Wang
- Yun Shi
View Affiliations

Affiliations: Department of Endocrine and Vascular Surgery, Taihe Hospital, Hubei Medical College, Shiyan, Hubei 442000, P.R. China
Published online on: July 29, 2014 https://doi.org/10.3892/or.2014.3365
Pages: 1647-1653

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The molecular mechanisms underlying genistein-mediated reversal of chemoresistance remains unknown. In the present study, we investigated the molecular mechanisms by which genistein overcomes chemoresistance and its effect on doxorubicin-induced cytotoxicity. Consistent with previous reports, genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells, and genistein reduced the chemoresistance of these cells. Genistein treatment increased the intracellular accumulation of doxorubicin but did not influence P-gp function. The combination of genistein and doxorubicin significantly induced cell cycle arrest and apoptosis. Genistein treatment strongly inhibited HER2/neu but not MDR-1 expression at both the mRNA and protein levels. Therefore, our results demonstrated that genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells, and the mechanisms likely involve an increase in the intracellular accumulation of doxorubicin and suppression of HER2/neu expression.

View Figures

View References

1	Trapé AP and Gonzalez-Angulo AM: Breast cancer and metastasis: on the way toward individualized therapy. Cancer Genomics Proteomics. 9:297–310. 2012.PubMed/NCBI
2	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar
3	Harbeck N: Never too late: reducing late breast cancer relapse risk. Curr Med Res Opin. 24:3295–3305. 2008. View Article : Google Scholar : PubMed/NCBI
4	Simstein R, Burow M, Parker A, Weldon C and Beckman B: Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system. Exp Biol Med. 228:995–1003. 2003.PubMed/NCBI
5	Payne KK and Manjili MH: Adaptive immune responses associated with breast cancer relapse. Arch Immunol Ther Exp. 60:345–350. 2012. View Article : Google Scholar : PubMed/NCBI
6	Joerger M and Thürlimann B: Chemotherapy regimens in early breast cancer: major controversies and future outlook. Expert Rev Anticancer Ther. 13:165–178. 2013. View Article : Google Scholar : PubMed/NCBI
7	Redden MH and Fuhrman GM: Neoadjuvant chemotherapy in the treatment of breast cancer. Surg Clin North Am. 93:493–499. 2013. View Article : Google Scholar : PubMed/NCBI
8	Fuksa L, Micuda S, Grim J, Ryska A and Hornychova H: Predictive biomarkers in breast cancer: their value in neoadjuvant chemotherapy. Cancer Invest. 30:663–678. 2012. View Article : Google Scholar : PubMed/NCBI
9	Weiss RB: The anthracyclines: will we ever find a better doxorubicin? Semin Oncol. 19:670–686. 1992.PubMed/NCBI
10	Prados J, Melguizo C, Ortiz R, et al: Doxorubicin-loaded nanoparticles: new advances in breast cancer therapy. Anticancer Agents Med Chem. 12:1058–1070. 2012. View Article : Google Scholar : PubMed/NCBI
11	Brunello A, Roma A, Falci C and Basso U: Chemotherapy and targeted agents for elderly women with advanced breast cancer. Recent Pat Anticancer Drug Discov. 3:187–201. 2008. View Article : Google Scholar : PubMed/NCBI
12	Alm El-Din MA, El-Badawy SA and Taghian AG: Breast cancer after treatment of Hodgkin’s lymphoma: general review. Int J Radiat Oncol Biol Phys. 72:1291–1297. 2008.
13	Khalil MY, Mapa M, Shin HJ and Shin DM: Advances in the management of malignant mesothelioma. Curr Oncol Rep. 5:334–341. 2003. View Article : Google Scholar : PubMed/NCBI
14	Giai M, Biglia N and Sismondi P: Chemoresistance in breast tumors. Eur J Gynaecol Oncol. 12:359–373. 1991.
15	Sakamoto T, Horiguchi H, Oguma E and Kayama F: Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. J Nutr Biochem. 21:856–864. 2010. View Article : Google Scholar : PubMed/NCBI
16	de Lemos ML: Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann Pharmacother. 35:1118–1121. 2001.PubMed/NCBI
17	Usui T: Pharmaceutical prospects of phytoestrogens. Endocr J. 53:7–20. 2006. View Article : Google Scholar : PubMed/NCBI
18	Sarkar FH, Adsule S, Padhye S, Kulkarni S and Li Y: The role of genistein and synthetic derivatives of isoflavone in cancer prevention and therapy. Mini Rev Med Chem. 6:401–407. 2006. View Article : Google Scholar : PubMed/NCBI
19	Ravindranath MH, Muthugounder S, Presser N and Viswanathan S: Anticancer therapeutic potential of soy isoflavone, genistein. Adv Exp Med Biol. 546:121–165. 2004. View Article : Google Scholar : PubMed/NCBI
20	Kanagasabai R, Krishnamurthy K, Druhan LJ and Ilangovan G: Forced expression of heat shock protein 27 (Hsp27) reverses P-glycoprotein (ABCB1)-mediated drug efflux and MDR1 gene expression in adriamycin-resistant human breast cancer cells. J Biol Chem. 286:33289–33300. 2011. View Article : Google Scholar : PubMed/NCBI
21	Lu L, Zhou D, Jiang X, Song K, Li K and Ding W: Loss of E-cadherin in multidrug resistant breast cancer cell line MCF-7/ Adr: possible implication in the enhanced invasive ability. Eur Rev Med Pharmacol Sci. 16:1271–1279. 2012.PubMed/NCBI
22	Zhang HC, Zhang F, Wu B, et al: Identification of the interaction between P-glycoprotein and Anxa2 in multidrug-resistant human breast cancer cells. Cancer Biol Med. 9:99–104. 2012.PubMed/NCBI
23	Gampenrieder SP, Rinnerthaler G and Greil R: Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future. J Oncol. 2013:7320472013. View Article : Google Scholar : PubMed/NCBI
24	Steward WP and Brown K: Cancer chemoprevention: a rapidly evolving field. Br J Cancer. 109:1–7. 2013. View Article : Google Scholar : PubMed/NCBI
25	Bartlett J, Canney P, Campbell A, et al: Selecting breast cancer patients for chemotherapy: the opening of the UK OPTIMA trial. Clin Oncol. 25:109–116. 2013. View Article : Google Scholar : PubMed/NCBI
26	Loo TW and Clarke DM: Location of the rhodamine-binding site in the human multidrug resistance P-glycoprotein. J Biol Chem. 277:44332–44338. 2002. View Article : Google Scholar : PubMed/NCBI
27	Ruefli AA, Tainton KM, Darcy PK, Smyth MJ and Johnstone RW: P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation. Cell Death Differ. 9:1266–1272. 2002. View Article : Google Scholar : PubMed/NCBI
28	Menard S, Pupa SM, Campiglio M and Tagliabue E: Biologic and therapeutic role of HER2 in cancer. Oncogene. 22:6570–6578. 2003. View Article : Google Scholar : PubMed/NCBI
29	Banerjee S, Li Y, Wang Z and Sarkar FH: Multi-targeted therapy of cancer by genistein. Cancer Lett. 269:226–242. 2008. View Article : Google Scholar : PubMed/NCBI
30	Tarkowski M, Kokocinska M and Latocha M: Genistein in chemoprevention and treatment. Pol Merkur Lekarski. 34:54–57. 2013.(In Polish).
31	Swami S, Krishnan AV, Peehl DM and Feldman D: Genistein potentiates the growth inhibitory effects of 1,25-dihydroxyvitamin D3 in DU145 human prostate cancer cells: role of the direct inhibition of CYP24 enzyme activity. Mol Cell Endocrinol. 241:49–61. 2005. View Article : Google Scholar
32	Yu Z, Tang Y, Hu D and Li J: Inhibitory effect of genistein on mouse colon cancer MC-26 cells involved TGF-beta1/Smad pathway. Biochem Biophys Res Commun. 333:827–832. 2005. View Article : Google Scholar : PubMed/NCBI
33	Pabona JM, Dave B, Su Y, et al: The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein. Genes Nutr. 8:79–90. 2013. View Article : Google Scholar
34	Zhu H, Cheng H, Ren Y, Liu ZG, Zhang YF and De Luo B: Synergistic inhibitory effects by the combination of gefitinib and genistein on NSCLC with acquired drug-resistance in vitro and in vivo. Mol Biol Rep. 39:4971–4979. 2012. View Article : Google Scholar : PubMed/NCBI
35	Tacar O, Sriamornsak P and Dass CR: Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol. 65:157–170. 2013. View Article : Google Scholar : PubMed/NCBI
36	Liu Y, Du F, Chen W, Yao M, Lv K and Fu P: Knockdown of dual specificity phosphatase 4 enhances the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin. Exp Cell Res. 319:3140–3149. 2013. View Article : Google Scholar : PubMed/NCBI
37	Shi R, Peng H, Yuan X, et al: Down-regulation of c-fos by shRNA sensitizes adriamycin-resistant MCF-7/ADR cells to chemotherapeutic agents via P-glycoprotein inhibition and apoptosis augmentation. J Cell Biochem. 114:1890–1900. 2013. View Article : Google Scholar : PubMed/NCBI
38	Coussens L, Yang-Feng TL, Liao YC, et al: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 230:1132–1139. 1985. View Article : Google Scholar : PubMed/NCBI
39	Harari D and Yarden Y: Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene. 19:6102–6114. 2000. View Article : Google Scholar : PubMed/NCBI
40	Seo HS, Choi HS, Choi HS, et al: Phytoestrogens induce apoptosis via extrinsic pathway, inhibiting nuclear factor-kappaB signaling in HER2-overexpressing breast cancer cells. Anticancer Res. 31:3301–3313. 2011.PubMed/NCBI
41	Choi EJ and Kim GH: Antiproliferative activity of daidzein and genistein may be related to ERα/c-erbB-2 expression in human breast cancer cells. Mol Med Rep. 7:781–784. 2013.PubMed/NCBI
42	Mai Z, Blackburn GL and Zhou JR: Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells. Mol Carcinog. 46:534–542. 2007. View Article : Google Scholar : PubMed/NCBI