Fulvestrant reverses doxorubicin resistance in multidrug-resistant breast cell lines independent of estrogen receptor expression

Huang,Yuan; Jiang,Donghai; Sui,Meihua; Wang,Xiaojia; Fan,Weimin

doi:10.3892/or.2016.5315

Fulvestrant reverses doxorubicin resistance in multidrug-resistant breast cell lines independent of estrogen receptor expression

Authors:
- Yuan Huang
- Donghai Jiang
- Meihua Sui
- Xiaojia Wang
- Weimin Fan
View Affiliations

Affiliations: Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China, Program of Innovative Cancer Therapeutics, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Afﬁliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China, Center for Cancer Biology and Innovative Therapeutics, Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
Published online on: December 14, 2016 https://doi.org/10.3892/or.2016.5315
Pages: 705-712
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Drug resistance, a major obstacle to successful cancer chemotherapy, frequently occurs in recurrent or metastatic breast cancer and results in poor clinical response. Fulvestrant is a new type of selective estrogen receptor (ER) downregulator and a promising endocrine therapy for breast cancer. In this study, we evaluated the combination treatment of fulvestrant and doxorubicin in ER-negative multidrug-resistant (MDR) breast cancer cell lines Bads‑200 and Bats‑72. Fulvestrant potentiated doxorubicin-induced cytotoxicity, apoptosis and G2/M arrest with upregulation of cyclin B1. It functioned as a substrate for P-glycoprotein (P-gp) without affecting its expression. Furthermore, fulvestrant not only restored the intracellular accumulation of doxorubicin but also relocalized it to the nuclei in Bats‑72 and Bads‑200 cells, which may be another potential mechanism of reversal of P-gp mediated doxorubicin resistance. These results indicated that the combination of fulvestrant and doxorubicin-based chemotherapy may be feasible and effective for patients with advanced breast cancer.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	McGuire WL, Horwitz KB, Pearson OH and Segaloff A: Current status of estrogen and progesterone receptors in breast cancer. Cancer. 39:(Suppl). S2934–S2947. 1977. View Article : Google Scholar
3	Dickson RB and Lippman ME: Estrogenic regulation of growth and polypeptide growth factor secretion in human breast carcinoma. Endocr Rev. 8:29–43. 1987. View Article : Google Scholar : PubMed/NCBI
4	Kuukasjärvi T, Kononen J, Helin H, Holli K and Isola J: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol. 14:2584–2589. 1996.PubMed/NCBI
5	Lück HJ and Roché H: Weekly paclitaxel: An effective and well-tolerated treatment in patients with advanced breast cancer. Crit Rev Oncol Hematol. 44:(Suppl). S15–S30. 2002. View Article : Google Scholar : PubMed/NCBI
6	Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK and Wood WC: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An intergroup trial (E1193). J Clin Oncol. 21:588–592. 2003. View Article : Google Scholar : PubMed/NCBI
7	Andre F and Pusztai L: Molecular classification of breast cancer: Implications for selection of adjuvant chemotherapy. Nat Clin Pract Oncol. 3:621–632. 2006. View Article : Google Scholar : PubMed/NCBI
8	Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI
9	Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, et al: Arimidex Study Group: Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: Results of overview analysis of two phase III trials. J Clin Oncol. 14:2000–2011. 1996.PubMed/NCBI
10	Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 16:453–461. 1998.PubMed/NCBI
11	Lønning PE, Bajetta E, Murray R, Tubiana-Hulin M, Eisenberg PD, Mickiewicz E, Celio L, Pitt P, Mita M, Aaronson NK, et al: Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol. 18:2234–2244. 2000.PubMed/NCBI
12	Vergote I and Robertson JF: Fulvestrant is an effective and well-tolerated endocrine therapy for postmenopausal women with advanced breast cancer: Results from clinical trials. Br J Cancer. 90:(Suppl 1). S11–S14. 2004. View Article : Google Scholar : PubMed/NCBI
13	Dowsett M, Nicholson RI and Pietras RJ: Biological characteristics of the pure antiestrogen fulvestrant: Overcoming endocrine resistance. Breast Cancer Res Treat. 93:(Suppl 1). S11–S18. 2005. View Article : Google Scholar : PubMed/NCBI
14	Osborne CK, Wakeling A and Nicholson RI: Fulvestrant: An oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer. 90:(Suppl 1). S2–S6. 2004. View Article : Google Scholar : PubMed/NCBI
15	Howell A: The future of fulvestrant (‘Faslodex’). Cancer Treat Rev. 31:(Suppl 2). S26–S33. 2005. View Article : Google Scholar : PubMed/NCBI
16	Shen H, Liu J, Wang R, Qian X, Xu R, Xu T, Li Q, Wang L, Shi Z, Zheng J, et al: Fulvestrant increases gefitinib sensitivity in non-small cell lung cancer cells by upregulating let-7c expression. Biomed Pharmacother. 68:307–313. 2014. View Article : Google Scholar : PubMed/NCBI
17	Sui M, Huang Y, Park BH, Davidson NE and Fan W: Estrogen receptor alpha mediates breast cancer cell resistance to paclitaxel through inhibition of apoptotic cell death. Cancer Res. 67:5337–5344. 2007. View Article : Google Scholar : PubMed/NCBI
18	Sui M, Jiang D, Hinsch C and Fan W: Fulvestrant (ICI 182,780) sensitizes breast cancer cells expressing estrogen receptor alpha to vinblastine and vinorelbine. Breast Cancer Res Treat. 121:335–345. 2010. View Article : Google Scholar : PubMed/NCBI
19	Chang J, Sui M and Fan W: Estrogen receptor α attenuates therapeutic efficacy of paclitaxel on breast xenograft tumors. Breast Cancer Res Treat. 134:969–980. 2012. View Article : Google Scholar : PubMed/NCBI
20	Jiang D, Sui M, Zhong W, Huang Y and Fan W: Different administration strategies with paclitaxel induce distinct phenotypes of multidrug resistance in breast cancer cells. Cancer Lett. 335:404–411. 2013. View Article : Google Scholar : PubMed/NCBI
21	Roepe PD: The P-glycoprotein efflux pump: How does it transport drugs? J Membr Biol. 166:71–73. 1998. View Article : Google Scholar : PubMed/NCBI
22	Sauna ZE, Kim IW and Ambudkar SV: Genomics and the mechanism of P-glycoprotein (ABCB1). J Bioenerg Biomembr. 39:481–487. 2007. View Article : Google Scholar : PubMed/NCBI
23	Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE and Gottesman MM: P-glycoprotein: from genomics tomechanism. Oncogene. 22:7468–7485. 2003. View Article : Google Scholar : PubMed/NCBI
24	Jiang D, Huang Y, Han N, Xu M, Xu L, Zhou L, Wang S and Fan W: Fulvestrant, a selective estrogen receptor down-regulator, sensitizes estrogen receptor negative breast tumors to chemotherapy. Cancer Lett. 346:292–299. 2014. View Article : Google Scholar : PubMed/NCBI
25	Zhu X, Sui M and Fan W: In vitro and in vivo characterizations of tetrandrine on the reversal of P-glycoprotein-mediated drug resistance to paclitaxel. Anticancer Res 25B. 1953–1962. 2005.
26	Duan Z, Choy E and Hornicek FJ: NSC23925, identified in a high-throughput cell-based screen, reverses multidrug resistance. PLoS One. 4:e74152009. View Article : Google Scholar : PubMed/NCBI
27	Ren D, Zhu Q, Li J, Ha T, Wang X and Li Y: Overexpression of angiopoietin-1 reduces doxorubicin-induced apoptosis in cardiomyocytes. J Biomed Res. 26:432–438. 2012. View Article : Google Scholar : PubMed/NCBI
28	Rebbaa A, Zheng X, Chou PM and Mirkin BL: Caspase inhibition switches doxorubicin-induced apoptosis to senescence. Oncogene. 22:2805–2811. 2003. View Article : Google Scholar : PubMed/NCBI
29	Zuryń A, Litwiniec A, Gackowska L, Pawlik A, Grzanka AA and Grzanka A: Expression of cyclin A, B1 and D1 after induction of cell cycle arrest in the Jurkat cell line exposed to doxorubicin. Cell Biol Int. 36:1129–1135. 2012. View Article : Google Scholar : PubMed/NCBI
30	Hu R, Hilakivi-Clarke L and Clarke R: Molecular mechanisms of tamoxifen-associated endometrial cancer (Review). Oncol Lett. 9:1495–1501. 2015.PubMed/NCBI
31	Min CR, Kim MJ, Park YJ, Kim HR, Lee SY, Chung KH and Oh SM: Estrogenic effects and their action mechanism of the major active components of party pill drugs. Toxicol Lett. 214:339–347. 2012. View Article : Google Scholar : PubMed/NCBI
32	Iqbal J, Ginsburg OM, Wijeratne TD, Howell A, Evans G, Sestak I and Narod SA: Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: A systematic review. Cancer Treat Rev. 38:318–328. 2012. View Article : Google Scholar : PubMed/NCBI
33	Feng R and Dong L: Knockdown of microRNA-127 reverses adriamycin resistance via cell cycle arrest and apoptosis sensitization in adriamycin-resistant human glioma cells. Int J Clin Exp Pathol. 8:6107–6116. 2015.PubMed/NCBI
34	Efferth T, Fabry U and Osieka R: Apoptosis and resistance to daunorubicin in human leukemic cells. Leukemia. 11:1180–1186. 1997. View Article : Google Scholar : PubMed/NCBI
35	De U, Chun P, Choi WS, Lee BM, Kim ND, Moon HR, Jung JH and Kim HS: A novel anthracene derivative, MHY412, induces apoptosis in doxorubicin-resistant MCF-7/Adr human breast cancer cells through cell cycle arrest and downregulation of P-glycoprotein expression. Int J Oncol. 44:167–176. 2014.PubMed/NCBI
36	Kelly PN and Strasser A: The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 18:1414–1424. 2011. View Article : Google Scholar : PubMed/NCBI
37	Llambi F and Green DR: Apoptosis and oncogenesis: Give and take in the BCL-2 family. Curr Opin Genet Dev. 21:12–20. 2011. View Article : Google Scholar : PubMed/NCBI
38	Bodley A, Liu LF, Israel M, Seshadri R, Koseki Y, Giuliani FC, Kirschenbaum S, Silber R and Potmesil M: DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA. Cancer Res. 49:5969–5978. 1989.PubMed/NCBI
39	Cirilli M, Bachechi F, Ughetto G, Colonna FP and Capobianco ML: Interactions between morpholinyl anthracyclines and DNA. The crystal structure of a morpholino doxorubicin bound to d(CGTACG). J Mol Biol. 230:878–889. 1993. View Article : Google Scholar : PubMed/NCBI
40	Kellogg GE, Scarsdale JN and Fornari FA Jr: Identification and hydropathic characterization of structural features affecting sequence specificity for doxorubicin intercalation into DNA double-stranded polynucleotides. Nucleic Acids Res. 26:4721–4732. 1998. View Article : Google Scholar : PubMed/NCBI