A771726, an anti-inflammatory drug, exerts an anticancer effect and reverses tamoxifen resistance in endocrine‑resistant breast cancer cells

Huang,Ou; Xie,Zuoquan; Zhang,Weili; Lou,Ying; Mao,Yan; Liu,Hongchun; Jiang,Min; Shen,Kunwei

doi:10.3892/or.2014.3249

A771726, an anti-inflammatory drug, exerts an anticancer effect and reverses tamoxifen resistance in endocrine‑resistant breast cancer cells

Authors:
- Ou Huang
- Zuoquan Xie
- Weili Zhang
- Ying Lou
- Yan Mao
- Hongchun Liu
- Min Jiang
- Kunwei Shen
View Affiliations

Affiliations: Comprehensive Breast Health Centre, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China, Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China, Department of Gastroenterology, Xiangcheng People's Hospital, Suzhou, Jiangsu 215131, P.R. China, Department of Breast Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
Published online on: June 12, 2014 https://doi.org/10.3892/or.2014.3249
Pages: 627-634

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

A771726, an orally available anti-inflammatory agent, has been approved for the treatment of multiple sclerosis by diminishing entire inflammatory responses through multiple signaling pathways. Recently, a few emerging studies have focused on the potential application of A771726 in cancer therapy, less on the treatment of breast cancer and particularly on overcoming drug resistance in breast cancer. We report here for the first time the cytotoxic activity and drug resistance reversal of A771726 in acquired tamoxifen-resistant breast cancer cell line MCF-7/LCC9. We discovered that A771726 treatment showed antiproliferative activities in MCF-7/LCC9 cells, which were even more sensitive to A771726 than their parental tamoxifen-sensitive cells (MCF‑7). A771726 also exerted pro-apoptotic activities and induced cell cycle arrest at the G1 phase. Notably, treatment of A771726 restored the sensitivity of MCF-7/LCC9 cells to tamoxifen. Western blot analysis revealed that A771726 decreased the phosphorylation level of Src, one key driver of tamoxifen resistance. Moreover, in order to comprehensively clarify the mechanisms of A771726 in anti-estrogen-resistant cells, we explored a genome-wide transcriptomic analysis, and showed that A771726 could modulate multiple signaling pathways (e.g. cell cycle, apoptosis, MAPK, metabolism and p53 signaling pathway) and cellular processes (e.g. signal transduction, transcription and cell cycle). Overall, our results indicate that A771726 alone and the combination of A771726 with anti-estrogens may be of therapeutic benefit for ER-positive and endocrine-resistant breast cancer.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar
2	Chlebowski RT, Manson JE, Anderson GL, et al: Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. J Natl Cancer Inst. 105:526–535. 2013.
3	McDonnell DP and Norris JD: Connections and regulation of the human estrogen receptor. Science. 296:1642–1644. 2002. View Article : Google Scholar : PubMed/NCBI
4	Brouckaert O, Paridaens R, Floris G, Rakha E, Osborne K and Neven P: A critical review why assessment of steroid hormone receptors in breast cancer should be quantitative. Ann Oncol. 24:47–53. 2013. View Article : Google Scholar : PubMed/NCBI
5	Pinkerton JV and Thomas S: Use of SERMs for treatment in postmenopausal women. J Steroid Biochem Mol Biol. 142C:142–154. 2014. View Article : Google Scholar
6	Goncalves R, Ma C, Luo J, Suman V and Ellis MJ: Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer. Nat Rev Clin Oncol. 9:223–229. 2012. View Article : Google Scholar : PubMed/NCBI
7	Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 365:1687–1717. 2005.PubMed/NCBI
8	Ali R, Nicholas RS and Muraro PA: Drugs in development for relapsing multiple sclerosis. Drugs. 73:625–650. 2013. View Article : Google Scholar : PubMed/NCBI
9	Oh J and O’Connor PW: Teriflunomide. Neurol Clin Pract. 3:254–260. 2013. View Article : Google Scholar
10	Tallantyre E, Evangelou N and Constantinescu CS: Spotlight on teriflunomide. Int MS J. 15:62–68. 2008.
11	Wiese MD, Rowland A, Polasek TM, Sorich MJ and O’Doherty C: Pharmacokinetic evaluation of teriflunomide for the treatment of multiple sclerosis. Expert Opin Drug Metab Toxicol. 9:1025–1035. 2013. View Article : Google Scholar : PubMed/NCBI
12	Oh J and O’Connor PW: Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 27:591–609. 2013. View Article : Google Scholar : PubMed/NCBI
13	Oh J and O’Connor PW: An update of teriflunomide for treatment of multiple sclerosis. Ther Clin Risk Manag. 9:177–190. 2013.PubMed/NCBI
14	Zhu S, Yan X, Xiang Z, Ding HF and Cui H: Leflunomide reduces proliferation and induces apoptosis in neuroblastoma cells in vitro and in vivo. PLoS One. 8:e715552013. View Article : Google Scholar : PubMed/NCBI
15	Hail N Jr, Chen P, Kepa JJ and Bushman LR: Evidence supporting a role for dihydroorotate dehydrogenase, bioenergetics, and p53 in selective teriflunomide-induced apoptosis in transformed versus normal human keratinocytes. Apoptosis. 17:258–268. 2012. View Article : Google Scholar
16	Ringshausen I, Oelsner M, Bogner C, Peschel C and Decker T: The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells. Leukemia. 22:635–638. 2008. View Article : Google Scholar : PubMed/NCBI
17	Hail N Jr, Chen P and Bushman LR: Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells: evidence supporting a role for teriflunomide in prostate cancer chemoprevention. Neoplasia. 12:464–475. 2010.
18	Dietrich S, Krämer OH, Hahn E, et al: Leflunomide induces apoptosis in fludarabine-resistant and clinically refractory CLL cells. Clin Cancer Res. 18:417–431. 2012. View Article : Google Scholar : PubMed/NCBI
19	Baumann P, Mandl-Weber S, Völkl A, et al: Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells. Mol Cancer Ther. 8:366–375. 2009. View Article : Google Scholar
20	Uckun FM: Rationally designed anti-mitotic agents with pro-apoptotic activity. Curr Pharm Des. 7:1627–1639. 2001. View Article : Google Scholar : PubMed/NCBI
21	White RM, Cech J, Ratanasirintrawoot S, et al: DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature. 471:518–522. 2011. View Article : Google Scholar : PubMed/NCBI
22	Somnay Y, Chen H and Kunnimalaiyaan M: Synergistic effect of pasireotide and teriflunomide in carcinoids in vitro. Neuroendocrinology. 97:183–192. 2013. View Article : Google Scholar : PubMed/NCBI
23	Musgrove EA and Sutherland RL: Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 9:631–643. 2009. View Article : Google Scholar : PubMed/NCBI
24	Mukherjee S and Conrad SE: c-Myc suppresses p21^WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells. J Biol Chem. 280:17617–17625. 2005.PubMed/NCBI
25	Abukhdeir AM, Vitolo MI, Argani P, et al: Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proc Natl Acad Sci USA. 105:288–293. 2008. View Article : Google Scholar : PubMed/NCBI
26	Riggins RB, Bouton AH, Liu MC and Clarke R: Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer. Vitam Horm. 71:201–237. 2005. View Article : Google Scholar : PubMed/NCBI
27	Razandi M, Pedram A, Jordan VC, Fuqua S and Levin ER: Tamoxifen regulates cell fate through mitochondrial estrogen receptor beta in breast cancer. Oncogene. 32:3274–3285. 2013. View Article : Google Scholar : PubMed/NCBI
28	Martin LA and Dowsett M: BCL-2: a new therapeutic target in estrogen receptor-positive breast cancer? Cancer Cell. 24:7–9. 2013. View Article : Google Scholar : PubMed/NCBI
29	Nehra R, Riggins RB, Shajahan AN, Zwart A, Crawford AC and Clarke R: BCL2 and CASP8 regulation by NF-κB differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and -resistant breast cancer cells. FASEB J. 24:2040–2055. 2010.
30	Ning Y, Riggins RB, Mulla JE, Chung H, Zwart A and Clarke R: IFNγ restores breast cancer sensitivity to fulvestrant by regulating STAT1, IFN regulatory factor 1, NF-κB, BCL2 family members, and signaling to caspase-dependent apoptosis. Mol Cancer Ther. 9:1274–1285. 2010.
31	Schwartz JL, Shajahan AN and Clarke R: The role of interferon regulatory factor-1 (IRF1) in overcoming antiestrogen resistance in the treatment of breast cancer. Int J Breast Cancer. 2011:9121022011. View Article : Google Scholar : PubMed/NCBI
32	Cook KL, Shajahan AN, Wärri A, Jin L, Hilakivi-Clarke LA and Clarke R: Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res. 72:3337–3349. 2012. View Article : Google Scholar : PubMed/NCBI
33	Geng Y and Sicinski P: Differences in regulation and function of E-cyclins in human cancer cells. Cell Cycle. 12:11652013. View Article : Google Scholar : PubMed/NCBI
34	Caldon CE, Sergio CM, Kang J, et al: Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther. 11:1488–1499. 2012. View Article : Google Scholar : PubMed/NCBI
35	Miller TW, Balko JM, Fox EM, et al: ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 1:338–351. 2011.
36	Lin JA, Fang SU, Su CL, et al: Silencing glucose-regulated protein 78 induced renal cell carcinoma cell line G1 cell-cycle arrest and resistance to conventional chemotherapy. Urol Oncol. 32:29.e1–29.e11. 2014. View Article : Google Scholar : PubMed/NCBI
37	Jiang M, Huang O, Zhang X, et al: Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. Molecules. 18:701–720. 2013. View Article : Google Scholar : PubMed/NCBI
38	Hiscox S, Jordan NJ, Smith C, et al: Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells. Breast Cancer Res Treat. 115:57–67. 2009. View Article : Google Scholar : PubMed/NCBI
39	Martinez-Outschoorn UE, Goldberg A, Lin Z, et al: Anti-estrogen resistance in breast cancer is induced by the tumor microenvironment and can be overcome by inhibiting mitochondrial function in epithelial cancer cells. Cancer Biol Ther. 12:924–938. 2011. View Article : Google Scholar