Combined treatment with ABT-737 and VX-680 induces apoptosis in Bcl-2- and c-FLIP-overexpressing breast carcinoma cells

Choi,Jung Eun; Woo,Seon Min; Min,Kyoung-Jin; Kang,Su Hwan; Lee,Soo Jung; Kwon,Taeg Kyu

doi:10.3892/or.2015.3728

Combined treatment with ABT-737 and VX-680 induces apoptosis in Bcl-2- and c-FLIP-overexpressing breast carcinoma cells

Authors:
- Jung Eun Choi
- Seon Min Woo
- Kyoung-Jin Min
- Su Hwan Kang
- Soo Jung Lee
- Taeg Kyu Kwon
View Affiliations

Affiliations: Department of Immunology, Keimyung University, School of Medicine, Dalseo-Gu, Daegu 704-701, Republic of Korea, Department of Surgery, Yeungnam University, College of Medicine, Nam‑gu, Daegu 705-703, Republic of Korea
Published online on: January 15, 2015 https://doi.org/10.3892/or.2015.3728
Pages: 1395-1401

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

ABT-737, a BH3-mimetic small-molecule inhibitor, binds with very high affinity to Bcl-2, Bcl-xL and Bcl-w, and inhibits their activity. Aurora kinase is one of the serine/threonine kinase family members and is a vital and critical regulator of mitosis and meiosis. In the present study, we investigated the effects and mechanisms of a combined treatment of ABT-737 and VX-680 (Aurora kinase inhibitor) in human breast cancer MDA-MB‑435S cells. ABT-737 plus VX-680 induced caspase-dependent apoptosis in the human breast cancer cells. Combined treatment with ABT-737 and VX-680 led to the downregulation of Bcl-2 expression at the transcriptional level and the downregulation of c-FLIP and Mcl-1 expression at the post-transcriptional level. Overexpression of Bcl-2 or c-FLIP could not block the induction of apoptosis caused by the combined treatment with ABT-737 and VX-680. However, overexpression of Mcl-1 partially inhibited the induction of apoptosis. In contrast, the combined treatment with ABT-737 and VX680 had no effect on the apoptosis in normal cells. Taken together, our study demonstrated that combined treatment with ABT-737 and VX-680 induced apoptosis in anti‑apoptotic protein (Bcl-2 or c-FLIP)-overexpressing cells.

View Figures

View References

1	Yip KW and Reed JC: Bcl-2 family proteins and cancer. Oncogene. 27:6398–6406. 2008. View Article : Google Scholar : PubMed/NCBI
2	Certo M, Del Gaizo Moore V, Nishino M, et al: Mitochondria primed by death signals determine cellular addiction to anti-apoptotic BCL-2 family members. Cancer Cell. 9:351–365. 2006. View Article : Google Scholar : PubMed/NCBI
3	Kim H, Rafiuddin-Shah M, Tu HC, et al: Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol. 8:1348–1358. 2006. View Article : Google Scholar : PubMed/NCBI
4	Oltersdorf T, Elmore SW, Shoemaker AR, et al: An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 435:677–681. 2005. View Article : Google Scholar : PubMed/NCBI
5	Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD and Letai A: Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 117:112–121. 2007. View Article : Google Scholar : PubMed/NCBI
6	Chauhan D, Velankar M, Brahmandam M, et al: A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene. 26:2374–2380. 2007. View Article : Google Scholar
7	Konopleva M, Contractor R, Tsao T, et al: Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 10:375–388. 2006. View Article : Google Scholar : PubMed/NCBI
8	van Delft MF, Wei AH, Mason KD, et al: The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 10:389–399. 2006. View Article : Google Scholar : PubMed/NCBI
9	Andrews PD, Knatko E, Moore WJ and Swedlow JR: Mitotic mechanics: the auroras come into view. Curr Opin Cell Biol. 15:672–683. 2003. View Article : Google Scholar : PubMed/NCBI
10	Hirota T, Kunitoku N, Sasayama T, et al: Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell. 114:585–598. 2003. View Article : Google Scholar : PubMed/NCBI
11	Farag SS: The potential role of Aurora kinase inhibitors in haematological malignancies. Br J Haematol. 155:561–579. 2011. View Article : Google Scholar : PubMed/NCBI
12	Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN Jr and Gandara DR: Aurora kinases as anticancer drug targets. Clin Cancer Res. 14:1639–1648. 2008. View Article : Google Scholar : PubMed/NCBI
13	Gritsko TM, Coppola D, Paciga JE, et al: Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin Cancer Res. 9:1420–1426. 2003.PubMed/NCBI
14	Katayama H, Brinkley WR and Sen S: The Aurora kinases: role in cell transformation and tumorigenesis. Cancer Metastasis Rev. 22:451–464. 2003. View Article : Google Scholar : PubMed/NCBI
15	Tallarida RJ: Drug synergism: its detection and applications. J Pharmacol Exp Ther. 298:865–872. 2001.PubMed/NCBI
16	Mitchell T and Sugden B: Stimulation of NF-kappa B-mediated transcription by mutant derivatives of the latent membrane protein of Epstein-Barr virus. J Virol. 69:2968–2976. 1995.PubMed/NCBI
17	Harrington EA, Bebbington D, Moore J, et al: VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med. 10:262–267. 2004. View Article : Google Scholar : PubMed/NCBI
18	Pugazhenthi S, Miller E, Sable C, et al: Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response element-binding protein. J Biol Chem. 274:27529–27535. 1999. View Article : Google Scholar : PubMed/NCBI
19	Tamatani M, Che YH, Matsuzaki H, et al: Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons. J Biol Chem. 274:8531–8538. 1999. View Article : Google Scholar : PubMed/NCBI
20	Catz SD and Johnson JL: Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene. 20:7342–7351. 2001. View Article : Google Scholar : PubMed/NCBI
21	Bourgarel-Rey V, Savry A, Hua G, et al: Transcriptional down-regulation of Bcl-2 by vinorelbine: identification of a novel binding site of p53 on Bcl-2 promoter. Biochem Pharmacol. 78:1148–1156. 2009. View Article : Google Scholar : PubMed/NCBI
22	Haldar S, Negrini M, Monne M, Sabbioni S and Croce CM: Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 54:2095–2097. 1994.PubMed/NCBI
23	Wu Y, Mehew JW, Heckman CA, Arcinas M and Boxer LM: Negative regulation of bcl-2 expression by p53 in hematopoietic cells. Oncogene. 20:240–251. 2001. View Article : Google Scholar : PubMed/NCBI
24	Ciechanover A and Schwartz AL: The ubiquitin system: pathogenesis of human diseases and drug targeting. Biochim Biophys Acta. 1695:3–17. 2004. View Article : Google Scholar : PubMed/NCBI
25	Song JH, Kandasamy K and Kraft AS: ABT-737 induces expression of the death receptor 5 and sensitizes human cancer cells to TRAIL-induced apoptosis. J Biol Chem. 283:25003–25013. 2008. View Article : Google Scholar : PubMed/NCBI