title: Combined treatment with ABT-737 and VX-680 induces apoptosis in Bcl-2- and c-FLIP-overexpressing breast carcinoma cells.
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.
authors.affiliation: Department of Immunology, Keimyung University, School of Medicine, Dalseo-Gu, Daegu 704-701, Republic of Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Choi
authors.affiliation: Department of Immunology, Keimyung University, School of Medicine, Dalseo-Gu, Daegu 704-701, Republic of Korea.
authors.forename: Seon Min
authors.initials: SM
authors.lastname: Woo
authors.affiliation: Department of Immunology, Keimyung University, School of Medicine, Dalseo-Gu, Daegu 704-701, Republic of Korea.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Min
authors.affiliation: Department of Surgery, Yeungnam University, College of Medicine, Nam‑gu, Daegu 705-703, Republic of Korea.
authors.forename: Su Hwan
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Surgery, Yeungnam University, College of Medicine, Nam‑gu, Daegu 705-703, Republic of Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Immunology, Keimyung University, School of Medicine, Dalseo-Gu, Daegu 704-701, Republic of Korea.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D005260:Female; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology*; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D001713:Biphenyl Compounds; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D004338:Drug Combinations; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C501332:ABT-737; C506386:CFLAR protein, human; C579095:MCL1 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576917:AURKA protein, human