title: YM155 enhances ABT-737-mediated apoptosis through Mcl-1 downregulation in Mcl-1-overexpressed cancer cells.
abstract: ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2, and Bcl-w, and it has been reported for anti-cancer effects in various types of cancer cells. However, ABT-737 fails to induce apoptosis in cancer cell with high levels of Mcl-1 expression. The pharmacological survivin inhibitor YM155 has been reported to induce downregulation of Mcl-1 expression. Therefore, we investigated the effect of YM155 to sensitize resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. We found that ABT-737 alone and YM155 alone did not induce apoptosis, but YM155 markedly sensitized ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma cells (U251MG), and human lung carcinoma cells (A549). In contrast, combined treatment with ABT-737 and YM155 did not increase apoptosis in normal mouse kidney cells (TCMK-1) and human mesangial cells (MC). YM155 induced lysosome-dependent downregulation of Mcl-1 expression in Mcl-1-overexpressed Caki cells. In addition, combined treatment with ABT-737 and YM155 induced loss of mitochondrial membrane potential and inhibited interaction of Bcl-xL and Bax. Taken together, our results suggested that YM155 effectively improves sensitivity to ABT-737 through downregulation of Mcl-1 expression.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Seon Min
authors.initials: SM
authors.lastname: Woo
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Min
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Seo
authors.affiliation: Department of Food Science and Technology, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.|KMF Co., Ltd., Yuram-ro, Dong-gu, Daegu, 41065, South Korea.
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Jeong
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea. kwontk@dsmc.or.kr.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D007093:Imidazoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009285:Naphthoquinones; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; C523798:sepantronium
keywords: ABT-737; Caki cells; Lysosome; Mcl-1; YM155