YM155 enhances ABT-737-mediated apoptosis through Mcl-1 downregulation in Mcl-1-overexpressed cancer cells

• Published in: Molecular and cellular biochemistry 2017-05, Vol.429 (1-2), p.91-102
• Main Authors: Woo, Seon Min, Min, Kyoung-jin, Seo, Bo Ram, Seo, Young Ho, Jeong, Yong-Jin, Kwon, Taeg Kyu
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biphenyl Compounds - pharmacology; Cancer; Cancer cells; Cancer treatment; Cardiology; Cell Line, Tumor; Cell Survival - drug effects; Cells; Cellular biology; Combined treatment; Down-Regulation; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gliomas; Humans; Imidazoles - pharmacology; Life Sciences; Lung cancer; Medical Biochemistry; Membrane Potential, Mitochondrial - drug effects; Mice; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Naphthoquinones - pharmacology; Neoplasms - drug therapy; Neoplasms - metabolism; Nitrophenols - pharmacology; Oncology; Piperazines - pharmacology; Sulfonamides - pharmacology
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-016-2938-0

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.