YM155 enhances ABT-737-mediated apoptosis through Mcl-1 downregulation in Mcl-1-overexpressed cancer cells
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 rep...
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Published in | Molecular and cellular biochemistry Vol. 429; no. 1-2; pp. 91 - 102 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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New York
Springer US
01.05.2017
Springer Springer Nature B.V |
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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. |
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AbstractList | 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. |
Audience | Academic |
Author | Seo, Young Ho Kwon, Taeg Kyu Min, Kyoung-jin Woo, Seon Min Seo, Bo Ram Jeong, Yong-Jin |
Author_xml | – sequence: 1 givenname: Seon Min surname: Woo fullname: Woo, Seon Min organization: Department of Immunology, School of Medicine, Keimyung University – sequence: 2 givenname: Kyoung-jin surname: Min fullname: Min, Kyoung-jin organization: Department of Immunology, School of Medicine, Keimyung University – sequence: 3 givenname: Bo Ram surname: Seo fullname: Seo, Bo Ram organization: Department of Immunology, School of Medicine, Keimyung University – sequence: 4 givenname: Young Ho surname: Seo fullname: Seo, Young Ho organization: College of Pharmacy, Keimyung University – sequence: 5 givenname: Yong-Jin surname: Jeong fullname: Jeong, Yong-Jin organization: Department of Food Science and Technology, Keimyung University, KMF Co., Ltd – sequence: 6 givenname: Taeg Kyu surname: Kwon fullname: Kwon, Taeg Kyu email: kwontk@dsmc.or.kr organization: Department of Immunology, School of Medicine, Keimyung University |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28120212$$D View this record in MEDLINE/PubMed |
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Keywords | ABT-737 Mcl-1 YM155 Caki cells Lysosome |
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Snippet | 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,... |
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SubjectTerms | 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 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 |
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Title | YM155 enhances ABT-737-mediated apoptosis through Mcl-1 downregulation in Mcl-1-overexpressed cancer cells |
URI | https://link.springer.com/article/10.1007/s11010-016-2938-0 https://www.ncbi.nlm.nih.gov/pubmed/28120212 https://www.proquest.com/docview/1885186237/abstract/ https://search.proquest.com/docview/1891882980 |
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