Abstract
The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL, but not Mcl-1, which may confer resistance to this agent in various cancers with high levels of Mcl-1. Here, we showed that the combination of gemcitabine and ABT-737 exhibited synergistic cytotoxicity and induced significant apoptosis in multiple cancer types, including lung, renal, bladder, and prostate cancers. The enhanced apoptosis induced by gemcitabine plus ABT-737 was accompanied by the greater extent of mitochondrial depolarization, caspases-3 activation, and PARP cleavage in 95-D and 5637 cell lines. Importantly, in ABT-737-resistant cancer cells, the interaction between USP9X and Mcl-1, which was increased by ABT-737 treatment, could be disrupted by gemcitabine, thus resulting in enhanced ubiquitination and the subsequent degradation of Mcl-1 and ultimately in the synergism of these two drugs. Moreover, the increased anticancer efficacy of gemcitabine combined with ABT-737 was further validated in a human lung cancer 95-D xenograft model in nude mice. Taken together, our data first showed the synergistic anticancer capabilities achieved by combining gemcitabine and ABT-737 and, second, opened new opportunities to use antiapoptotic Bcl-2 family members, which drive tumor cell resistance in current anticancer therapies, therapeutically.
© 2011 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology*
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Caspases / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Deoxycytidine / analogs & derivatives*
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Deoxycytidine / chemistry
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Deoxycytidine / pharmacology
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Drug Synergism
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Gemcitabine
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Humans
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Mice, Nude
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasms / genetics
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Neoplasms / metabolism*
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Nitrophenols / chemistry
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Nitrophenols / pharmacology*
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Piperazines / chemistry
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Piperazines / pharmacology
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA Interference
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
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Ubiquitin Thiolesterase / genetics
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Ubiquitin Thiolesterase / metabolism*
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Xenograft Model Antitumor Assays
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bcl-2-Associated X Protein / metabolism
Substances
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ABT-737
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Antineoplastic Agents
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Biphenyl Compounds
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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USP9X protein, human
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bcl-2-Associated X Protein
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Deoxycytidine
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Ubiquitin Thiolesterase
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Caspases
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Gemcitabine