title: Synergistic antitumor activity of gemcitabine and ABT-737 in vitro and in vivo through disrupting the interaction of USP9X and Mcl-1.
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.
authors.affiliation: 1Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.forename: Tian-yu
authors.initials: TY
authors.lastname: Cai
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Liu-qing
authors.initials: LQ
authors.lastname: Yang
authors.forename: Hai
authors.initials: H
authors.lastname: Jiang
authors.forename: Xiao-wu
authors.initials: XW
authors.lastname: Dong
authors.forename: Yong-Zhou
authors.initials: YZ
authors.lastname: Hu
authors.forename: Neng-ming
authors.initials: NM
authors.lastname: Lin
authors.forename: Qiao-jun
authors.initials: QJ
authors.lastname: He
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C506234:USP9X protein, human; D051028:bcl-2-Associated X Protein; D003841:Deoxycytidine; D043222:Ubiquitin Thiolesterase; D020169:Caspases; D000093542:Gemcitabine