title: GDC-0941 sensitizes breast cancer to ABT-737 in vitro and in vivo through promoting the degradation of Mcl-1.
abstract: The present study showed that GDC-0941 potently sensitized breast cancer to ABT-737 in vitro and in vivo. ABT-737 exhibited limited lethality in breast cancer cells; however, when combined with GDC-0941, it displayed strong synergistic cytotoxicity and enhanced caspase-mediated apoptosis. GDC-0941 promoted proteasomal degradation of Mcl-1, of which the overexpression has been validated to confer ABT-737 resistance, thereby enhanced the anticancer efficacy of ABT-737. Furthermore, the combination of GDC-0941 and ABT-737 exerted increased anti-tumor efficacy on MDA-MB-231 xenograft models. Overall, our data described unprecedentedly the promising therapeutic potential and underlying mechanisms of combining GDC-0941 with ABT-737 in treating breast cancer.
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, #388 Yuhangtang Road, Hangzhou, Zhejiang, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.forename: Wan-jing
authors.initials: WJ
authors.lastname: Ding
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Neng-ming
authors.initials: NM
authors.lastname: Lin
authors.forename: Hong-hai
authors.initials: HH
authors.lastname: Wu
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; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D009596:Nitrophenols / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D007191:Indazoles; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D020169:Caspases