title: Sorafenib sensitizes (-)-gossypol-induced growth suppression in androgen-independent prostate cancer cells via Mcl-1 inhibition and Bak activation.
abstract: The natural BH3-mimetic (-)-gossypol shows promising efficacy in ongoing phase II/III clinical trials for human prostate cancer. Here, we show for the first time, that treatment with (-)-gossypol and multikinase inhibitor sorafenib synergistically suppresses the growth of androgen-independent prostate cancer cells (AI-PC) in vitro and in vivo. Our data suggest that sorafenib attenuates (-)-gossypol-induced Mcl-1 upregulation in AI-PCs. In this way, it serves as a potent chemosensitizer to affect cell death. Interestingly, (-)-gossypol and sorafenib induce cell death via two distinct pathways among different AI-PCs; DU145 cells via apoptosis and PC-3 via autophagy. The appointed death pathway may depend on the level of proapoptotic protein Bak, although the level of antiapoptotic protein Bcl-2 plays some role in it. DU145 cells with high Bak level prefer apoptosis induction, whereas PC-3 cells with low Bak prefer the induction of autophagy. Furthermore, inhibiting nondominant death pathways, that is, autophagy in DU145 and apoptosis in PC-3, enhances cell killing by (-)-gossypol/sorafenib combination therapy. Ultimately, our data expose a new action for sorafenib as an enhancer of (-)-gossypol-induced cell growth suppression and reveal a novel cell death mode by Bak activation manners in AI-PCs. These new insights may facilitate the rational design of clinical trials by selecting patients most likely to benefit from the Bcl-2-targeted molecular therapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, PR China.
authors.forename: Jiqin
authors.initials: J
authors.lastname: Lian
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Ni
authors.forename: Xufang
authors.initials: X
authors.lastname: Dai
authors.forename: Chang
authors.initials: C
authors.lastname: Su
authors.forename: Amber Rae
authors.initials: AR
authors.lastname: Smith
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006072:Gossypol / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D000077157:Sorafenib; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
chemical_list: D000728:Androgens; C494772:BAK1 protein, human; D001557:Benzenesulfonates; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D009536:Niacinamide; D000077157:Sorafenib; D006072:Gossypol