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: Jiqin Lian, Zhenhong Ni, Xufang Dai, Chang Su, Amber Rae Smith, Liang Xu, Fengtian He
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 2 Pg. 416-26 (Feb 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22188816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgens
• BAK1 protein, human
• Benzenesulfonates
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• Phenylurea Compounds
• Proto-Oncogene Proteins c-bcl-2
• Pyridines
• bcl-2 Homologous Antagonist-Killer Protein
• Niacinamide
• Sorafenib
• Gossypol

Topics

• Androgens (metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Benzenesulfonates (administration & dosage, pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Female
• Gossypol (administration & dosage, pharmacology)
• Humans
• Male
• Mice
• Mice, Nude
• Myeloid Cell Leukemia Sequence 1 Protein
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Pyridines (administration & dosage, pharmacology)
• Sorafenib
• Time Factors
• Xenograft Model Antitumor Assays
• bcl-2 Homologous Antagonist-Killer Protein (metabolism)