Sanjeev Banerjee, M. Choi, A. Aboukameel
Apr 1, 2010
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Quality indicators
Journal
Pancreas
Abstract
Objective: Overexpression of antiapoptotic Bcl-2 family proteins confers resistance to conventional therapy in pancreatic cancer patients. Apogossypolone (ApoG2) is an analogue of (−)−gossypol, exhibiting binding activity with Ki values of 35 nmol/L for Bcl-2 and 25 nmol/L for Mcl-1. The present study was designed to test our hypothesis whether inactivation of Bcl-2 family of proteins using ApoG2 could sensitize pancreatic cancer cells to the cytotoxic effect of gemcitabine. Methods: Two pancreatic cancer cell lines were treated with ApoG2, gemcitabine, and their combination; cytotoxicity and apoptosis was confirmed by MTT and histone/DNA enzyme-linked immunosorbent assay. Coimmunoprecipitation experiments were performed to elucidate the mechanism of action of ApoG2. In vivo efficacy of ApoG2 was evaluated in a xenograft model to confirm its therapeutic benefit with gemcitabine. Results: When ApoG2 was combined with gemcitabine, increased cytotoxicity and apoptosis was evident. Coimmunoprecipitation experiment revealed that ApoG2 blocks the heterodimerization of Mcl-1/Bax and Bcl-2/Bim in cells. Furthermore, administration of ApoG2 with gemcitabine resulted in a statistically higher antitumor activity compared with either ApoG2 or gemcitabine alone in a severe combined immunodeficiency mouse xenograft model. Conclusions: Apogossypolone, which functions as a potent pan-Bcl-2 family inhibitor, seems therapeutically promising for future translational studies including the treatment of pancreatic cancer.