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  • Title: Preclinical studies of apogossypolone, a novel pan inhibitor of bcl-2 and mcl-1, synergistically potentiates cytotoxic effect of gemcitabine in pancreatic cancer cells.
    Author: Banerjee S, Choi M, Aboukameel A, Wang Z, Mohammad M, Chen J, Yang D, Sarkar FH, Mohammad RM.
    Journal: Pancreas; 2010 Apr; 39(3):323-31. PubMed ID: 19823097.
    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.
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