Preclinical studies of apogossypolone, a novel pan inhibitor of bcl-2 and mcl-1, synergistically potentiates cytotoxic effect of gemcitabine in pancreatic cancer cells.

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.