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.
OBJECTIVE: Overexpression of antiapoptotic Bcl-2 family proteins confers resistance to conventional therapy in pancreatic cancerpatients. 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 immunodeficiencymouse 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.
Authors: M C Wei; W X Zong; E H Cheng; T Lindsten; V Panoutsakopoulou; A J Ross; K A Roth; G R MacGregor; C B Thompson; S J Korsmeyer Journal: Science Date: 2001-04-27 Impact factor: 47.728
Authors: J L Wang; Z J Zhang; S Choksi; S Shan; Z Lu; C M Croce; E S Alnemri; R Korngold; Z Huang Journal: Cancer Res Date: 2000-03-15 Impact factor: 12.701
Authors: Atsushi Imai; Benjamin D Zeitlin; Fernanda Visioli; Zhihong Dong; Zhaocheng Zhang; Sudha Krishnamurthy; Emily Light; Frank Worden; Shaomeng Wang; Jacques E Nör Journal: Cancer Res Date: 2011-12-08 Impact factor: 12.701
Authors: James M Cleary; Caio Max S Rocha Lima; Herbert I Hurwitz; Alberto J Montero; Catherine Franklin; Jianning Yang; Alison Graham; Todd Busman; Mack Mabry; Kyle Holen; Geoffrey I Shapiro; Hope Uronis Journal: Invest New Drugs Date: 2014-06-11 Impact factor: 3.850