Abstract 1034: Combination therapy with gossypol reveals synergism against gemcitabine resistance in cancer cells with high Bcl-2 expression

Abstract

Abstract Gemcitabine is an anticancer agent used in breast, non-small cell lung, pancreatic and ovarian cancer. However, many cancers have been showed to be resistant to gemcitabine. Recent studies have demonstrated that gemcitabine resistance can be overcome when combined with gossypol. Gossypol is an inhibitor of Bcl-2 that induces apoptosis in various cancer cell lines. The aim of our study was to determine whether gossypol can overcome gemcitabine resistance via its interaction with the Bcl-2 protein. IC50 of gossypol and gemcitabine, as well as baseline expression of Bcl-2 were determined in 10 cell lines derived from nasopharyngeal (n=4), breast (n=3) and gastric (n=3)cancers. High Bcl-2 baseline expression that was observed in 3/10 cell lines, had higher IC50 to gemcitabine. Upregulation of Bcl-2 levels were also observed after treatment in cell lines that high Bcl-2 baseline expression. These findings suggest an interaction between Bcl-2 protein and gemcitabine resistance. Furthermore, in 7/10 cell lines that were sensitive to gemcitabine, five showed low Bcl-2 expression, suggesting that Bcl-2 levels plays a role in gemcitabine response in cancer. To determine whether gossypol can overcome gemcitabine resistance, combination treatments were carried out either by adding the drugs simultaneously or sequentially to the cell lines. Dual drug treatment was found to be synergistic to cell lines that have both high Bcl-2 level and were resistant to single agent, gemcitabine. Intrestingly cell lines that were sensitive to both drugs, and had high Bcl-2 level were also synergistic when treated with the combined drugs. In contrast, cell lines that were sensitive to both drugs and had low Bcl-2 level were antagonistic to combined drug treatments. The (-) enatiomer of gossypol (AT101) has been reported to be more potent than gossypol in inhibiting cell growth and inducing apoptosis in cancer cells. This suggests that AT101 is a more effective drug than gossypol in overcoming gemcitabine resistance. Cell lines treated with AT101 had lower IC50 compared to those treated with gossypol. Two cell lines (HK1 and AGS) that were intermediate responders to gossypol demonstrated higher sensitivity when treated with AT101, suggesting that AT101 is a more effective drug than gossypol. Futhermore, in vitro durg response studies comparing the 2 drugs in 35 gastric cell lines reveals an overall hypersensitive to AT101 compared to gossypol. Current studies are underway to investigate combination treatment of AT101 with gemcitabine, as well as its interactions with the Bcl-2 family proteins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1034.