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| Gossypol, A Phytochemical Compound With BH3 Mimetic Property, Sensitizes Cultured Thoracic Cancer Cells to Apo2L/TRAIL (TNF Receptor Apoptosis Inducing Ligand)-Mediated Apoptosis. |
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Back to 86th Annual Meeting Back to Program Outline Objective: We have previously demonstrated that the mitochondria-dependent death signaling cascade is essential for chemotherapy-induced sensitization of cultured thoracic cancer cells to Apo2L/TRAIL (T). Gossypol (G), a polyphenol isolated from cottonseed oil, interacts with BH3-binding pockets of Bcl2 or BclXL to functionally disable them and to induce apoptosis via the mitochondria-mediated death pathway. We hypothesize that G, through its ability to activate the pro-apoptotic function of mitochondria, synergistically interacts with the apoptosis-inducing ligand T to potentiate the effect of T in cultured thoracic cancer cells. Methods: Cultured cancer cells from lung (H460, H322), esophagus (TE2, TE12) and pleura (H211, H290) were either concurrently (G+T x 36 hours) or sequentially (G x 8 hours followed by G+T x 36 hours) treated with drug combinations. Cell viability and apoptosis were evaluated by MTT and TUNEL assays. Apo2L/TRAIL IC50 values were estimated from respective viability dose-response curves. Results: Concurrent exposure of thoracic cancer cells to G (2.5 to 10 μM) and T (5 to 100 ng/ml) resulted in supra-additive cytotoxicity. Normalizing for the mild G-induced growth inhibitory effect revealed a profound sensitization of all cancer cells to T evidenced by the drastic reduction of T IC50's (Figure A). While having a weak enhancing effect in T-sensitive cells (H460, H322, H290), G profoundly potentiate the cytotoxicity of this ligand in resistant cells (TE2, TE12, H211). More importantly, substantial induction of apoptosis was observed in combination-treated cells (Figure B). This combination was not toxic to primary normal cells. The G/G+T schedule was more effective than the G+T combination in enhancing T effect . The synergistic cytotoxicity of these drug combinations was totally abrogated by either overexpression of Bcl2 (stable transfectants created by retrovirus-mediated gene transfer) or by the selective caspase 9 inhibitor LEHD-fmk (40 μM) providing evidence that the mitochondria-mediated signaling cascade played an essential role in this process. Conclusions: Gossypol, a mitochondria-targeted anticancer drug currently in active preclinical development, synergized with Apo2L/TRAIL to induce profound apoptosis of cultured thoracic cancer cells in vitro. This drug combination deserves further development for clinical application in the treatment of thoracic cancers. 
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