Abstract #4602: Resveratrol attenuates the anticancer efficacy of paclitaxel in MDA-MB-435s human breast cancer cells in vitro and in vivo

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Background: Recent studies reported that resveratrol can induce apoptosis in cancer cells and also sensitize them to anticancer drugs. Paclitaxel is an effective chemotherapeutic agent for various cancers by disrupting the formation of normal spindles at metaphase and resulting in G2/M cell cycle arrest and apoptosis. In addition, combination of paclitaxel with resveratrol was shown to have a synergistic apoptotic activity in some cancer cell lines in vitro . In the present study, we studied the modulating effect of resveratrol on paclitaxel-induced cell death in the estrogen receptor-negative MDA-MB-435s human breast cancer cells in vitro and also in vivo . Methods: Cell viability and cell cycle were analyzed. The levels of MAPKs and apoptosis-related proteins were also determined by Western blotting. To evaluate the effect in vivo , experiments using cancer cell xenografts were performed in female athymic BALB/c nu/nu mice, and the animals were treated with paclitaxel (10 mg/kg, i.p., once a week), resveratrol (16.5 mg/kg, i.p., three times a week), or combination of both for 4 weeks. Results: Resveratrol diminished the susceptibility of MDA-MB-435s human breast cancer cells to paclitaxel-induced cell death in vitro in a concentration-dependent manner. Cell cycle analysis revealed that while paclitaxel alone predominantly induced G2/M cell cycle arrest and resveratrol alone induced S-phase arrest, combination of paclitaxel and resveratrol mainly induced S-phase arrest. Mechanistically, the observed suppression of paclitaxel-induced cell death by resveratrol was largely not attributable to its antioxidant activity. Paclitaxel inactivated anti-apoptotic Bcl-2 family protein Bcl-xL, but combination of paclitaxel and resveratrol failed to inactivate Bcl-xL. In vivo experiments using athymic nude mice showed that after 2 or 4 weeks of treatment with paclitaxel alone, the tumor growth was significantly suppressed by 64.8-72.4% compared to the control. However, combination of resveratrol with paclitaxel strongly diminished the anticancer activity of paclitaxel (based on tumor volume). TUNEL analysis of the tumor tissue collected at the end of the experiments showed that animals receiving combination treatment had significantly fewer TUNEL-positive cells compared with animals treated with paclitaxel alone. Conclusion: The results of the present study showed that co-administration of resveratrol with paclitaxel significantly diminished the anticancer efficacy of paclitaxel in athymic nude mice grafted with MDA-MB-435s cells, suggesting that the strategy of combined use of resveratrol with paclitaxel may not be suitable for certain types of cancer. (Grant support - NIH CA92391 and CA97019). Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4602.