Abstract 1698: Resveratrol potentiates the cytotoxic profile of docetaxel and doxorubicin via inhibiting the activity and expression of p-glycoprotein molecules

Abstract P-glycoprotein is membrane protein highly abundant in tumor cells which facilitate the effluxes of several chemotherapeutic agents to the extracellular compartment. Several P-glycoprotein blockers of synthetic origin were suggested as adjuvant therapy for cancer; however, manifested several toxic side effects. Resveratrol was found to block p-glycoprotein with potential use as adjuvant therapy for several p-glycoprotein substrates such as docetaxel and doxorubicin. Herein, we have assessed the interactive characteristics of resveratrol with docetaxel and doxorubicin and further investigated the molecular bases of this interaction in three different solid tumor cell lines (MCF-7, HeLa and HepG2). Resveratrol per se was found to possess anti-cancer properties; however with relatively low potency in all tested cell lines (IC50 ranges from 8.0 to 19.1µg/ml). Doxorubicin and docetaxel showed IC50‘s ranged from 0.28 to 0.42 µg/ml and from 22.3 to 67.1 ng/ml, respectively. Resveratrol combination with doxorubicin and docetaxel significantly increased the potencies of both chemotherapeutic agents showing IC50‘s ranging from 0.07 to 0.2 µg/ml and from 6.2 to 45.7 ng/ml, respectively. The combination index showed synergistic interaction between resveratrol and doxorubicin or docetaxel in MCF-7 cell line, while additive interaction in HeLa and Hep-G2 cell lines. Real time PCR revealed that the expression of BAX and BcL2 were simultaneously elevated due to combination of resveratrol with doxorubicin or docetaxel in all tested cell lines while p-53 showed marginal elevation in MCF-7 and HepG2 cell lines. The p-glycoprotein efflux activity was significantly inhibited with subsequent accumulation of p-glycoprotein substrate within the intracellular compartment of all tested cell lines. Also the expression level of mdr1 gene was down regulated after resveratrol combination with doxorubicin or docetaxel in all tested cell lines. In conclusion, resveratrol potentiates the anti-cancer effects of doxorubicin and docetaxel via increasing their intracellular level due to p-glycoprotein activity inhibition and down regulation of mdr1 gene. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1698. doi:10.1158/1538-7445.AM2011-1698