Resistance to chemotherapy (chemoresistance) is a serious problem in malignant mesothelioma, a highly aggressive neoplasm. Gamma-tocotrienol (gamma-T3) can sensitize various cancerous cells to chemotherapeutic agents by inhibiting pathways that lead to treatment resistance. In this study, we investigated the modulating effect of tocotrienol-rich fraction (TRF) from rice bran, which is abundant in gamma-T3, on chemoresistance in human MM H28 cells. TRF treatment caused a marked reduction in the viability of H28 cells in a dose-dependent manner, while cisplatin treatment had no effect on the cells, indicating that H28 cells are resistant to cisplatin. A significant increase in cytotoxicity was observed in H28 cells treated with TRF, and this effect was enhanced by the combination treatment with cisplatin. The cytotoxic effect was closely related to the inhibition of phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Inactivation of Akt signaling by TRF or the combination with cisplatin mitigated cisplatin-induced activation of Akt, resulting in reducing the chemoresistance H28 cells to cisplatin. Reduced cell viability and attenuated chemoresistance of the H28 cells against cisplatin were also observed following the use of a PI3K inhibitor, LY294002. These results suggest that the combination therapy of cisplatin with TRF is a plausible strategy for achieving tolerance for the chemotherapeutic agent in MM therapy.
Copyright 2010 John Wiley & Sons, Ltd.