고려대학교

초록/요약

a-tocopheryl succinate (TOS), a vitamin E analog, is a promising anticancer agent due to its abilities to inhibit proliferation and to induce apoptosis in a variety of human malignant cell lines, while being relatively less active toward normal cells. However, the molecular mechanisms underlying apoptotic effects of TOS are not precisely understood. We found that the human lung cancer A549 and H460 cell lines were much more sensitive to TOS-induced apoptosis compared with the human glioblastoma T98G and U87MG cell lines. Our data suggested that the differential TOS sensitivity was not caused by the differences in the uptake and retention of TOS between TOS-sensitive and -resistant cancer cells. The differential ability of cancer cells to generate ROS in response to TOS appears to be an important factor determining the susceptibility of cells to TOS-induced apoptosis. Our further study suggests that TOS-induced generation of ROS is involved in the caspase-independent apoptosis. Taken together, our findings suggest the important role of ROS generation in TOS-induced caspase-independent apoptosis of cancer cells. Multidrug resistance protein 1 (MRP1) is one of the representative members of the ATP-binding cassette superfamily of transporters that is involved in resistance to chemotherapeutic agents in cancer patients. MRP1 functions as an efflux pump of drugs, primarily those conjugated to glutathione (GSH). Decreases in the intracellular concentration of GSH have been shown to enhance the response of MRP1-overexpressing cells to MRP1-substrate drugs by limiting the available drug-GSH conjugates. We report here that a-tocopheryl succinate (TOS) decreased intracellular GSH concentration and blocked MRP1 function in glioblastoma cells. Functional blockade by TOS of MRP1 was confirmed by the enhanced accumulation of etoposide (VP-16), an MRP1-substrate drug. As a result, co-treatment of TOS with VP-16 or treatment with liposomes containing both TOS and VP-16 greatly enh