Alpha-tocopheryl succinate enhances doxorubicin-induced apoptosis in human gastric cancer cells via promotion of doxorubicin influx and suppression of doxorubicin efflux

Doxorubicin (DOXO), a chemotherapy drug, is widely used in clinic for treating a variety of cancers. However, the treatment eventfully fails due to drug resistance and toxicity. Therefore, a combination strategy is needed to increase efficacy and reduce toxicity of DOXO. alpha-tocopheryl succinate (alpha-TOS) exhibits anticancer actions in vitro and in vivo. Here, we reported that combination of DOXO + alpha-TOS cooperatively acted to induce apoptosis in SGC-7901 cells. alpha-TOS enhanced cellular level of DOXO via promotion of DOXO influx and suppression of DOXO efflux. DOXO induced MDR1 mRNA and protein expression and alpha-TOS inhibited this event, indicating that alpha-TOS suppressed DOXO efflux via inhibition of MDR1. Furthermore, combination of DOXO + alpha-TOS induced increased levels of Fas and Bax protein expression and cleavage of caspase-8 and caspase-9, suggesting that combination treatment induced Fas/caspase-8 and Bax mediated mitochondria dependent apoptosis. Taken together, our results demonstrated that alpha-TOS enhanced DOXO anticancer efficiency via promotion of DOXO influx and suppression of MDR-1 mediated DOXO efflux. (C) 2011 Elsevier Ireland Ltd. All rights reserved.