Investigation of the molecular mechanisms of apoptosis induced by a novel vitamin E derivative ([alpha]-TEA) in human breast and ovarian cancer using cell culture

by 1976- Shun, Ming-chieh

Vitamin E derivative, RRR-?-tocopheryl succinate (vitamin E succinate, VES), is a potent pro-apoptotic agent, inducing apoptosis by restoring both transforming growth factor-? (TGF-?) and Fas (CD95) apoptotic signaling pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)-mediated apoptosis. Objectives of these studies were to characterize signaling events involved in the pro-apoptotic actions of a naturally occurring from of vitamin E, ?-tocotrienol, and a novel vitamin E analog, ?-tocopherol ether acetic acid analog [?-TEA; 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid]. Like VES, ?-TEA and ?-tocotrienol induced estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells to undergo high levels of apoptosis in a concentration- and time-dependent fashion. Like VES, the two compounds induced either no or lower levels of apoptosis in normal human mammary epithelial cells and immortalized but nontumorigenic human MCF-10A cells. The pro-apoptotic mechanisms triggered by the structurally distinct ?-TEA and ?-tocotrienol were identical to those previously reported for VES, that is ?-TEA- and ?-tocotrienol-induced apoptosis involved up-regulation of TGF-? receptor II expression and TGF-?-, Fas- and JNK-signaling pathways. These data provide a better understanding of the anticancer actions of a dietary form of vitamin E (?-tocotrienol) and a novel non-hydrolyzable vitamin E analog (?-TEA). 19