Pro-apoptotic Mechanisms of Action of a Novel Vitamin E Analog (α-TEA) and a Naturally Occurring Form of Vitamin E (δ-Tocotrienol) in MDA-MB-435 Human Breast Cancer Cells

Abstract

Vitamin E derivative, RRR-α-tocopheryl succinate (vitamin E succinate, VES), is a potent pro-apoptotic agent, inducing apoptosis by restoring both transforming growth factor-β (TGF-β) 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 form of vitamin E, δ-tocotrienol, and a novel vitamin E analog, α-tocopherol ether acetic acid analog [α-TEA; 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid]. Like VES, α-TEA and δ-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 α-TEA and δ-tocotrienol were identical to those previously reported for VES, that is, α-TEA- and δ-tocotrienol-induced apoptosis involved up-regulation of TGF-β receptor II expression and TGF-β-, Fas- and JNK-signaling pathways. These data provide a better understanding of the anticancer actions of a dietary form of vitamin E (δ-tocotrienol) and a novel nonhydrolyzable vitamin E analog (α-TEA).