| Previous studies from our lab have shown that the vitamin E derivative, RRR-alpha-tocopherol succinate (vitamin E succinate, VES) induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo DNA synthesis arrest, cellular differentiation, and apoptosis. Several studies have demonstrated VES to be a potent pro-apoptotic agent inducing apoptosis by restoring both transforming growth factor-beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)-mediated apoptosis. In an effort to develop a more clinically useful vitamin E-based chemotherapeutic agent, a non-hydrolyzable ether analog of RRR-alpha-tocopherol; namely, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid (called RRR-alpha-tocopherol ether acetic acid analog; and abbreviated alpha-TEA) has been produced. Specific aim I studies investigated the individual effects of alpha-TEA and a naturally occurring from of vitamin E, delta-tocotrienol, as anticancer agents against breast cancer in vitro, and characterized signaling events involved in the pro-apoptotic and differentiation actions of alpha-TEA in human MDA-MB-435 and MCF-7 breast cancer cell lines. The pro-apoptotic mechanisms triggered by the structurally distinct alpha-TEA and delta-tocotrienol were identical to those previously reported for VES, that is alpha-TEA- and delta-tocotrienol-induced apoptosis involved sensitizing both cell lines to TGF-beta and Fas apoptotic signaling, involving up-regulation of TGF-beta receptor II protein expression and signaling apoptosis by TGF-beta, and Fas converging on JNK signaling pathway. Specific aim II characterized the apoptotic effects of alpha-TEA on components of the Fas/CD95 apoptotic pathway in cisplatin-sensitive, A2780S, and cisplatin-resistant, A2780/cp70R human ovarian cancer cells. Specific aim III studies showed alpha-TEA to induce MDA-MB-435 human breast cancer cells to undergo cellular differentiation. Specific aim IV studies showed alpha-TEA to modulate ErbB family members and signaling. Taken together, these findings demonstrated that alpha-TEA-induced apoptosis is by downregulation of c-FLIP and survivin through the activity of Akt and elimination of tumor cells through Fas-mediated apoptosis, and showed alpha-TEA to be a potent inducer of apoptosis in both human breast and ovarian cancer cells in culture. |
