Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells

Nutr Cancer. 2004;48(1):95-105. doi: 10.1207/s15327914nc4801_13.


Vitamin E derivative, RRR-alpha-tocopheryl succinate (vitamin E succinate, VES), is 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. Objectives of these studies were to characterize signaling events involved in the pro-apoptotic actions of a naturally occurring form of vitamin E, delta-tocotrienol, and a novel vitamin E analog, alpha-tocopherol ether acetic acid analog [alpha-TEA; 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid]. Like VES, alpha-TEA and delta-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 alpha-TEA and delta-tocotrienol were identical to those previously reported for VES, that is, alpha-TEA- and delta-tocotrienol-induced apoptosis involved up-regulation of TGF-beta receptor II expression and TGF-beta-, Fas- and JNK-signaling pathways. These data provide a better understanding of the anticancer actions of a dietary form of vitamin E (delta-tocotrienol) and a novel nonhydrolyzable vitamin E analog (alpha-TEA).

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / prevention & control
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Receptors, Transforming Growth Factor beta / drug effects
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Tocopherols
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology*
  • fas Receptor / drug effects
  • fas Receptor / metabolism


  • Anticarcinogenic Agents
  • Receptors, Transforming Growth Factor beta
  • fas Receptor
  • Vitamin E
  • tocotrienol, delta
  • 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid
  • Tocopherols