Tocotrienol-induced cytotoxicity is unrelated to mitochondrial stress apoptotic signaling in neoplastic mammary epithelial cells

Biochem Cell Biol. 2005 Feb;83(1):86-95. doi: 10.1139/o04-127.


Tocotrienols and tocopherols represent the 2 subgroups within the vitamin E family of compounds, but tocotrienols display significantly greater apoptotic activity against a variety of cancer cell types. However, the exact mechanism mediating tocotrienol-induced apoptosis is not understood. Studies were conducted to determine the effects of tocotrienols on mitochondrial-stress-mediated apoptotic signaling in neoplastic +SA mammary epithelial cells grown in vitro. Exposure for 24 h to 0-20 micromol/L gamma-tocotrienol resulted in a dose-responsive increase in +SA cells undergoing apoptosis, as determined by flow cytometric analysis of Annexin V staining. However, tocotrienol-induced apoptosis was not associated with a disruption or loss of mitochondrial membrane potential, or the release of mitochondrial cytochrome c into the cytoplasm, as determined by JC-1 flow cytometric staining and ELISA assay, respectively. Interestingly, apoptotic +SA cells showed a paradoxical decrease in mitochondrial levels of pro-apoptotic proteins Bid, Bax, and Bad, and a corresponding increase in mitochondrial levels of anti-apoptotic proteins, Bcl-2 and Bcl-xL, suggesting that mitochondrial membrane stability and integrity might actually be enhanced for a limited period of time following acute tocotrienol exposure. In summary, these findings clearly demonstrate that tocotrienol-induced apoptosis occurs independently of mitochondrial stress apoptotic signaling in neoplastic +SA mammary epithelial cells.

Publication types

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

MeSH terms

  • Animals
  • Annexin A5 / analysis
  • Apoptosis / drug effects*
  • Cell Death / drug effects
  • Cell Survival
  • Chromans / pharmacology
  • Chromans / toxicity*
  • Cytochromes c / metabolism
  • Female
  • Genes, bcl-2 / genetics
  • Mammary Glands, Animal / drug effects
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Animal / metabolism*
  • Mammary Neoplasms, Animal / pathology*
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Signal Transduction / drug effects*
  • Stress, Mechanical
  • Tumor Cells, Cultured
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology
  • Vitamin E / toxicity


  • Annexin A5
  • Chromans
  • Vitamin E
  • plastochromanol 8
  • Cytochromes c