Synergistic antiproliferative effects of gamma-tocotrienol and statin treatment on mammary tumor cells

Lipids. 2007 Dec;42(12):1113-23. doi: 10.1007/s11745-007-3102-0. Epub 2007 Aug 14.


Statins are potent inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and display anticancer activity, but their clinical use is limited by their high-dose toxicity. Similarly, gamma-tocotrienol, an isoform of vitamin E, also reduces HMGCoA reductase activity and displays potent anticancer activity. Studies were conducted to determine if combined low dose treatment of gamma-tocotrienol with individual statins resulted in a synergistic antiproliferative effect on neoplastic mouse +SA mammary epithelial cells. Treatment with 3-4 microM gamma-tocotrienol or 2-8 microM simvastatin, lovastatin or mevastatin alone resulted in a significant decrease, whereas treatment with 10-100 microM pravastatin had no effect on +SA cell growth. However, combined treatment of subeffective doses (0.25 or 10 microM) of individual statins with 0.25-2.0 microM gamma-tocotrienol resulted in a dose-responsive synergistic inhibition in +SA cell proliferation. Additional studies showed that treatment with subeffective doses of individual statins or gamma-tocotrienol alone had no effect, whereas combined treatment of these compounds resulted in a relatively large decrease in intracellular levels of phosphorylated (activated) MAPK, JNK, p38, and Akt. These findings strongly suggest that combined low dose treatment of gamma-tocotrienol with individual statins may have potential value in the treatment of breast cancer without causing myotoxicity that is associated with high dose statin treatment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Chromans / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Lovastatin / analogs & derivatives
  • Lovastatin / pharmacology
  • MAP Kinase Kinase 4 / metabolism
  • Mammary Neoplasms, Animal / metabolism
  • Mammary Neoplasms, Animal / pathology
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects
  • Pravastatin / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Simvastatin / pharmacology
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Chromans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Vitamin E
  • mevastatin
  • plastochromanol 8
  • Lovastatin
  • Simvastatin
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Pravastatin