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

Abstract

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.

• Authors: Vikram B Wali, Paul W Sylvester
• Journal: Lipids (Lipids) Vol. 42 Issue 12 Pg. 1113-23 (Dec 2007) ISSN: 0024-4201 [Print] United States
• PMID: 17701065 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

• 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, pharmacology)
• MAP Kinase Kinase 4 (metabolism)
• Mammary Neoplasms, Animal (metabolism, pathology)
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphorylation (drug effects)
• Pravastatin (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Simvastatin (pharmacology)
• Vitamin E (analogs & derivatives, pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)