Combined treatment of gamma-tocotrienol with statins induce mammary tumor cell cycle arrest in G1.

Abstract

Statins and gamma-tocotrienol (a rare isoform of vitamin E) both inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase activity and display anticancer activity. However, clinical application of statins has been limited by high dose toxicity. Previous studies showed that combined statin and gamma-tocotrienol treatment synergistically inhibits growth of highly malignant +SA mammary epithelial cells in culture. To investigate the mechanism mediating this growth inhibition, studies were conducted to determine the effect of combination low dose gamma-tocotrienol and statin treatment on +SA mammary tumor cell cycle progression. Treatment with 0.25 microM simvastatin, lovastatin, mevastatin, 10 microM pravastatin or 2.0 microM gamma-tocotrienol alone had no effect, while combined treatment of individual statins with gamma-tocotrienol significantly inhibited +SA cell proliferation during the 4-day culture period. Flow cytometric analysis demonstrated that combined treatment induced cell cycle arrest in G1. Additional studies showed that treatment with 0.25 microM simvastatin or 2 microM gamma-tocotrienol alone had no effect on the relative intracellular levels of cyclin D1, CDK2, CDK4 and CDK6, but combined treatment caused a large reduction in cyclin D1 and CDK2 levels. Combined treatments also caused a relatively large increase in p27, but had no effect on p21 and p15 levels, and resulted in a large reduction in retinoblastoma (Rb) protein phosphorylation at ser780 and ser807/811. Similar effects were observed following combined treatment of gamma-tocotrienol with low doses of lovastatin, mevastatin and pravastatin. These findings demonstrate that combination low dose statin and gamma-tocotrienol treatment induced mammary tumor cell cycle arrest at G1, resulting from an increase in p27 expression, and a corresponding decrease in cyclin D1, CDK2, and hypophosphorylation of Rb protein. These findings suggest that combined treatment of statins with gamma-tocotrienol may provide significant health benefits in the treatment of breast cancer in women, while avoiding myotoxicity associated with high dose statin monotherapy.

• Authors: Vikram B Wali, Sunitha V Bachawal, Paul W Sylvester
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 234 Issue 6 Pg. 639-50 (Jun 2009) ISSN: 1535-3702 [Print] England
• PMID: 19359655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Neoplasm Proteins
• Vitamin E
• plastochromanol 8

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Breast Neoplasms (diet therapy, metabolism, pathology)
• Cell Line, Tumor
• Chromans (agonists, pharmacology)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Drug Synergism
• Female
• G1 Phase (drug effects)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (agonists, pharmacology)
• Mammary Neoplasms, Animal (drug therapy, metabolism, pathology)
• Mice
• Neoplasm Proteins (metabolism)
• Vitamin E (agonists, analogs & derivatives, pharmacology)