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Synergistic Antiproliferative Effects of γ-Tocotrienol and Statin Treatment on Mammary Tumor Cells

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Lipids

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, γ-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 γ-tocotrienol with individual statins resulted in a synergistic antiproliferative effect on neoplastic mouse +SA mammary epithelial cells. Treatment with 3–4 μM γ-tocotrienol or 2–8 μM simvastatin, lovastatin or mevastatin alone resulted in a significant decrease, whereas treatment with 10–100 μM pravastatin had no effect on +SA cell growth. However, combined treatment of subeffective doses (0.25 or 10 μM) of individual statins with 0.25–2.0 μM γ-tocotrienol resulted in a dose-responsive synergistic inhibition in +SA cell proliferation. Additional studies showed that treatment with subeffective doses of individual statins or γ-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 γ-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.

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Acknowledgments

This work was performed at the College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA and supported in part by National Institutes of Health Grant CA 86833. The authors would like to thank the Malaysian Palm Oil Board and Carotech Bhd. for their support in generously providing γ-tocotrienol for use in these studies.

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  1. College of Pharmacy, University of Louisiana at Monroe, 700 University Ave., Monroe, LA, 71209-0470, USA

    Vikram B. Wali & Paul W. Sylvester

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  1. Vikram B. Wali
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  2. Paul W. Sylvester
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Correspondence to Paul W. Sylvester.

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Wali, V.B., Sylvester, P.W. Synergistic Antiproliferative Effects of γ-Tocotrienol and Statin Treatment on Mammary Tumor Cells. Lipids 42, 1113–1123 (2007). https://doi.org/10.1007/s11745-007-3102-0

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