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Suppression in Mevalonate Synthesis Mediates Antitumor Effects of Combined Statin and γ-Tocotrienol Treatment

  • Original Article
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Lipids

Abstract

Statins directly inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity, while γ-tocotrienol, an isoform of vitamin E, enhances the degradation and reduces cellular levels of HMGR in various tumor cell lines. Since treatment with statins or γ-tocotrienol alone induced a dose-responsive inhibition, whereas combined treatment with subeffective doses of these agents resulted in a synergistic inhibition in +SA mammary tumor cell growth, studies were conducted to investigate the role of the HMGR pathway in mediating the antiproliferative effects of combined low dose statin and γ-tocotrienol. Treatment with 8 μM simvastatin inhibited cell growth and isoprenylation of Rap1A and Rab6, and supplementation with 2 μM mevalonate reversed these effects. However, the growth inhibitory effects of 4 μM γ-tocotrienol were not dependent upon suppression in mevalonate synthesis. Treatment with subeffective doses of simvastatin (0.25 μM), lovastatin (0.25 μM), mevastatin (0.25 μM), pravastatin (10 μM), or γ-tocotrienol (2 μM) alone had no effect on protein prenylation or mitogenic signaling, whereas combined treatment with these agents resulted in a significant inhibition in +SA cell growth, and a corresponding decrease in total HMGR, Rap1A and Rab6 prenylation, and MAPK signaling, and mevalonate supplementation reversed these effects. These findings demonstrate that the synergistic antiproliferative effects of combined low dose statin and γ-tocotrienol treatment are directly related to an inhibition in HMGR activity and subsequent suppression in mevalonate synthesis.

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Abbreviations

HMGR:

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

MAPK:

Mitogen-activated protein kinase

FPP:

Farnesyl pyrophosphate

GGPP:

Geranylgeranyl pyrophosphate

ERK:

Extracellular signal-regulated kinase

BSA:

Bovine serum albumin

DMEM:

Dulbecco’s modified Eagle’s medium

PBS:

Phosphate buffered saline

MTT:

3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide

SDS:

Sodium dodecyl sulfate

PVDF:

Polyvinylidene fluoride

TBST:

10 mM Tris–HCl containing 50 mM NaCl and 0.1% Tween 20, pH 7.4

TBS:

0.05 M Tris-buffered saline (TBS) pH 7.6

PI3K:

Phosphatidylinositol 3-kinase

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Acknowledgments

This work was performed at the College of Pharmacy, University of Louisiana at Monroe, Monroe, LA and supported in part by grants from the National Institutes of Health (Grant CA 86833) and First Tech International Ltd.

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Authors and Affiliations

  1. College of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA, 71209-470, USA

    Vikram B. Wali, Sunitha V. Bachawal & Paul W. Sylvester

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  1. Vikram B. Wali
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  2. Sunitha V. Bachawal
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  3. Paul W. Sylvester
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Correspondence to Paul W. Sylvester.

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Wali, V.B., Bachawal, S.V. & Sylvester, P.W. Suppression in Mevalonate Synthesis Mediates Antitumor Effects of Combined Statin and γ-Tocotrienol Treatment. Lipids 44, 925–934 (2009). https://doi.org/10.1007/s11745-009-3344-0

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  • DOI: https://doi.org/10.1007/s11745-009-3344-0

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