Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo

McAnally JA, Gupta J, Sodhani S, Bravo L, Mo H.

Exp Biol Med (Maywood). 2007 Apr;232(4):523-31.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the membrane anchorage and biologic functions of growth-related proteins. Contrary to preclinical studies showing the growth-suppressive activity of statins, competitive inhibitors of HMG CoA reductase, clinical application of statins in cancer is precluded by their lack of activity at levels prescribed for the prevention of cardiovascular disease and by their dose-limiting toxicities at high doses. The dysregulated and elevated HMG CoA reductase activity in tumors retains sensitivity to the isoprenoid-mediated posttranscriptional down-regulation, an action that complements the statin-mediated inhibition and may lead to synergistic impact of blends of isoprenoids and lovastatin on tumor HMG CoA reductase activity and consequently tumor growth. d-gamma- and d-delta-tocotrienols, vitamin E isomers containing an isoprenoid moiety, and lovastatin-induced concentration-dependent inhibition of the 48-hr proliferation of murine B16 melanoma cells with IC50 values of 20 +/- 3, 14 +/- 3, and 1.5 +/- 0.4 microM respectively. A blend of lovastatin (1 microM) and d-gamma-tocotrienol (5 microM) totally blocked cell growth, an impact far exceeding the sum of inhibitions induced by lovastatin (12%) and d-gamma-tocotrienol (8%) individually. Synergistic impact of these two agents was also shown in human DU145 prostate carcinoma and human A549 lung carcinoma cells. C57BL6 mice were fed diets supplemented with 12.5 mg lovastatin/kg body weight, 62.5 mg d-delta-tocotrienol/kg body weight, or a blend of both agents for 22 days following B16 cell implantation; only the latter had significantly lower tumor weight than those with no supplementation. Co-administration of isoprenoids that posttranscriptionally down-regulate tumor reductase may lower the effective dose of statins and offer a novel approach to cancer chemo-prevention and/or therapy.

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Tocotrienols, a group of Vitamin E stereoisomers, offer many health benefits including their ability to lower cholesterol levels, and provide anticancer and tumor-suppressive activities. Several recent studies determined the cardioprotective abilities of tocotrienols, although the number is only 1% compared to the study with tocopherols. Both in acute perfusion experiments and in chronic models, tocotrienols attenuate myocardial ischemia-reperfusion injury, artherosclerosis, and reduced ventricular arrythmias. Apart from the antioxidative role of tocotrienols, it appears that tocotrienols mediated cardioprotection is also achieved through the preconditioning-like effect, the best yet devised method of cardioprotection. Hence, tocotrienols likely fulfills the definition of a pharmacological preconditioning agent and give a tremendous opportunity to place tocotrienols as an important therapeutic option in cardiovascular system.