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.
Vitamin E is a generic term for all tocopherol and tocotrienol derivatives. The most abundant and active form of vitamin E isoforms in vivo is alpha-tocopherol, but recently the roles of other forms of vitamin E have received renewed attention. In this review, we summarize the differences among alpha-, beta-, gamma-, delta-tocopherols and tocotrienols specifically regarding the following points; (i) their radical-scavenging efficacies and chemical reactivity with metal ions in solution, (ii) their physical effects at the liposomal membrane interior, and (iii) their protective effects against cell toxicity. Moreover, the physiological significance and future prospects for using vitamin E, especially tocotrienols, for the prevention and treatment of disease are discussed.