Potential antitumor effects of statins (Review).

Statins, which have been introduced to the clinic for the treatment of hypercholesterolemia, are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid (MA). MA is the precursor in the biosynthesis of isoprenoid compounds including cholesterol, dolichol and ubiquinone. Furthermore, mevalonate-derived prenyl groups enable precise cellular localization and function of many proteins such as Ras and Rho proteins. Therefore, besides lowering cholesterol level, statins exert pleiotropic effects on many essential cellular functions including cell proliferation, differentiation, and survival but also participate in the regulation of cell shape and motility. Statins have been shown to inhibit proliferation and to induce apoptosis in a variety of tumor cells. They have also been found to display antitumor effects against melanoma, mammary carcinoma, pancreatic adenocarcinoma, fibrosarcoma, glioma, neuroblastoma, and lymphoma in animal tumor models resulting in retardation of tumor growth, and/or inhibition of the metastatic process. In preclinical studies statins have also been demonstrated to potentiate the antitumor effects of some cytokines and chemotherapeutics. The molecular mechanisms underlying antitumor activity of statins have not been fully elucidated but interference with the function of Ras and Rho family GTPases, inhibition of the activity of certain cyclin-dependent kinases (CDK), and activation of CDK inhibitors, all seem to participate in this activity. The results of several clinical studies of statins in cancer patients including phase I, phase I/II, and phase II trials have been published. Although evaluation of the therapeutic efficacy is not the purpose of early clinical trials and all conclusions might be premature at this stage, some preliminary conclusions have already been drawn. The results of these studies do not show any significant therapeutic effects of statins in cancer patients. However, the results of one of these studies suggest that statins could effectively strengthen the therapeutic activity of some chemotherapeutics. This observation seems to agree with the results of preclinical studies. However, as toxic side effects of statins have been particularly evident in their combination with some other drugs great caution should be advised while planning clinical trials based on combination therapy including statins in cancer patients.