The statins as anticancer agents.

Abstract

3-Hydroxy-3-methylgutaryl CoA reductase inhibitors, commonly referred to as the statins, have proven therapeutic and preventative effects in cardiovascular diseases. Recently, there are emerging interests in their use as anticancer agents based on preclinical evidence of their antiproliferative, proapoptotic, anti-invasive, and radiosensitizing properties. Inhibition of 3-hydroxy-3-methylgutaryl CoA reductase by the statins interferes with the rate-limiting step of the mevalonate pathway, leading to reduced levels of mevalonate and its downstream products, many of which play important roles in critical cellular functions such as membrane integrity, cell signaling, protein synthesis, and cell cycle progression. Perturbations of these processes in neoplastic cells by the statins may therefore result in control of tumor initiation, growth, and metastasis. The statins have demonstrated growth inhibitory activity in cancer cell lines and preclinical tumor models in animals. Phase I trials of statins in humans have demonstrated myotoxicity as their main dose-limiting toxicity, and Phase II trials in various tumor types are ongoing to evaluate their efficacy. Potential future directions in the development of the statins as anticancer agents include combinations with chemotherapeutic or other molecular-targeted agents, combinations with radiotherapy, maintenance therapy in minimal disease status, and as chemopreventive therapy.