Mini-reviewStatins and cancer: Current and future prospects
Introduction
The mevalonate pathway is an important metabolic pathway that provides cells with bioactive molecules that are crucial for multiple cellular processes. The end products of the mevalonate pathway include sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme-A, isopentenyl tRNA and ubiquinone [1], [2] (Fig. 1). Blockage of the mevalonate pathway results in decreased levels of mevalonate and its downstream products. Blockage of this pathway may also significantly influence other important cellular functions.
Statins are inhibitors of the first committed enzyme of mevalonate pathway, 3-hydroxy-methylglutaryl (HMG) CoA reductase (Fig. 1). As structural analogs of HMG-CoA reductase, statins block the conversion of HMG-CoA to mevalonic acid [3]. The statin family consists of several drugs: lovastatin (Mevacor®), simvastatin (Zocor®), mevastatin (Compactin®), fluvastatin (Lescol®), pravastatin (Pravachol®), atorvastatin (Lipitor®), rosuvastatin (Crestor®) and cerivastatin (Baycol®; cerivastatin was withdrawn from the market in 2001). Of these drugs, cerivastatin, simvastatin and lovastatin are the most lipophilic, followed by mevastatin, fluvastatin, atorvastatin, rosuvastatin and pravastatin. Pravastatin is extremely hydrophilic compared with the other statins.
Because of their cholesterol-lowering properties, statins have been widely prescribed for the treatment of hypercholesterolemia and are among the most widely used pharmaceutical agents in the world. Extensive clinical trials have demonstrated that statins reduce the risk of myocardial infarction, ischemic stroke, and the development of peripheral arterial disease. Indeed, statins may improve the outcome of these diseases even when they are administered after the diagnosis [4], [5], [6]. Recently, there has been growing interest in the mechanisms beyond cholesterol reduction by which statins influence physiology because experimental and clinical evidence has indicated that some of the cholesterol-independent or “pleiotropic” effects of statins may be beneficial for different diseases. These effects include improved endothelial function and/or stabilization of the atherosclerotic plaque, anti-inflammatory and immuno-modulatory effects, neuroprotective effects (such as reduced risk of dementia), positive effects on bone metabolism, anticancer effects (reviewed in [1], [7], [8]), and improved progression of chronic kidney disease [9]. However, contrasting results have also been observed; for instance, statins do not benefit the cognitive function of patients with dementia [1], [8].
The pleiotropic effects of statins may be explained by the fact that, while inhibiting cholesterol biosynthesis, statins also inhibit the synthesis of a variety of other metabolites, particularly isoprenoids, which serve as substrates for the post-transcriptional modification of many proteins. These intermediates are necessary for various essential cell functions and may explain the pharmacological properties of statins that are not based on cholesterol reduction.
In the present review, the anticancer effects of statins will be discussed, with special emphasis on their potential benefits in cancer prevention and treatment. This review also offers insights into the possible molecular mechanisms of statins anticancer activity and the future directions of statins in the clinic.
Section snippets
Anticancer effects of statins in vitro
Numerous in vitro experimental data have shown that statins exhibit antitumor effects against various leukemia cells and solid tumor cells of different origins (Table 1). These effects primarily result from the suppression of proliferation and the induction of apoptosis by statins.
The several conclusions can be drawn from the experimental data presented in Table 1. First, different statins have strong antiproliferative and proapoptotic effects on various tumor cell lines of differing origins.
Statins and cancer risk
The first connection between lipid-lowering therapy and cancer risk was observed with animal studies in the early 1990s. Lovastatin administration was associated with a higher incidence of hepatocellular and pulmonary cancers [45], whereas simvastatin induced thyroid hypertrophy and follicular adenomas in rats [46]. However, the statin-associated carcinogenesis was induced by doses greatly higher than those commonly used to treat hypercholesterolemia. Later, it was found that pravastatin
Statins and cancer treatment
The promising in vitro anticancer effects of statins have stimulated investigations into their possible application as a single anticancer agent in clinical practice. There are relatively few clinical trials available that have specifically explored the potential benefit of statins in cancer treatment. However, conflicting results have been reported regarding their efficacy (the details regarding the clinical studies are given in Table 3).
The first beneficial (although modest) effect of statins
Statins combined with other anticancer drugs
The side effects of statin administration are myopathy, rhabdomyolysis and hepatotoxicity. In early clinical studies, quinone has been used to reverse lovastatin-induced myopathy. Because the doses required to inhibit proliferation and increase apoptosis are associated with high toxicity, the use of the statins as a monotherapy for cancer treatment, particularly solid tumors, could be restricted, and it appears doubtful that statins will be utilized in the future as a monotherapy for cancer
The molecular mechanisms of anticancer effects of statins
The inhibition of HMG-CoA reductase by statins leads to reduced levels of mevalonate and its downstream products, including cholesterol, ubiquinone, and dolichol, and, most important, reduced levels of the isoprenoid intermediates geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) (Fig. 1). GGPP and FPP, collectively known as isoprenoids, bind to several important proteins, including the small GTP-binding Ras and Rho proteins. Protein prenylation facilitates protein
Conclusions
Statins are inhibitors of 3-hydroxy-methylglutaryl (HMG) CoA reductase that lower cholesterol and prevent cardiovascular disease. They are among the most widely prescribed drugs. Recently, there has been growing interest in their mechanism(s) of action beyond cholesterol reduction because experimental and clinical evidence have indicated that some of the cholesterol-independent or “pleiotropic” effects of statins may be beneficial for different diseases, including cancer. In the past few years,
Acknowledgment
This work was supported by funds of the Ministry of Science, Education and Sport of the Republic of Croatia (Project No. 098-0982913-2748).
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