The Role of Statins in Cancer Prevention and Treatment
The Role of Statins in Cancer Prevention and Treatment
Statins inhibit the activity of the rate-limiting enzyme in the cholesterol biosynthetic pathway, HMG-CoA reductase, and are widely prescribed for lowering plasma lipid levels. Several statins have antitumor effects in experimental models, and observational studies suggest that this anticancer activity in the laboratory may translate into effective treatments and/or preventive strategies for certain human cancers. This paper reviews the laboratory and clinical evidence that statins have anticancer activity, discusses the possible mechanisms by which tumor growth may be inhibited by this class of drugs, and outlines strategies for the evaluation of these agents in the prevention and treatment of human cancers.
HMG-CoA reductase inhibitors (or "statins") are US Food and Drug Administration (FDA)- approved for treating hypercholesteremia. Members of this drug class currently available in North America are listed in Table 1.[1,2] Statins produce reductions in low-density lipoprotein (LDL) cholesterol of up to 60% by inhibiting the rate-limiting step in hepatic cholesterol biosynthesis and have been shown to decrease cardiovascular morbidity and mortality in both primary and secondary prevention studies (reviewed in ). Beyond lipid-lowering, however, the statins have effects on numerous other biologic pathways, suggesting that they may be useful for treating conditions other than cardiovascular disease (reviewed in [4-6]). For example, statins have antithrombotic and anti-inflammatory activity that may account for their apparent ability to decrease the risk of venous thromboembolism and ischemic stroke, prevent osteoporosis, and retard the progression of multiple sclerosis. In addition, they are generating much interest in their anticancer activity, which is the subject of this review. The pleiotropic activities of statins are summarized in Table 2.[1,5,7-14] General Information Over 76 million prescriptions for statins were filled in the United States in 2000, making statins the most widely prescribed drug class for lowering cholesterol and among the most widely prescribed of all drug classes. While they all competitively inhibit the enzyme HMG-CoA reductase, the six statins currently available in North America differ in their synthesis, structure, potency, metabolism, and pharmacokinetic and pharmacodynamic properties (Table 1). These dissimilarities may account for the observation that the individual drugs seem to have disparate anticancer activities.[15,16] Biochemistry
Lovastatin, a mevinic acid derivative produced by fermentation of Aspergillus terreus, was the first statin marketed in the United States for cholesterol-lowering. Pravastatin (Pravachol) and simvastatin (Zocor) are the two other fungal-derived, "natural" statins. Fluvastatin (Lescol) was the first entirely synthetic statin and has been followed by atorvastatin (Lipitor), cerivastatin, and rosuvastatin (Crestor). Cerivastatin has been voluntarily removed from the US market because of its association with a higher than expected number of fatal cases of rhabdomyolysis. All statins are competitive inhibitors of HMG-CoA reductase to prevent the conversion of HMG-CoA to mevalonate (Figure 1). Disruption of this step results in an overall decrease in the amount of cholesterol produced by the liver and, therefore, a lowering of plasma cholesterol levels. Although cholesterol is the most widely studied product, several key intermediate products of this biochemical pathway are also affected by statins. It is the inhibition of these intermediates that accounts for the panoply of biologic effects that statins have beyond cholesterol reduction. Products of the cholesterol biosynthesis pathway with particular relevance to oncology include geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), which are used by their respective transferase enzymes for posttranslational modification of certain cellular proteins. For example, Ras requires the addition of a farnesyl moiety for activity, and targeting this farnesylation step with farnesyl transferase inhibitors is an active area of cancer treatment investigation. Similarly, Rho GTP-binding proteins are involved in cell signaling processes and require geranylgeranylation for activity. Inhibition of Rho protein activity by disruption of geranylgeranylation is also a promising potential cancer treatment strategy and is discussed below. Pharmacology
The pharmacology of HMG CoA reductase inhibitors has been reviewed in detail recently. The statins are orally administered and are variably absorbed from the gastrointestinal tract with bioavailabilities ranging from < 5% (lovastatin, simvastatin)to 25% (fluvastatin). The statins concentrate in the liver, where they reduce hepatic cholesterol synthesis, resulting in upregulation of hepatic LDL receptors, which in turn results in increased clearance of LDL cholesterol from plasma. Since statins concentrate in the liver, little drug circulates in plasma and that which does circulate is highly protein bound. Except for rosuvastatin, the statins are extensively metabolized in the liver to active (atorvastatin, lovastatin, simvastatin) or inactive (fluvastatin, pravastatin) metabolites. All statins are eliminated predominantly by biliary excretion into feces; however, the elimination half-lives vary considerably (Table 1). The statins differ in their solubility properties; pravastatin and rosuvastatin are hydrophilic, whereas the remaining members of the class are lipophilic. Pravastatin is unique among the statins in that it is not metabolized by the cytochrome P450 system and hence has fewer potential medication interactions than other members of the class. Toxicity
Statins have been used safely in millions of people worldwide, but cerivastatin was withdrawn from the US market after postmarketing surveillance revealed a higher than expected incidence of fatal rhabdomyolysis. Liver and muscle are the primary targets of statin toxicity. In large, randomized cardiovascular clinical trials, elevations of serum transaminase levels to greater than three times normal were observed in 1% to 3% of participants receiving statins (reviewed in ). No study, however, has demonstrated a significant difference between statins and placebo for serious hepatic adverse events. All statins may be associated with asymptomatic elevations of serum creatinine kinase or with symptomatic muscle injury (reviewed in [20,21]), but the incidence of these events is low (< 1% and 0.1%, respectively). Moreover, in four major cardiovascular trials involving over 50,000 participants, no significant differences in the incidence of muscle injury were observed in the statin and placebo groups. Rhabdomyolysis is a rare but potentially fatal complication of statin use. Cerivastatin accounted for nearly half of all reported fatal rhabdomyolysis cases through 2001 (31 of 73 total cases), and the rate of fatal rhabdomyolysis with cerivastatin was 16 to 80 times greater than that for any other statin. It must be noted, however, that these 73 statin-associated rhabdomyolysis deaths occurred in the context of nearly 500,000,000 statin prescriptions dispensed, indicating that serious muscle complications due to these drugs are rare. Moreover, the risk of muscle injury is highest when statins are administered concurrently with certain other medications that increase plasma statin levels, including fibric acid derivatives (eg, gemfibrozil), azoles (eg, itraconazole [Sporanox], fluconazole), erythromycin, and some immunosuppressive agents (eg, cyclosporine). Do Statins Cause or Prevent Cancer? The results of toxicology studies in animals raised the concern early on that statins might cause cancer (reviewed in ), and a meta-analysis of cholesterol-reduction studies reported a small but nonsignificant excess of cancer deaths in participants treated with cholesterol-lowering agents. As a result, later cardiovascular trials included cancer incidence as a secondary end point, and multiple epidemiologic investigations have been conducted to assess the possibility that statins might cause harm. Major human studies in which the effect of statins on cancer incidence has been evaluated are summarized in Table 3.[24-44] In general, statins are safe and well tolerated by most people who take them, and there is no persuasive evidence linking these drugs to the development of cancer in humans. Neither the increase in breast cancer cases seen in one study nor the small increased incidence of malignancy in one elderly population has been replicated in several larger investigations. Moreover, later metaanalyses and epidemiologic studies do not demonstrate an increased risk of cancer (Table 3). On the contrary, the preponderance of currently available data suggests that statins may prevent cancer. This was first hinted at in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCAPS), in which lovastatin was compared to placebo for the primary prevention of cardiovascular disease, and a 50% reduction in new cases of melanoma was observed in the treatment group. Results of subsequent case-control studies further support the hypothesis that statins prevent certain malignancies, including melanoma, and cancers of the breast, colon, and possibly prostate.[37-40,44,45] Do Statins Help Treat Cancer? Lovastatin and Brain Tumors
Lovastatin has been evaluated in a phase I trial in which the maximum tolerated dose was 25 mg/kg/d (in four divided doses) administered on days 1 through 7 of a 28-day cycle. The dose-limiting toxicity was myopathy, which was preventable by treatment with ubiquinone (also known as coenzyme Q), a downstream derivative of mevalonate whose production is inhibited by statins (see Figure 1). One partial response was documented in a patient with a high-grade glioma among 88 patients treated in the study. An ensuing phase I/II trial evaluated lovastatin alone or combined with radiation in patients with anaplastic astrocytoma and glioblastoma multiforme.[ 47] Patients with newly diagnosed tumors received combinedmodality treatment, and those with relapsed disease were treated with the statin alone. Cohorts of three patients in the combined-modality group each received a lovastatin dose of 20, 25, and 30 mg/kg/d for the first 7 days of 28-day cycles. No unexpected neurologic toxicity was observed at any lovastatin dose level. There were two minor and two partial responses in this group (response duration: 160-236 days) and no complete responses. In nine patients with relapsed tumors treated with the drug alone at a dose of 30 mg/kg/d using the same schedule, one patient had a partial response lasting in excess of 405 days, one had a minor response, and one had stable disease. Lovastatin was associated with little toxicity in this study, and no patient discontinued the drug due to adverse events. Although two patients experienced episodes of arthralgias (which readily responded to treatment with analge-sics), no patients developed myopathy. These studies suggest that lovastatin is well-tolerated at high doses and may have modest anticancer activity in high-grade brain tumors. By contrast, a phase II study of lovastatin (35 mg/kg/d for 7 days repeated every 28 days) in advanced gastric cancer demonstrated no responses among 16 patients. Effect of Administration Schedule
Although it is likely that statins, like most anticancer agents, will be effective in some tumor types but not others, the intermittent administration schedule employed in the studies above may have been inappropriate and might lead to the abandonment of a promising agent prematurely. Laboratory investigations point to a growth inhibitory mechanism of action for statins in cancer (see below); thus, a continuous administration schedule may be preferred. For example, fluvastatin was administered daily for 14 days every 4 weeks in a phase I study with 12 pediatric patients with refractory solid tumors.[ 49] The maximum tolerated dose of fluvastatin administered on this schedule was 8 mg/kg/d, and despite the poor prognosis of this group of patients, there were 6 partial responses with two anaplastic astrocytoma patients remaining alive 22 months after initiating treatment. In another report, a patient with relapsed acute myelogenous leukemia (AML) treated with lovastatin, 40 mg four times daily continuously for 2 months, experienced a decline in the peripheral blast count, which persisted for an additional 3 months after stopping the drug.