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Pharmacological Actions of Statins: a Critical Appraisal in the Management of Cancer

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Pharmacological Actions of Statins: a Critical Appraisal in the Management of Cancer 1521-0081/12/6401-102–146$25.00 PHARMACOLOGICAL REVIEWS Vol. 64, No. 1 Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 4994/3736181 Pharmacol Rev 64:102–146, 2012 ASSOCIATE EDITOR: MICHAEL M. GOTTESMAN Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer Patrizia Gazzerro, Maria Chiara Proto, Giuseppina Gangemi, Anna Maria Malfitano, Elena Ciaglia, Simona Pisanti, Antonietta Santoro, Chiara Laezza, and Maurizio Bifulco Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano, Italy (P.G., M.C.P., G.G., A.M.M., E.C., S.P., A.S., M.B.); and Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy (C.L.) Abstract ................................................................................ 103 I. Introduction............................................................................. 103 II. The isoprenylated proteins ............................................................... 104 Downloaded from III. The pharmacology of statins .............................................................. 105 A. Chemical structure and pharmacological activity ........................................ 105 B. Pharmacokinetic properties of statins .................................................. 106 C. Metabolism of the statins in health and disease ......................................... 107 1. Cytochrome P450-mediated metabolism of statins .................................... 107 pharmrev.aspetjournals.org 2. Statin excretion ................................................................... 108 3. Factors that may affect statin metabolism ........................................... 108 a. Race or ethnicity ............................................................... 108 b. Food intake .................................................................... 108 c. Ageandsex.................................................................... 108 d. Concomitant diseases ........................................................... 108 4. Clinically relevant drug-drug interactions with HMG-CoA reductase inhibitors .......... 109 a. Statins and CYP3A4 inhibitors................................................... 109 by guest on November 10, 2014 b. Statins and calcium antagonists.................................................. 109 c. Statins and macrolides/ketolide antibiotics ........................................ 110 d. Statins and protease inhibitors................................................... 110 e. Statins and organic anion-transporting polypeptide 1B1 inhibitors................... 110 f. Other interactions .............................................................. 110 g. Statin interactions with cytochrome P450 inducers................................. 111 IV. Effects of the statins on tissues and biological processes ..................................... 111 A. Statins and immune system ........................................................... 111 1. Statin effects on the major histocompatibility complex ................................ 111 2. Statin effects on costimulation ...................................................... 111 3. Statin effects on adhesion molecules................................................. 112 4. Statin effects on inflammatory mediators ............................................ 112 5. Molecular mechanisms of statin immunoregulation ................................... 112 B. Statins and endothelial function ....................................................... 112 1. Statins and angiogenesis ........................................................... 112 2. Statins and endothelial dysfunction ................................................. 113 3. Statins and endothelial progenitor cell biology........................................ 114 C. Statins and vascular smooth muscle cell function........................................ 114 D. Statins and platelet function .......................................................... 115 E. Statins and metabolism ............................................................... 117 F. Statins and bone ..................................................................... 118 G. Statins and nervous system ........................................................... 119 Address correspondence to: Prof. Maurizio Bifulco, Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano (Salerno), Italy. E-mail: [email protected] This article is available online at http://pharmrev.aspetjournals.org. http://dx.doi.org/10.1124/pr.111.004994. 102 STATINS AND CANCER: PROS AND CONS 103 V. Statins and cancer....................................................................... 120 A. Effects of statins in cancer ............................................................ 120 B. Statins and cancer risk prevention ..................................................... 124 C. Statins in cancer treatment ........................................................... 129 D. Clinical trials: monotherapy and combined therapy using statins in human cancer.......... 130 VI. Conclusions and future directions ......................................................... 135 Acknowledgments ....................................................................... 137 References .............................................................................. 137 Abstract——Statins, among the most commonly pre- health have to be taken into account in subjects scribed drugs worldwide, are cholesterol-lowering treated with statins. Some evidence has shown a di- agents used to manage and prevent cardiovascular chotomous effect of statins with either cancer-inhibit- and coronary heart diseases. Recently, a multifaceted ing or -promoting effects. To date, clinical trials failed action in different physiological and pathological con- to demonstrate a reduced cancer occurrence in statin ditions has been also proposed for statins, beyond users and no sufficient data are available to define the anti-inflammation and neuroprotection. Statins have long-term effects of statin use over a period of 10 been shown to act through cholesterol-dependent and years. Moreover, results from clinical trials performed -independent mechanisms and are able to affect sev- to evaluate the therapeutic efficacy of statins in can- eral tissue functions and modulate specific signal cer did not suggest statin use as chemotherapeutic or transduction pathways that could account for statin adjuvant agents. Here, we reviewed the pharmacology pleiotropic effects. Typically, statins are prescribed in of the statins, providing a comprehensive update of middle-aged or elderly patients in a therapeutic regi- the current knowledge of their effects on tissues, bio- men covering a long life span during which metabolic logical processes, and pathological conditions, and we processes, aging, and concomitant novel diseases, in- dissected the disappointing evidence on the possible cluding cancer, could occur. In this context, safety, future use of statin-based drugs in cancer therapy. toxicity, interaction with other drugs, and the state of I. Introduction (Fig. 1). GGPP and FPP are lipid attachments that con- stitute key intermediates for post-translational events of Many studies have highlighted the fact that statins, several cell signaling proteins, including the small besides their application in cardiovascular and coronary GTPase family members Ras, Rac, and Rho (Chow, heart diseases as cholesterol-lowering agents, exhibit a 2009). The attachment of these lipids also known as wide range of pleiotropic effects that may significantly isoprenylation is fundamental for the activation and contribute to the treatment of conditions other than intracellular transport of these proteins that act as mo- cardiac diseases, such as inflammatory and neurological lecular switches controlling multiple pathways and cell pathologic conditions and even tumors. The commonly functions such as maintenance of cell shape, motility, known pharmacological activity of statins relies on a factor secretion, differentiation, and proliferation. Con- potent inhibition of the endogenous mevalonate path- sidering that the key role of these prenylated proteins is way, which leads directly to the biosynthesis of choles- an obvious expectance that statin effects may extend terol and isoprenoids. Statins bind to mammalian HMG- beyond their cholesterol-lowering actions. These cholesterol- CoA reductase at nanomolar concentrations, leading to an effective displacement of the natural substrate HMG- endothelial progenitor cells; ER, endoplasmic reticulum; ERK, extra- CoA, which binds instead at micromolar concentrations cellular signal-regulated protein kinase; FOLFIRI, folinic acid (leu- (Moghadasian, 1999). The interactions between statins covorin)/5-FU/irinotecan; FPG, fasting plasma glucose; FPP, farne- and HMG-CoA reductase prevent the conversion of syl pyrophosphate; GGPP, geranyl-geranyl pyrophosphate; HCC, hepatocellular carcinoma; HDL-C, high-density lipoprotein choles- HMG-CoA to L-mevalonate resulting in the inhibition of terol; ICAM, intercellular adhesion molecule; IFN, interferon; IL, the downstream cholesterol biosynthesis and numerous interleukin; JNK, c-Jun NH2-terminal kinase; LDL-C, low-density isoprenoid metabolites such as geranylgeranyl pyro- lipoprotein-cholesterol; LFA-1, lymphocyte function-associated anti- phosphate (GGPP1) and farnesyl pyrophosphate
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