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Pharmacotherapy Statins and cancer L.V.A.M. Beex Although proliferating malignant cells consume cholesterol, this may not completely explain the observed inverse relation between plasma cholesterol levels and the incidence of cancer. Results of studies and meta-analysis, investigating possible adverse effects of cholesterollowering therapy did not disclose any consistent promoting or preventive activity of statins on the incidence of frequently occurring cancers. However, statin use may reduce the rate of dedifferentiation and recurrence of established prostate and breast cancer. Furthermore, lipoprotein (-like) ligands for low- and high density lipoprotein receptors on tumour cells can serve as carriers for targeted anti-cancer therapies. (Belg J Med Oncol 2013:7(2):46-49) Introduction There is a well-known relationship between low levels of cholesterol and an increased risk for dying from cancer.1,2 The most important mechanism for that is an increased consumption of cholesterol by cancer cells.3 However, there remains a less understood weak relationship between low levels of cholesterol long before the onset of cancer, suggesting that a causal connection is not completely excluded. So the question remains whether lowering of cholesterol levels by medical treatment could enhance the risk for subsequent cancer. Cholesterol levels can be lowered effectively by the use of statins. Cholesterol synthesis and statins The synthesis of cholesterol by the mevalonate pathway is predominantly located in the liver but in addition also in macrophages and other peripheral cells. AcetylCoenzyme A (ACoA) and subsequently beta-hydroxy-beta methylglutaryl CoA (HMG-CoA) are formed from waste products of carbohydrates and fatty acids. HMG-CoA is transformed into HMG-CoA mevalonic acid, by the activity of HMGCoA reductase. After several more enzymatic steps, HMG-CoA mevalonic acid is transformed into farnesyl pyrophosphate and thereafter converted to cholesterol but also to other molecules, including geranyl pyrophosphate. Both farnesyl pyrophos- phate and geranyl pyrophosphate contribute to the lipidation of cellular proteins (=prenylation), enabling those proteins to attach the cell membrane for interaction with (proliferative) cell activity.4,5 The transport of cholesterol is carrier-bound by lipoproteins, i.e. Low Density Lipoproteins (LDL) and High Density Lipoproteins (HDL). Statins are competitive antagonists of HMG-CoA reductase and therefore can reduce the production of cholesterol and other end products of the mevalonate pathway, and this occurs predominantly in liver cells. Consequently, the production of LDLreceptors (LDLR) on the surface of hepatocytes is upregulated, allowing the binding of LDL cholesterol out of the blood with the decrease of LDL cholesterol levels as a consequence. Moreover, statins may prevent the synthesis of precursors of LDL in the liver. The extensive use of statins has resulted in the decrease of cardiovascular morbidity and mortality.6 Statins may have hydrophilic (atorvastatin, pravastatin, rosuvastatin) or lipophilic (simvastatin, fluvastatin, pitavastatin) properties. Hydrophilic statins are more hepatocyte-specific (by active transport in those cells) as compared to lipophilic statins and therefore have less general and cell-specific side-effects.7 Lipophilic statins also inhibit the production of cholesterol and sterols in other cells, including cancer cells. Some statins, especially the lipophylic statins Author: L.V.A.M. Beex MD PhD, Department of medical oncology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands, tel: +31 24 361 88 00. e-mail: [email protected]. Conflict of interest: the author has nothing to disclose and indicates no potential conflict of interest. Keywords: cancer, cholesterol, cholesterol receptors, mevalonate pathway, statins. Belgian Journal of Medical Oncology 46 volume 7, issue 2, 2013 pitavastatin and simvastatin and the hydrophilic rosuvastatin, can increase the levels of HDL cholesterol.8 Cancer and cholesterol metabolism Cholesterol is of importance to the integrity of cellular membranes and to cellular signal transduction processes and therefore may facilitate proliferation. In cancer cells, LDL-receptors (LDL-R) may be excessively activated with an increased cellular metabolism of LDL cholesterol and a decrease of plasma cholesterol levels as a consequence, which can often be found in patients with cancer progression.3,9-12 In contrast to most normal cells, hepatocytes, but cancer cells as well, are able to bind HDL-cholesterol by appropriate HDL-receptors (i.e. Scavenger Receptor B1).13 HDL cholesterol is important for its role in transporting cholesterol back to the liver cells. HDL cholesterol has also anti-inflammatory, antioxidant and anti-thrombotic properties, favouring the anti- atherogenic effects of this lipoprotein.7,8 Potentially, the presence of both receptor types in cancer cells could suggest they might be involved in the initiation and progression of cancer. The increased availability of cholesterol receptors in cancer cells is puzzling when taking the coincident upregulation of the mevalonate pathway in those cells into account. The latter has been observed by increased levels of HMG-CoA reductase levels in cancer cells.5 Llaverias et al have suggested that in (breast)cancer cells the upregulated mevalonate pathway primarily induces molecules for prenylation of cellular proteins and to a lesser extent for the production of cholesterol. The lack of sufficient cholesterol, not fulfilling the requirements for malignant cells, may therefore contribute to the increased cholesterol receptor activity and subsequent cholesterol consumption.14 Statins and incidence of cancer Based on suggestions of an increased cancer incidence with the use of statins, Thompson et al. reviewed the available literature on this topic and found five, mostly small and older studies, that were compatible with these suggestions.15 An increased incidence of cancer was found in particular when the use of statins was combined with drugs inhibiting the uptake of cholesterol, or in participants with the lowest LDL-cholesterol levels. However, in six studies, including three meta-analyses, no such relation was found. In fact, in one of the included studies the use of lipophylic (hydrophobic) statins was correlated with a decreased incidence of breast cancer.16 Brugts et al. published a meta-analysis of ten trials with in total 70,388 men and women who either suffered from cardio-vascular disease (in 20% of cases) or had an increased risk for cardio-vascular disease, and who were randomised for statin use or not. After a median observation time of four years, a significant decrease in severe cardio-vascular incidents and death was found (HR 0.81 and 0.88 respectively). However, the risk for cancer was about equal in both groups (HR 0.97).17 Beneficial and adverse effects of statins were also investigated by Baigent et al. In their reported metaanalysis no differences in cancer incidence or mortality were detected in 21 randomised trials comparing the use of statins versus placebo or no therapy in 129,526 men and women. The median observation times in the included studies ranged from two to six years.18 In the same report, the effects of high versus low dose statins on the incidence of cancer in five trials did not disclose any significant differences either. More recently, the long-term effects of simvastatin use, (a lipophylic statin) have been published.19 In the Heart Protection Study, which was first published in 2002, 15,454 men and 5082 women at risk for cardiovascular disease were randomised for the use of simvastatin 40 mg daily or placebo.20 After a median trial (and protocol medication) duration of 5,3 years, the 17,519 patients that were alive at that time were allowed to continue with study medication or to opt for simvastatin. Simvastatin use reduced cardiovascular events and death with 23% and 18% respectively. After a follow-up period of eleven years, no significant effect of statin use on either cancer incidence or mortality was found. In Table 1 an overview of the mentioned studies is given. Although in individual studies the number of participating women may have been limited, the total number of women in the meta-analysis and in the Heart Protection Study were still considerable and cancer incidence in both men and women, just as in the total group, did not seem to be influenced by the use of statins.17 The same was true when data were analysed for different cancer types (gastrointestinal, respiratory, breast, genitourinary and others).18,19 In a large prospective cohort study in 368 familydoctor practices in England and Wales over 225,000 new users of statins (without manifest cardiovascular Belgian Journal of Medical Oncology volume 7, issue 2, 2013 47 2 Pharmacotherapy Table 1. Statin use and cancer incidence. Meta analysis Number of trials Randomisation Participants (% women) Follow-up (median, yrs) HR incidence of cancer Brugts et al.17 10 statin versus placebo or usual control 70.388 (34) 3.2-5.5 0.97 (0.89-1.05) Baignent et al.18 21* statin versus placebo or no therapy 129.526 (29) 2-6 1.00 (0.95-1.04) Baignent et al.18 5 high versus low dose statins 39.612 (19) 2-7 1.02 (0.89-1.10) HPS19 1 simvastatin versus placebo 20.536 (24) 11 0.98 (0.92-1.05) HR death by cancer 0.99 (0.91-1.09) no difference *Including 9 trials overlapping with analysis from Brugts et al. HPS = Heart Protection Study disease) and more than 1.7 million non-users were followed for side-effects of therapy.21 After five years of observation, statin users versus non-users proved to have more severe myopathies, liver function abnormalities, acute renal insufficiency and cataract. A comprehensive analysis of the effects of statins on the incidence of cancer showed that the risk for oesophageal cancer in statin users, both men and women, was significantly lower. For stomach, colon, lung, breast, renal cell, prostate cancer and melanoma no significant interactions were found with the use of statins.21 On the basis of these observations, one should not be reluctant to prescribe statins as there are no indications for an increased risk to develop cancer. On the other hand, there are no hard arguments to prescribe statins to prevent cancer. However, the effects for special target groups, e.g. patients with a metabolic syndrome, may be different. The common occurrence of adiposity in this syndrome, with consequently higher levels of oestrogens, may for instance complicate interpretations of effects of the use of statins for the risk of postmenopausal breast cancer. Statins and recurrence of cancer In a review article of Papadopoulos et al. the authors point to different possible interactions of statins on the development of prostate cancer.22 Direct reduction of cholesterol as a ligand for cell membrane LDL cholesterol receptors may lead to tumour suppression. Low dosages of statins promote angiogenesis. For high doses, however, anti-angiogenic effects have been reported. Statins may induce cell apoptosis. The anti-inflammatory properties of statins may reduce progression of prostate cancer. The clinical importance of these effects remains unclear. However, lipophilic statins, such as simvastatin, have proven to delay the progression of prostate carcinoma to hormone independency.23,24 In a retrospective study, the use of statins (n=236) at time of radical prostatectomy correlated with a reduction of the risk for biochemical (prostate-specific antigen, PSA) recurrence with 30%.25 It was also found that the metabolic syndrome behaves as a stimulating factor in the progression of prostate cancer.26 In a prospective Danish study with over 18,000 women with primary breast cancer, 3,282 received a prescription for statins. Especially the use of simvastatin (lipophilic) was correlated with a 10% reduction in the risk for relapse during ten years of follow-up. For hydrophilic statins such a relationship was not found.27 In accordance with this, in cell lines of well or poorly differentiated cancers, simvastatin (lipophylic) proved to be more effective in inhibiting cell proliferation as compared to pravastatin (hydrophilic).28 In the 2012 November edition of the N Engl J Med, Nielsen et al. describe the effects of the use of statins for cancer-related mortality in the Danish population. The authors found a non dose-response reduction in cancerrelated mortality of up to 15% by users of statins for all of thirteen cancer types, whereas for most of the remaining fourteen cancer types the same trend was found but differences in awareness for cancer, smoking and concomitant medication betweenstatin users and non-users may have compromised these results.29 Lipoprotein receptors as targets for therapy The (by statin use enhanced) increased production Belgian Journal of Medical Oncology 48 volume 7, issue 2, 2013 Key messages for clinical practice 1. Patients with cancer may have low cholesterol levels by an increased cholesterol consumption by cancer cells. The use of cholesterol-lowering statins does not consistently increase or decrease the incidence of cancer but may be beneficial to patients with established breast or prostate cancer, both by decreasing the availability of plasma cholesterol and by interference with the cancer cell mevalonate pathway. 2. Cholesterol receptors on tumour cells may serve as targets for anti-cancer therapy. and activation of cholesterol receptors on cancer cells also offers a possibility for attacking tumour cells. LDL’s are already involved in the delivery of photo sensitisers to tumour cells.30 The structure of HDL also allows the transport of hydrophobic substances through the body. HDL can bind to the aforementioned HDL receptors on tumour cells. So it may be possible to carry appropriate chemotherapeutics (e.g. paclitaxel) very effectively to tumour cells.31,32 HDL-cholesterol particles can also be used as nano molecules, carrying RNA particles that interfere with the production of (proliferating) proteins (small interference RNA, siRNA), into cancer cells.33 5. Clendening JW, Penn LZ. Oncogene 2012; 31(48):4967-78. 6. Steinberg D. New Engl J Med 2008;359:1426-27. 7. Sirtori C. Pharmac Ther 1993;60:431-59. 8. Yamashita S, Tsubakio-Yamamoto K, Ohama T, et al. J Atheroscler Thromb 2010;17:436-51. 9. Vitols S, Angelin B, Ericsson S, et al. Proc Natl Acad Sci USA 1990;87: 2598-602. 10.Graziani SR, Igreja FA, Hegg R, et al. Gynecol Oncol 2002;85:493-7. 11. Ades A, Carvalho JP, Graziani SR, et al. Gynecol oncol 2001;82:84-7. 12.Gorin A, Gabitova L, Astsaturov I. Current Opinion in Pharmacol 2012;1 2:1-7. 13.Lacko AG, Nair M, Ptokai L, et al. Expert Opin Drug Deliv 2007;4:665-75. 14.Llaverias G, Danilo C, Mercier I, et al. Am J Pathology 2011;178:402-12. 15.Thompson JS, Sood A, Arora R. Am J Ther 2010;17:e100-4. Conclusion No enhancing effects of statins on the incidence or mortality of cancer during short and long observation times have been found. Instead, statins may have anti-cancer properties. However, until now this has not been established for most types of cancer. Despite this overall conclusion, it is worth mentioning that especially lipophilic statins, such as simvastatin, may have a protective effect for the occurrence of oesophageal carcinoma and may reduce recurrences of poorly differentiated prostate cancer or breast cancer. In addition, there is a possibility that there are also beneficial effects for patients with cancer and the metabolic syndrome. Finally, lipoproteinreceptors on tumour cells may serve as targets for LDL or HDL as transport molecules or as nano particles in the treatment of cancer. 16. Cauley JA, McTiernan A, Rodabough RJ, et al. J Natl Cancer Inst 2006;98:700–7. 17. Brugts JJ, Yetgin T, Hoeks SE, et al. BMJ 2009; 338:b2376; BMJ Dutch edition 2009;24:34-41. 18.Baignent C, Keech A, Kearney PM, et al. Lancet 2005;366:1267-78. 19.Heart Protection Study Collaborative Group, Bulbulia R, Bowman L, Wallendszus K, Parish S, Armitage J, Peto R, Collins R. Lancet 2011; 378:2013-20. 20.Heart Protection Study Collaborative Group. Lancet 2002;360:7-22. 21.Hippisley-Cox J, Coupland C. BMJ 2010;340:c2197. 22.Papadopoulos G, Delakas D, Nakopoulou L, et al. Eur J Cancer 2011; 47:819-30. 23.Boudreau DM, Yu O, Johnson J. Expert Opin Drug Saf 2010;9(4):603-21. 24.Banez LL, Klink JC, Jachandran J, et al. Cancer Epidemiol Biomarkers Prev 2010;19:722-8. 25.Hamilton RJ, Banez LL, Aronson WJ, et al. Cancer 2010;116:3389-98. 26.Flanagan J, Gray PK, Hahn N, et al. Ann Oncology 2011;22:801-7. 27. Ahern TP, Pedersen L, Tarp M, et al. J Natl Cancer Inst 2011;103(19):1461-8. References 28.Menter DG, Ramsauer VP, Harirforoosh S, et al. PLoS One 2011;6:e28813. 1. Law MR and Thompson SG. Cancer Causes Control 1991;2:253-61. 29.Nielsen SF, Nordestgaard BG, Bojesen SE. N Engl J Med 2012;376:1792- 2. Jacobs DR, Blackburn H, Higgins M, et al. Circulation 1992;86:1046-60. 802. 3. Peterson C, Vitols S, Rudling M. Med Oncol Tumor Pharmacother 30.Huntosova V, Buzova D, Petrovajova D, et al. Int J Pharm 2012;436:463-71. 1985;2:143-7. 31.Lacko AG, Nair M, Ptokai L, et al. Expert Opin Drug Deliv 2007;4:665-75. 4. Thurner M, Nussbaumer O, Gruenbacher G. Clin Cancer Res 2012;18: 32.Mooberry LK, Nair M, Paranjape S, et al. J Drug Target 2010;18:53-8. 3524-31. 33.Shazad MM, Mangala LS, Han HD, et al. Neoplasia 2011;13:309-19. Belgian Journal of Medical Oncology volume 7, issue 2, 2013 49 2