This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Duncan, R. E. Articles by Archer, M. C. Search for Related Content PubMed PubMed Citation Articles by Duncan, R. E. Articles by Archer, M. C.

Statins and Cancer Development

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Michael C. Archer, Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2. Phone: 416-978-8195; Fax: 416-971-971-2366. E-mail: m.archer{at}utoronto.ca

	Abstract

Top Abstract References

 
There is epidemiologic evidence that the hydrophilic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor pravastatin increases the incidence of some extrahepatic cancers, although this finding has been attributed to chance. We hypothesize that pravastatin is able to promote the development of cancer by causing an induction of HMG-CoA reductase and, hence, mevalonate synthesis in extrahepatic tissues. We have shown that mevalonate, the product of HMG-CoA reductase, promotes the growth of breast cancer cells. Because there is no uptake of pravastatin by most extrahepatic cells, this statin will be unable to mitigate the increase in mevalonate synthesis in extrahepatic tissues that accompanies the decrease in circulating cholesterol caused by its inhibition of hepatic HMG-CoA reductase.

A disturbing increased incidence of cancers has been reported in two randomized controlled trials of the hydrophilic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor pravastatin—Prospective Study of Pravastatin in the Elderly at Risk (PROSPER; ref. 1) and Cholesterol and Recurrent Events (CARE; ref. 2). In the PROSPER trial, the reduction in deaths from vascular events was completely negated by the increase in deaths from cancer. In the CARE trial, breast cancer occurred in a significantly greater number of women treated with pravastatin. Randomized controlled trials of the lipophilic statins simvastatin (3) and lovastatin (4), however, have not shown an increased cancer incidence. The authors of both the PROSPER and CARE trials suggested that the increased incidence of cancer occurred by chance. Indeed, Shepherd et al. (5) suggest that the hydrophilic nature of pravastatin, which minimizes its uptake by extrahepatic tissues, should minimize its side effects. We hypothesize, however, that the absence of uptake of pravastatin by extrahepatic tissues indirectly mediates a cancer-promoting effect when coupled with the ability of this statin to lower serum cholesterol by inhibiting HMG-CoA reductase in the liver.

Both lipophilic and hydrophilic statins lower serum cholesterol concentrations by competitively inhibiting the activity of HMG-CoA reductase in the liver, resulting in reduced hepatic synthesis of mevalonate, a precursor of cholesterol. A decrease in serum cholesterol concentration causes a compensatory induction of HMG-CoA reductase and, hence, mevalonate synthesis in extrahepatic cells (6). We have recently shown that mevalonate promotes the growth in mice of tumors derived from human breast cancer cells, probably through enhanced proliferation (7). This result suggests that the induction of mevalonate synthesis in extrahepatic tissues that follows statin-mediated serum cholesterol reduction may promote the growth of occult neoplastic or preneoplastic cells (7). Indeed, in rodents, lowering of serum cholesterol by the unabsorbed bile acid–binding resin cholestyramine has been shown to promote mammary gland carcinogenesis (8, 9). There is evidence, however, that diffusion-mediated uptake of the lipophilic statins mitigates the increase in mevalonate synthesis in extrahepatic tissues that accompanies the decrease in serum cholesterol that they induce (10). Thus, lipophilic statins may be expected not to promote, and may even inhibit, cancer development. Indeed, no increased risk of cancer has thus far been reported in randomized controlled trials of the lipophilic statins (3, 4). In the follow-up to one trial, an indication of overall decreased risk of cancer death was seen in simvastatin users (11) and, in another, a significant reduction in incidence of melanomas was reported with lovastatin use (4). Several studies in rodents have also shown a protective effect of lipophilic statins on the growth of diverse tumor types (12-15) and on breast cancer cell growth in culture (16, 17).

Unlike the lipophilic statins, uptake of pravastatin by cells is mediated by a sodium-independent bile acid transporter (18). Because of the absence of this transporter on most extrahepatic cells (18), pravastatin has been shown to inhibit HMG-CoA reductase only in the liver and ileum, where the transporter is present (19), and does not inhibit the growth of breast cancer cells in culture (16, 17). Pravastatin, therefore, like cholestyramine, will be unable to mitigate the increase in mevalonate synthesis in extrahepatic tissues that accompanies the decrease in circulating cholesterol. Thus, increased mevalonate synthesis in extrahepatic tissues may explain the increased overall and site-specific risk of cancer that has been reported in some (1, 2), but not all (20-22), trials of pravastatin. This effect may be especially pronounced in the elderly that are expected to harbor a larger number of preneoplastic and occult neoplastic lesions that could be promoted by the increased mevalonate production and may help to explain the increased overall and site-specific risk of cancer in the PROSPER trial where the mean age of participants was 75 years.

A number of well-characterized rodent models are available for the experimental study of cancer. However, rats and mice that are commonly used in experimental cancer studies are generally unresponsive to the hypocholesterolemic effects of statins (23), precluding the use of these rodent models for direct investigation of our hypothesis. Studies of extrahepatic HMG-CoA reductase activity in pravastatin-treated humans would clearly be invasive, particularly because blood mononuclear leukocytes seem to transport pravastatin and, therefore, are not representative of most extrahepatic tissues in this regard (24). Evidence linking the putative induction of mevalonate synthesis in extrahepatic tissues by pravastatin to cancer risk will probably require the development of a new animal model.

We hypothesize that hydrophilic pravastatin promotes the development of cancer by causing an increase in mevalonate synthesis in extrahepatic tissues. It is important that differences in the pharmacologic properties of hydrophilic and lipophilic statins are recognized when considering extrahepatic effects of these compounds, including effects on extrahepatic cancers. Attempts to analyze the risk of cancer associated with statin use by performing meta-analyses in which trials of pravastatin and the lipophilic statins are pooled ignores the different effects of these two classes of statins on extrahepatic mevalonate synthesis and, therefore, on a biologically plausible mediator of cancer risk. Such oversight may temper findings of risk where one legitimately exists, or generalize and exaggerate risk without cause. There is clearly an urgent need for further controlled trials of the individual statins with inclusion of cancer mortality as a clinical end point.

	Footnotes

 
Grant support: U.S. Army Medical Acquisition Activity grant DAMD17-99-1-9409. The content of the information does not necessarily reflect the position or the policy of the US Government and no official endorsement should be inferred.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/12/05; revised 5/ 4/05; accepted 5/16/05.

	References

Top Abstract References

 

1. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623–30.[CrossRef][Medline]
2. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med 1996;335:1001–9.[Abstract/Free Full Text]
3. Pedersen TR, Kjekshus J, Berg K, et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4s). Lancet 1994;344:1383–9.[CrossRef][Medline]
4. Downs JR, Clearfield DO, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998;279:1615–22.[Abstract/Free Full Text]
5. Shepherd J, Blauw GJ, Murphy MB, on behalf of the PROSPER investigators. Authors' reply. Lancet 2003;361:428.
6. Harwood HJJ, Bridge DM, Stacpoole PW. In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Studies in normal subjects. J Clin Invest 1987;79:1125–32.
7. Duncan RE, El-Sohemy A, Archer MC. Mevalonate promotes the growth of tumors derived from human cancer cells in vivo and stimulates proliferation in vitro with enhanced cyclin-dependent kinase-2 activity. J Biol Chem 2004;279:33079–84.[Abstract/Free Full Text]
8. Melhem MF, Gabriel HF, Eskander ED, Rao KN. Cholestyramine promotes 7,12-dimethylbenzanthracene induced mammary cancer in Wistar rats. Br J Cancer 1987;56:45–8.[Medline]
9. Rao KN, Melhem MF, Gabriel HF, Eskander ED, Kazanecki ME, Amenta JS. Lipid composition and de novo cholesterogenesis in normal and neoplastic rat mammary tissues. J Natl Cancer Inst 1988;80:1248–53.[Abstract/Free Full Text]
10. Stone BG, Evans CD, Prigge WF, Duane WC, Gebhard RL. Lovastatin treatment inhibits sterol synthesis and induces HMG-CoA reductase activity in mononuclear leukocytes of normal subjects. J Lipid Res 1989;30:1943–52.[Abstract]
11. Pedersen TR, Wilhelmsen L, Faergeman O, et al. Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4s) of cholesterol lowering. Am J Cardiol 2000;86:257–62.[CrossRef][Medline]
12. Hawk MA, Cesen KT, Siglin JC, Stoner GD, Ruch RJ. Inhibition of lung tumor cell growth in vitro and mouse lung tumor formation by lovastatin. Cancer Lett 1996;109:217–22.[CrossRef][Medline]
13. Inano H, Suzuki K, Onoda M, Wakabayashi K. Anti-carcinogenic activity of simvastatin during the promotion phase of radiation-induced mammary tumorigenesis of rats. Carcinogenesis 1997;18:1723–7.[Abstract/Free Full Text]
14. Kikuchi T, Nagata Y, Abe T. In vitro and in vivo antiproliferative effects of simvastatin, an HMG-CoA reductase inhibitor, on human glioma cells. J Neurooncol 1997;34:233–9.[CrossRef][Medline]
15. Matar P, Rozados VR, Roggero EA, Scharovsky OG. Lovastatin inhibits tumor growth and metastasis development of a rat fibrosarcoma. Cancer Biother Radiopharm 1998;13:387–93.[Medline]
16. Mueck AO, Seeger H, Wallwiener D. Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells. Menopause 2003;10:332–6.[CrossRef][Medline]
17. Seeger H, Wallwiener D, Mueck AO. Statins can inhibit proliferation of human breast cancer cells in vitro. Exp Clin Endocrinol Diabetes 2003;111:47–8.[CrossRef][Medline]
18. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 1998;19:26–37.[CrossRef][Medline]
19. Koga T, Shimada Y, Kuroda M, Tsujita Y, Hasegawa K, Yamazaki M. Tissue-selective inhibition of cholesterol synthesis in vivo by pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Biochim Biophys Acta 1990;1045:115–20.[Medline]
20. West of Scotland Coronary Prevention Study Group. West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet 1996;348:1339–42.[CrossRef][Medline]
21. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The long-term intervention with pravastatin in ischaemic disease (LIPID) study group. N Engl J Med 1998;339:1349–57.[Abstract/Free Full Text]
22. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT). JAMA 2002;288:2998–3007.[Abstract/Free Full Text]
23. Krause BR. Lack of predictability of classical animal models for hypolipidemic activity: a good time for mice? Atherosclerosis 1998;140:15–24.[CrossRef][Medline]
24. Romano M, Diomede L, Sironi M, et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest 2000;80:1095–100.[Medline]

This article has been cited by other articles:

				A. Villagra, N. Ulloa, X. Zhang, Z. Yuan, E. Sotomayor, and E. Seto Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene Expression J. Biol. Chem., December 7, 2007; 282(49): 35457 - 35470. [Abstract] [Full Text] [PDF]

				E. D. Flick, L. A. Habel, K. A. Chan, S. K. Van Den Eeden, V. P. Quinn, R. Haque, E. J. Orav, J. D. Seeger, M. C. Sadler, C. P. Quesenberry Jr., et al. Statin Use and Risk of Prostate Cancer in the California Men's Health Study Cohort Cancer Epidemiol. Biomarkers Prev., November 1, 2007; 16(11): 2218 - 2225. [Abstract] [Full Text] [PDF]

				V. Haydont, C. Bourgier, M. Pocard, A. Lusinchi, J. Aigueperse, D. Mathe, J. Bourhis, and M.-C. Vozenin-Brotons Pravastatin Inhibits the Rho/CCN2/Extracellular Matrix Cascade in Human Fibrosis Explants and Improves Radiation-Induced Intestinal Fibrosis in Rats Clin. Cancer Res., September 15, 2007; 13(18): 5331 - 5340. [Abstract] [Full Text] [PDF]

				S. A. Hall, S. T. Page, T. G. Travison, R. B. Montgomery, C. L. Link, and J. B. McKinlay Do Statins Affect Androgen Levels in Men? Results from the Boston Area Community Health Survey Cancer Epidemiol. Biomarkers Prev., August 1, 2007; 16(8): 1587 - 1594. [Abstract] [Full Text] [PDF]

				D. M. Boudreau, O. Yu, D. L. Miglioretti, D. S.M. Buist, S. R. Heckbert, and J. R. Daling Statin Use and Breast Cancer Risk in a Large Population-Based Setting Cancer Epidemiol. Biomarkers Prev., March 1, 2007; 16(3): 416 - 421. [Abstract] [Full Text] [PDF]

				S. Bonovas and N. M. Sitaras Does pravastatin promote cancer in elderly patients? A meta-analysis Can. Med. Assoc. J., February 27, 2007; 176(5): 649 - 654. [Abstract] [Full Text] [PDF]

				B. Belay, P. F. Belamarich, and C. Tom-Revzon The Use of Statins in Pediatrics: Knowledge Base, Limitations, and Future Directions Pediatrics, February 1, 2007; 119(2): 370 - 380. [Abstract] [Full Text] [PDF]

				R. E. Duncan, A. El-Sohemy, and M. C. Archer Statins and the Risk of Cancer JAMA, June 21, 2006; 295(23): 2720 - 2720. [Full Text] [PDF]

				J. A. Cauley, A. McTiernan, R. J. Rodabough, A. LaCroix, D. C. Bauer, K. L. Margolis, E. D. Paskett, M. Z. Vitolins, C. D. Furberg, and R. T. Chlebowski Statin use and breast cancer: prospective results from the Women's Health Initiative. J Natl Cancer Inst, May 17, 2006; 98(10): 700 - 707. [Abstract] [Full Text] [PDF]

				J. E. Celis, P. Gromov, J. M. A. Moreira, T. Cabezon, E. Friis, I. M. M. Vejborg, G. Proess, F. Rank, and I. Gromova Apocrine Cysts of the Breast: Biomarkers, Origin, Enlargement, and Relation with Cancer Phenotype Mol. Cell. Proteomics, March 1, 2006; 5(3): 462 - 483. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Duncan, R. E. Articles by Archer, M. C. Search for Related Content PubMed PubMed Citation Articles by Duncan, R. E. Articles by Archer, M. C.