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Exp Clin Endocrinol Diabetes 2020; 128(04): 255-262
DOI: 10.1055/a-0668-5692
Review
© Georg Thieme Verlag KG Stuttgart · New York

Statins and Colorectal Cancer – A Systematic Review

Małgorzata Dobrzycka
1   Department of General, Endocrine and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
,
Piotr Spychalski
1   Department of General, Endocrine and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
,
Andrzej J. Łachiński
1   Department of General, Endocrine and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
,
Paulina Kobiela
1   Department of General, Endocrine and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
2   Department of Neonatology, Medical University of Gdańsk, Gdańsk, Poland
,
Piotr Jędrusik
2   Department of Neonatology, Medical University of Gdańsk, Gdańsk, Poland
3   Department of Internal Medicine, Hypertension, and Angiology, Medical University of Warsaw, Warsaw, Poland
,
Jarek Kobiela
1   Department of General, Endocrine and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
› Author Affiliations
Further Information

Publication History

received 12 June 2018
revised 30 July 2018

accepted 31 July 2018

Publication Date:
27 August 2018 (online)

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Abstract

Objectives Statins act by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase and are an important drug class in the treatment of lipid disorders. They lower cholesterol levels and modulate cardiovascular disease risk in both primary and secondary prevention. In addition, some studies have shown that statins may have an effect on colorectal cancer development and treatment. Our objective is to summarize published studies on the effect of statins on colorectal carcinogenesis.

Methods A systematic review of the PubMed and Cochrane databases was performed to identify studies published between April 2010 and April 2018 that investigated the association between statin use and colorectal cancer incidence, mortality, and treatment.

Results Overall, 126 articles were identified with our search strategy. Based on the eligibility criteria, 69 studies were excluded from the review process. In vitro and animal studies have shown a potential chemopreventive effect of statins and their efficacy in adjuvant therapy of colorectal cancer. The anticarcinogenic effect on cancer risk in human studies was heterogeneous. Some studies reported better overall and cancer specific survival rates in patients using statins before and during colorectal cancer treatment. Statins also show a potential role in chemoprevention of colorectal cancer in patients with inflammatory bowel disease.

Conclusions Accumulating evidence suggests that statins may have a role in colorectal cancer prevention and treatment. Further studies are necessary to define the associations between individual statin characteristics, their doses and colorectal cancer.

Keywords

colorectal cancer - cancer risk - statins
 

  • References

  • 1 Athyros VG, Katsiki N, Tziomalos K. et al. Statins and cardiovascular outcomes in elderly and younger patients with coronary artery disease: A post hoc analysis of the GREACE study. Arch Med Sci 2013; 9: 418-426
    PubMedSearch in Google Scholar
  • 2 Feussner G. Hmg Coa reductase inhibitors. Curr Opin Lipidol 1994; 5: 59-68
    CrossrefPubMedSearch in Google Scholar
  • 3 Blumenthal RS. Statins: Effective antiatherosclerotic therapy. Am Heart J 2000; 139: 577-583
    CrossrefPubMedSearch in Google Scholar
  • 4 Blum CB. Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Am J Cardiol 1994; 73: 3D-11D
    CrossrefPubMedSearch in Google Scholar
  • 5 Aronow WS. State of the art paper Lipid-lowering therapy in older persons. Arch Med Sci 2015; 1: 43-56
    CrossrefPubMedSearch in Google Scholar
  • 6 Corcos L, Le Jossic-Corcos C. Statins: Perspectives in cancer therapeutics. Dig Liver Dis 2013; 45: 795-802
    CrossrefPubMedSearch in Google Scholar
  • 7 Stryjkowska-Góra A, Karczmarek-Borowska B, Góra T. et al. Statins and cancers. Contemp Oncol (Poznan, Poland) 2015; 19: 167-175
    PubMedSearch in Google Scholar
  • 8 Paraskevas KI, Tzovaras AA, Briana DD. et al. Emerging indications for statins: A pluripotent family of agents with several potential applications. Curr Pharm Des 2007; 13: 3622-3636
    CrossrefPubMedSearch in Google Scholar
  • 9 Danesh FR, Anel RL, Zeng L. et al. Immunomodulatory effects of HMG-CoA reductase inhibitors. Arch Immunol Ther Exp (Warsz) 2003; 51: 139-148
    PubMedSearch in Google Scholar
  • 10 Garcia-Ruiz C, Morales A, Fernandez-Checa JC. Statins and protein prenylation in cancer cell biology and therapy. Anticancer Agents Med Chem 2012; 12: 303-315
    CrossrefPubMedSearch in Google Scholar
  • 11 Yeganeh B, Wiechec E, Ande SR. et al. Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease. Pharmacol Ther 2014; 143: 87-110
    CrossrefPubMedSearch in Google Scholar
  • 12 Pradelli D, Soranna D, Scotti L. et al. Statins and primary liver cancer. Eur J Cancer Prev 2013; 22: 229-234
    CrossrefPubMedSearch in Google Scholar
  • 13 Liu Y, Tang W, Wang J. et al. Association between statin use and colorectal cancer risk: A meta-analysis of 42 studies. Cancer Causes Control 2014; 25: 237-249
    CrossrefPubMedSearch in Google Scholar
  • 14 Livingstone E, Hollestein LM, van Herk-Sukel MPP. et al. Statin use and its effect on all-cause mortality of melanoma patients: A population-based Dutch cohort study. Cancer Med 2014; 3: 1284-1293
    CrossrefPubMedSearch in Google Scholar
  • 15 Boudreau DM, Yu O, Johnson J. Statin use and cancer risk: A comprehensive review. Expert Opin Drug Saf 2010; 9: 603-621
    CrossrefPubMedSearch in Google Scholar
  • 16 Lim T, Lee I, Kim J. et al. Synergistic effect of simvastatin plus radiation in gastric cancer and colorectal cancer: Implications of BIRC5 and connective tissue growth factor. Int J Radiat Oncol Biol Phys 2015; 93: 316-325
    CrossrefPubMedSearch in Google Scholar
  • 17 Harmey JH, Bouchier-Hayes D. Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: Implications for anti-angiogenic therapy. Bioessays 2002; 24: 280-283
    CrossrefPubMedSearch in Google Scholar
  • 18 Ishikawa S, Hayashi H, Kinoshita K. et al. Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer. Int J cancer 2014; 135: 2528-2536
    CrossrefPubMedSearch in Google Scholar
  • 19 Bergman M, Salman H, Djaldetti M. et al. Statins as modulators of colon cancer cells induced cytokine secretion by human PBMC. Vascul Pharmacol 2011; 54: 88-92
    CrossrefPubMedSearch in Google Scholar
  • 20 Qi X-F, Kim D-H, Yoon Y-S. et al. Involvement of oxidative stress in simvastatin-induced apoptosis of murine CT26 colon carcinoma cells. Toxicol Lett 2010; 199: 277-287
    CrossrefPubMedSearch in Google Scholar
  • 21 Li M, Huang Y, Dong X. et al. Simvastatin downregulated C35 expression and inhibited the proliferation of colon cancer cells Lovo and HT29 in vitro. Biosci Trends 2016; 10: 227-230
    CrossrefPubMedSearch in Google Scholar
  • 22 Li G, Zheng J, Xu B. et al. Simvastatin inhibits tumor angiogenesis in HER2-overexpressing human colorectal cancer. Biomed Pharmacother 2017; 85: 418-424
    CrossrefPubMedSearch in Google Scholar
  • 23 Yang P-M, Liu Y-L, Lin Y-C. et al. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res 2010; 70: 7699-7709
    CrossrefPubMedSearch in Google Scholar
  • 24 Wu X, Song M, Qiu P. et al. Synergistic chemopreventive effects of nobiletin and atorvastatin on colon carcinogenesis. Carcinogenesis 2017; 38: 455-464
    CrossrefPubMedSearch in Google Scholar
  • 25 Malicki S, Winiarski M, Matlok M. et al. PC. IL-6 and IL-8 responses of colorectal cancer in vivo and in vitro cancer cells subjected to simvastatin. J Physiol Pharmacol 2009; 60: 141-146
    PubMedSearch in Google Scholar
  • 26 Al-Haidari AA, Syk I, Thorlacius H. HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation. Biochem Biophys Res Commun 2014; 446: 68-72
    CrossrefPubMedSearch in Google Scholar
  • 27 Kodach LL, Jacobs RJ, Voorneveld PW. et al. Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell „stemness“ via the bone morphogenetic protein pathway. Gut 2011; 60: 1544-1553
    CrossrefPubMedSearch in Google Scholar
  • 28 Lee J, Lee I, Han B. et al. Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J Natl Cancer Inst 2011; 103: 674-688
    CrossrefPubMedSearch in Google Scholar
  • 29 Jiang Q, Christen S, Shigenaga MK. et al. γ-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001; 74: 714-722
    CrossrefPubMedSearch in Google Scholar
  • 30 Rezaei M, Zeidooni L, Hashemitabar M. et al. Gamma-tocopherol enhances apoptotic effects of lovastatin in human colorectal carcinoma cell line (HT29). Nutr Cancer. 2014; 66: 1386-1393
    CrossrefPubMedSearch in Google Scholar
  • 31 Yang Z, Xiao H, Jin H. et al. Synergistic actions of atorvastatin with gamma-tocotrienol and celecoxib against human colon cancer HT29 and HCT116 cells. Int J cancer 2010; 126: 852-863
    PubMedSearch in Google Scholar
  • 32 Karagkounis G, DeVecchio J, Ferrandon S. et al. Simvastatin enhances radiation sensitivity of colorectal cancer cells. Surg Endosc 2018; 32: 1533-1539
    CrossrefPubMedSearch in Google Scholar
  • 33 Wagner B, Löb S, Lindau D. et al. Simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells by decreased expression of VCAM-1 and β1 integrin. Int J Oncol 2011; 39: 1593-1600
    PubMedSearch in Google Scholar
  • 34 Suh N, Reddy BS, DeCastro A. et al. Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by Suppressing the p65/ -Catenin/Cyclin D1 Signaling Pathway in Rats. Cancer Prev Res 2011; 4: 1895-1902
    CrossrefPubMedSearch in Google Scholar
  • 35 Huang EH, Johnson LA, Eaton K. et al. Atorvastatin induces apoptosis in vitro and slows growth of tumor xenografts but not polyp formation in MIN mice. Dig Dis Sci 2010; 55: 3086-3094
    CrossrefPubMedSearch in Google Scholar
  • 36 Guan F, Liu AB, Li G. et al. Deleterious Effects of High Concentrations of (-)-Epigallocatechin-3-Gallate and Atorvastatin in Mice With Colon Inflammation. Nutr Cancer 2012; 64: 847-855
    CrossrefPubMedSearch in Google Scholar
  • 37 Mori H, Yamada Y, Kuno T. et al. Aberrant crypt foci and β-catenin accumulated crypts; significance and roles for colorectal carcinogenesis. Mutat Res Mutat Res 2004; 566: 191-208
    PubMedSearch in Google Scholar
  • 38 Yasuda Y, Shimizu M, Shirakami Y. et al. Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci 2010; 101: 1701-1707
    CrossrefPubMedSearch in Google Scholar
  • 39 Mohammed A, Janakiram NB, Brewer M. et al. Multitargeted low-dose GLAD combination chemoprevention: A novel and promising approach to combat colon carcinogenesis. Neoplasia 2013; 15: 481-490
    CrossrefPubMedSearch in Google Scholar
  • 40 Pereira MA, Warner BM, Knobloch TJ. et al. Chemoprevention of mouse lung and colon tumors by suberoylanilide hydroxamic acid and atorvastatin. Int J cancer 2012; 131: 1277-1286
    CrossrefPubMedSearch in Google Scholar
  • 41 Broughton T, Sington J, Beales ILP. Statin use is associated with a reduced incidence of colorectal cancer: A colonoscopy-controlled case-control study. BMC Gastroenterol 2012; 12: 36
    CrossrefPubMedSearch in Google Scholar
  • 42 Mamtani R, Lewis JD, Scott FI. et al. Disentangling the association between statins, cholesterol, and colorectal cancer: A nested case-control study. 2016; 13: e1002007
    PubMedSearch in Google Scholar
  • 43 Mansouri D, McMillan DC, Roxburgh CSD. et al. The impact of aspirin, statins and ACE-inhibitors on the presentation of colorectal neoplasia in a colorectal cancer screening programme. Br J Cancer 2013; 109: 249-256
    CrossrefPubMedSearch in Google Scholar
  • 44 Clancy Z, Keith SW, Rabinowitz C. et al. Statins and colorectal cancer risk: A longitudinal study. Cancer Causes Control 2013; 24: 777-782
    CrossrefPubMedSearch in Google Scholar
  • 45 Lipkin SM, Chao EC, Moreno V. et al. Genetic Variation in 3-Hydroxy-3-Methylglutaryl CoA Reductase Modifies the Chemopreventive Activity of Statins for Colorectal Cancer. Cancer Prev Res 2010; 3: 597-603
    CrossrefPubMedSearch in Google Scholar
  • 46 Broughton T, Sington J, Beales ILP. Statin use is associated with a reduced incidence of colorectal adenomatous polyps. Int J Colorectal Dis 2013; 28: 469-476
    CrossrefPubMedSearch in Google Scholar
  • 47 Jacobs EJ, Newton CC, Thun MJ. et al. Long-term use of cholesterol-lowering drugs and cancer incidence in a large United States cohort. Cancer Res 2011; 71: 1763-1771
    CrossrefPubMedSearch in Google Scholar
  • 48 Fujimoto M, Higuchi T, Hosomi K. et al. Association between statin use and cancer: Data mining of a spontaneous reporting database and a claims database. Int J Med Sci 2015; 12: 223-233
    CrossrefPubMedSearch in Google Scholar
  • 49 Robertson DJ, Riis AH, Friis S. et al. Neither Long-Term Statin Use nor Atherosclerotic Disease Is Associated With Risk of Colorectal Cancer. Clin Gastroenterol Hepatol 2010; 8: 1056-1061
    CrossrefPubMedSearch in Google Scholar
  • 50 Cheng M-H, Chiu H-F, Ho S-C. et al. Statin use and the risk of colorectal cancer: A population-based case-control study. World J Gastroenterol 2011; 17: 5197
    CrossrefPubMedSearch in Google Scholar
  • 51 Björkhem-Bergman L, Backheden M, Söderberg Löfdal K. Statin treatment reduces the risk of hepatocellular carcinoma but not colon cancer-results from a nationwide case-control study in Sweden. Pharmacoepidemiol Drug Saf 2014; 23: 1101-1106
    CrossrefPubMedSearch in Google Scholar
  • 52 Limburg PJ, Mahoney MR, Ziegler KLA. et al. Randomized Phase II Trial of Sulindac, Atorvastatin, and Prebiotic Dietary Fiber for Colorectal Cancer Chemoprevention. Cancer Prev Res 2011; 4: 259-269
    CrossrefPubMedSearch in Google Scholar
  • 53 Renman D, Lundberg E, Gunnarsson U. et al. Statin consumption as a risk factor for developing colorectal cancer: A retrospective case study. World J Surg Oncol 2017; 15: 222
    CrossrefPubMedSearch in Google Scholar
  • 54 Vinogradova Y, Coupland C, Hippisley-Cox J. Exposure to statins and risk of common cancers: A series of nested case-control studies. BMC Cancer 2011; 11: 409
    CrossrefPubMedSearch in Google Scholar
  • 55 Sehdev A, Shih Y-CT, Huo D. et al. The role of statins for primary prevention in non-elderly colorectal cancer patients. Anticancer Res 2014; 34: 5043-5050
    PubMedSearch in Google Scholar
  • 56 Simon MS, Rosenberg CA, Rodabough RJ. et al. Prospective Analysis of Association Between Use of Statins or Other Lipid-Lowering Agents and Colorectal Cancer Risk. Ann Epidemiol 2012; 22: 17-27
    CrossrefPubMedSearch in Google Scholar
  • 57 Samadder NJ, Mukherjee B, Huang S-C. et al. Risk of colorectal cancer in self-reported inflammatory bowel disease and modification of risk by statin and NSAID use. Cancer 2011; 117: 1640-1648
    CrossrefPubMedSearch in Google Scholar
  • 58 Ananthakrishnan AN, Cagan A, Cai T. et al. Statin Use Is Associated With Reduced Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2016; 14: 973-979
    CrossrefPubMedSearch in Google Scholar
  • 59 Shao Y-Y, Hsu C-H, Yeh K-H. et al. Statin Use Is Associated With Improved Prognosis of Colorectal Cancer in Taiwan. Clin Colorectal Cancer 2015; 14: 177-184.e4
    CrossrefPubMedSearch in Google Scholar
  • 60 Zanders MMJ, van Herk-Sukel MPP, Vissers PAJ. et al. Are metformin, statin and aspirin use still associated with overall mortality among colorectal cancer patients with diabetes if adjusted for one another?. Br J Cancer 2015; 113: 403-410
    CrossrefPubMedSearch in Google Scholar
  • 61 Cardwell CR, Hicks BM, Hughes C. et al. Statin Use After Colorectal Cancer Diagnosis and Survival: A Population-Based Cohort Study. J Clin Oncol 2014; 32: 3177-3183
    CrossrefPubMedSearch in Google Scholar
  • 62 Gray RT, Loughrey MB, Bankhead P. et al. Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study. Br J Cancer 2017; 116: 1652-1659
    CrossrefPubMedSearch in Google Scholar
  • 63 Voorneveld PW, Reimers MS, Bastiaannet E. et al. Statin Use After Diagnosis of Colon Cancer and Patient Survival. Gastroenterology 2017; 153: 470-479.e4
    CrossrefPubMedSearch in Google Scholar
  • 64 Hoffmeister M, Jansen L, Rudolph A. et al. Statin use and survival after colorectal cancer: the importance of comprehensive confounder adjustment. J Natl Cancer Inst 2015; 107: djv045
    PubMedSearch in Google Scholar
  • 65 Lakha F, Theodoratou E, Farrington SM. et al. Statin use and association with colorectal cancer survival and risk: Case control study with prescription data linkage. BMC Cancer. 2012; 12: 487
    CrossrefPubMedSearch in Google Scholar
  • 66 Parker-Ray N, Barakat J, Roy PK. et al. Statin use does not prevent recurrent adenomatous polyp formation in a VA population. Indian J Gastroenterol 2010; 29: 106-111
    CrossrefPubMedSearch in Google Scholar
  • 67 Lash TL, Riis AH, Ostenfeld EB. et al. Associations of Statin Use With Colorectal Cancer Recurrence and Mortality in a Danish Cohort. Am J Epidemiol 2017; 186: 679-687
    CrossrefPubMedSearch in Google Scholar
  • 68 Fransgaard T, Thygesen LC, Gögenur I. Statin use is not associated with improved 30-day survival in patients undergoing surgery for colorectal cancer. Int J Colorectal Dis 2018; 33: 199-207
    CrossrefPubMedSearch in Google Scholar
  • 69 Ng K, Ogino S, Meyerhardt JA. et al. Relationship between statin use and colon cancer recurrence and survival: results from CALGB 89803. J Natl Cancer Inst 2011; 103: 1540-1551
    CrossrefPubMedSearch in Google Scholar
  • 70 Armstrong D, Raissouni S, Price Hiller J. et al. Predictors of Pathologic Complete Response After Neoadjuvant Treatment for Rectal Cancer: A Multicenter Study. Clin Colorectal Cancer 2015; 14: 291-295
    CrossrefPubMedSearch in Google Scholar
  • 71 Mace AG, Gantt GA, Skacel M. et al. Statin Therapy Is Associated With Improved Pathologic Response to Neoadjuvant Chemoradiation in Rectal Cancer. Dis Colon Rectum 2013; 56: 1217-1227
    CrossrefPubMedSearch in Google Scholar
  • 72 Lee J, Hong YS, Hong JY. et al. Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab. Invest New Drugs 2014; 32: 535-541
    CrossrefPubMedSearch in Google Scholar
  • 73 Baas JM, Krens LL, Bos MM. et al. Safety and efficacy of the addition of simvastatin to cetuximab in previously treated KRAS mutant metastatic colorectal cancer patients. Anticancer Drugs 2015; 26: 872-877
    CrossrefPubMedSearch in Google Scholar
  • 74 Krens LL, Simkens LHJ, Baas JM. et al. Statin Use Is Not Associated with Improved Progression Free Survival in Cetuximab Treated KRAS Mutant Metastatic Colorectal Cancer Patients: Results from the CAIRO2 Study. PLoS One 2014; 9: e112201
    CrossrefPubMedSearch in Google Scholar
  • 75 Hardie C, Jung Y, Jameson M. Effect of statin and aspirin use on toxicity and pathological complete response rate of neo-adjuvant chemoradiation for rectal cancer. 2016. 12 Asia Pac J Clin Oncol 2016; Jun 12: 167-173
    PubMedSearch in Google Scholar
  • 76 Lim SH, Kim TW, Hong YS. et al. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer 2015; 113: 1421-1426
    CrossrefPubMedSearch in Google Scholar
  • 77 Kurisu S, Ishibashi K, Kato Y. et al. Effects of lipid-lowering therapy with strong statin on serum polyunsaturated fatty acid levels in patients with coronary artery disease. Heart Vessels 2013; 28: 34-38
    CrossrefPubMedSearch in Google Scholar
  • 78 Saku K, Zhang B, Noda K. et al. Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial. Circ J 2011; 75: 1493-1505
    CrossrefPubMedSearch in Google Scholar
  • 79 Vallianou NG, Kostantinou A, Kougias M. et al. Statins and cancer. Anticancer Agents Med Chem 2014; 14: 706-712
    CrossrefPubMedSearch in Google Scholar
  • 80 Gray RT, Coleman HG, Hughes C. et al. Statin use and survival in colorectal cancer: Results from a population-based cohort study and an updated systematic review and meta-analysis. Cancer Epidemiol 2016; 45: 71-81
    CrossrefPubMedSearch in Google Scholar
  • 81 Emilsson L, García-Albéniz X, Logan RW. et al. Examining Bias in Studies of Statin Treatment and Survival in Patients With Cancer. JAMA Oncol 2018; 4: 63
    CrossrefPubMedSearch in Google Scholar