Statins are cholesterol-lowering drugs that some integrativein cancer care, a patient-centered approach combining the best of conventional care, self care, and evidence-informed complementary care in an integrated plan oncologists use off-label to improve survival, although statins can have serious side effects.
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Modes of action
Statins inhibit the production of mevalonate, which also reduces the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as RAS.1Abdullah MI, de Wolf E, Jawad MJ, Richardson A. The poor design of clinical trials of statins in oncology may explain their failure – Lessons for drug repurposing. Cancer Treatment Reviews. 2018 Sep;69:84-89; Shimoyama S. Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers. Cancer Chemotherapy and Pharmacology. 2011 Apr;67(4):729-39; Yu R, Longo J et al. Statin-induced cancer cell death can be mechanistically uncoupled from prenylation of RAS family proteins. Cancer Research. 2018 Mar 1;78(5):1347-1357.
“Comparative analyses of gene expression profiles in breast cancer cell lines showed significant upregulation of the mevalonate and proapoptotic pathways following atorvastatin treatment.”2Bjarnadottir O, Kimbung S et al. Global transcriptional changes following statin treatment in breast cancer. Clinical Cancer Research. 2015 Aug 1;21(15):3402-11.
Simvastatin decreases viability significantly by the induction of apoptosis, which is probably initiated by the mitochondrial caspase 9.3Chapman-Shimshoni D, Yuklea M, Radnay J, Shapiro H, Lishner M. Simvastatin induces apoptosis of B-CLL cells by activation of mitochondrial caspase 9. Experimental Hematology. 2003 Sep;31(9):779-83.
The antitumor activity of liposomal pravastatin seems to result primarily from a local inhibition of tumor inflammation and stimulation of antitumor immune response.4Coimbra M, Banciu M et al. Liposomal pravastatin inhibits tumor growth by targeting cancer-related inflammation. Journal of Controlled Release. 2010 Dec 20;148(3):303-10.
Statins act as DNMT inhibitors, demethylating the BMP2 promoter, activating BMP signaling, inducing differentiation of CRC cells, and reducing ‘stemness.'5Kodach LL, Jacobs RJ 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 Nov;60(11):1544-53.
Many observational and preclinical studies point to anticancer characteristics of statins:
- Inhibiting tumor growth
- Promoting programmed cell death
- Preventing the development of new blood vessels
- Preventing metastasis
All these processes play an important role in cancer causation, leading to oncologists’ interest in the role of statins in cancer prevention and treatment.
Through 3-hydroxy-3-methylglutaryl coenzyme A inhibition, statins show anti-tumoral properties modifying several steps of RAS/RAF/MEK/ERK, PI3K/AKT/mTOR and Wnt/β-catenin signaling cascades.6Ampuero J, Romero-Gomez M. Prevention of hepatocellular carcinoma by correction of metabolic abnormalities: role of statins and metformin. World Journal of Hepatology. 2015 May 18;7(8):1105-11.
Based on preclinical studies, researchers suggest that statins, through disturbing lipid metabolism, may influence pathways that signal cell growth and survival, thus leading to programmed cell death.7Apostolova SN, Toshkova RA, Momchilova AB, Tzoneva RD. Statins and alkylphospholipids as new anticancer agents targeting lipid metabolism. Anticancer Agents in Medicinald Chemistry. 2016;16(12):1512-1522.
The antineoplastic effect (inhibiting or preventing the growth and spread of tumors or malignant cells) of statins might also arise from a number of non-cholesterol-mediated mechanisms, such as immunoregulation, antioxidant activity and indirect anti-inflammatory properties.8Alfaqih MA, Allott EH, Hamilton RJ, Freeman MR, Freedland SJ. The current evidence on statin use and prostate cancer prevention: are we there yet? Nature Reviews. Urology. 2017 Feb;14(2):107-119.
The anticancer effect of statins is a much more complex phenomenon and not only a result of their cholesterol-lowering effect.9Stryjkowska-Góra A, Karczmarek-Borowska B, Góra T, Krawczak K. Statins and cancers. Contemporary Oncology (Pozn). 2015;19(3):167-75.
Only lipophilic statins are able to permeate the cell membrane and affect cellular functions. Their study demonstrated that all lipophilic statins tested (lovastatin, atorvastatin, fluvastatin, and simvastatin) but not a hydrophilic statin (pravastatin) significantly inhibited the cell proliferation of breast cancer cell lines.”10Yao H, He G et al. Triple-negative breast cancer: is there a treatment on the horizon? Oncotarget. 2017 Jan 3;8(1):1913-1924.
More on safety and precautions
Liver function test (LFT) monitoring is necessary. Physicians must check LFTs at baseline, approximately 12 weeks after starting statin therapy, and then at 12 months.
Statin disposition and adverse events are linked to several pharmacogenetic variants. Risk for statin-associated musculoskeletal symptoms (SAMS) and other serious statin side effects may be increased based on genetic variations that affect statin exposure systemically. Evidence supports pharmacogenetic testing to determine which statins would be the safest and most effective for the individual patient, thereby improving adherence to therapy as well as mitigating the need to discontinue the statin. For more information see The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and statin-associated musculoskeletal symptoms ›
Some preclinical evidence indicates that statins may induce resistance to chemotherapy.11Ahmadi Y, Karimian R, Panahi Y. Effects of statins on the chemoresistance—the antagonistic drug-drug interactions versus the anti-cancer effects. Biomedicine and Pharmacotherapy. 2018 Dec;108:1856-1865.
Notable preclinical evidence
Clinical evidence is summarized in How can statins help you? What the research says ›
Improving treatment outcomes
We present preclinical evidence for cancer types missing clinical evidence.
Thyroid cancer
- The combination of paclitaxel and lovastatin did not enhance the treatment effect in anaplastic thyroid carcinoma cell lines.12Chung YS, Cho S et al. Is there a treatment advantage when paclitaxel and lovastatin are combined to dose anaplastic thyroid carcinoma cell lines? Thyroid. 2011 Jul;21(7):735-44.
- Rosuvastatin induced autophagic changes in B-CPAP papillary thyroid cancer cells in lower doses and caused a shift from autophagy to apoptosis.13Zeybek ND, Gulcelik NE et al. Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells. Journal of Endocrinology. 2011 Jul;210(1):105-15.
Body terrain
Microbiome
Mevastatin and other HMG-CoA reductase inhibitors may enhance the antiproliferative effect of butyrate in colon cancer cells.14Wächtershäuser A, Akoglu B, Stein J. HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2. Carcinogenesis. 2001 Jul;22(7):1061-7.
Managing side effects and promoting wellness
Pravastatin pre-administration prevented the nephrotoxicity induced by cisplatin in mice.15An Y, Xin H, Yan W, Zhou X. Amelioration of cisplatin-induced nephrotoxicity by pravastatin in mice. Experimental and Toxicologic Pathology. 2011 Mar;63(3):215-9.
Helpful links for professionals
Wiggins BS, Saseen JJ et al; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; Council on Hypertension; Council on Quality of Care and Outcomes Research; and Council on Functional Genomics and Translational Biology. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2016 Nov 22;134(21):e468-e495.
Yeganeh B, Wiechec E et al. Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease. Pharmacology & Therapeutics. 2014 Jul;143(1):87-110.
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