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Statins and cancer prevention

Key Points

  • Statins function in the mevalonate pathway as small-molecule inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which lowers cholesterol. These agents are effective in preventing cardiovascular disease (CVD), largely because of this effect.

  • Large randomized controlled trials (RCTs) that analysed the effects of statins and other lipid-lowering agents (for example, fibrates, nicotinic acid and cholestyramine) to prevent CVD included safety monitoring to address whether statins increased cancer incidence and cancer mortality. Ironically, these results were the first to suggest that statins can prevent cancer.

  • In addition to the HMG-CoA-dependent effects, statins have important cholesterol/HMG-CoA-independent effects, such as effects on lymphocyte-function-associated antigen 1 (LFA1), that are thought to contribute to potential cancer prevention.

  • Important work in preclinical models of colorectal and breast cancer, and melanoma, indicates that statin anticancer effects involve the inhibition of geranylgeranylation, primarily of Rho proteins.

  • Secondary results of the CVD RCTs, as well as observational and preclinical studies, indicate that statins have a strong potential for preventing colorectal cancer and melanoma.

  • The beneficial effects of statins on inhibiting carcinogenesis could involve their effects on important disease pathways including inflammation, immunomodulation and angiogenesis.

  • Statins are broad-spectrum agents. Current research is revealing important new statin targets (such as LFA1, Rho isoforms, and post-prenylation enzymes) leading to the development of more-specifically targeted agents for cancer prevention.

Abstract

Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.

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Figure 1: Mevalonate pathway.
Figure 2: Prenylation pathway, as illustrated by the prenylation of the Rho family of small G-proteins.

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Acknowledgements

This work was supported in part by the University of Texas M.D. Anderson Cancer Center support grants from the National Cancer Institute, National Institutes of Health Department of Health and Human Services.

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DATABASES

Entrez Gene

AKT

BCL2

CRP

HMGCR

ICAM1

NF-κB

p21

p27

RAC

RAP

RAS

RHOA

RHOB

RHOC

VCAM1

National Cancer Institute

breast cancer

colorectal cancer

lymphoma

melanoma

prostate cancer

Glossary

CHOLESTEROL

A lipid ringed sterol used by the body for the production of hormones, vitamin D and cell membranes; high levels in the blood stream are a marker for heart disease.

CARDIOVASCULAR DISEASE

Disease caused by atherosclerosis of the coronary arteries.

MEVALONATE

A fatty acid formed from HMG-CoA by HMG-CoA reductase, and an essential intermediate in the biosynthesis of cholesterol or geranylgeranyl pyrophosphate, which leads to the isoprenylation of the small G-proteins.

RANDOMIZED CONTROLLED TRIAL

A study of individuals who are randomized to a therapy, which is used to evaluate the effect of a therapy versus a placebo. Resistant to bias from unmeasured risk factors as these should be distributed equally in both groups.

OBSERVATIONAL STUDIES

Studies in which data on risk factors and disease outcomes are collected to detect associations between risk factors and disease. Individuals are not randomized, and choose their own exposure to risk factors, so bias can occur and might be undetected.

POPULATION-BASED STUDY

A type of observational study in which the entire population of a geographical area (county, state or country) is studied for risk factors, and disease outcomes are recorded as they occur, to detect associations between risk factors and the incidence of disease. Minimizes selection bias.

ANGIOGENESIS

The generation of new blood vessels, particularly arterial supply vessels. Can occur after trauma, ischaemic (lack of oxygen) injury or during the growth of a tumour.

NEURODEGENERATION

A group of neurological diseases, affecting the central nervous system, that involve the loss of neurons. These diseases include Alzheimer disease and Parkinson disease.

AGE-RELATED MACULAR DEGENERATION

A disease that blurs the central, high-resolution vision of the eye by damaging the macula. It is the main cause of central vision loss in Americans who are 50 or more years old.

OSTEOPOROSIS

A condition that is characterized by a decrease in bone mass as well as by decreased bone density and increased risk of bone fracture.

LIPID RAFTS

Cholesterol-rich areas of the cell membrane.

SEVERE COMBINED IMMUNODEFICIENT MOUSE

(SCID mouse). Mice with this defect in their immune system do not have B cells or T cells. Therefore, they can accept tumour cells from another species without rejection.

C-REACTIVE PROTEIN

(CRP). An inflammatory mediator produced by the liver in response to pro-inflammatory signals. Raised levels of CRP correlate with cardiovascular disease risk and are thought to indicate instability of inflamed atherosclerotic plaques.

AZOXYMETHANE

A potent carcinogen that is used to induce colon cancer in rats and mice. Treatment with azoxymethane activates the epidermal growth factor receptor and stimulates the synthesis of transforming growth factor-α.

ABERRANT CRYPT FOCI

A pre-cancerous change that represents early clonal precursors of colorectal neoplasia; presumed to precede microadenomas.

PERILLYL ALCOHOL

A naturally occurring isoprenoid.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Include aspirin, ibuprofen, celecoxib, and many others. Associated with the decreased occurence of colon cancer and colon polyps.

CYCLOOXYGENASE 2 INHIBITORS

Drugs that specifically inhibit the cyclooxygenase 2 enzyme (for example, rofecoxib), which have been associated with decreased colon polyps cancer. A subset of NSAIDs.

C3 EXOENZYME

ADP-ribosyltransferase isolated from Clostridium botulinum. Substrates include the Rho proteins. ADP-ribosylation inactivates these signalling proteins.

OSTEOBLASTS

Cells originating in the bone marrow that generate new bone. These cells are stimulated by statins, which might explain the decreased risk of fracture in statin users.

TPRAS

A transgenic mouse model that contains a mutated human T24 HRAS gene driven by a 2.5 kb promoter region from the mouse tyrosinase gene that enables expression within melanocytes.

ISOPRENYLATION

Post-translational covalent addition of a farnesyl (15-mer) or a geranylgeranyl (20-mer) moiety to proteins that lack transmembrane domains, which allows them to localize to membranes and perform their usual function.

RELATIVE RISK

A measure of the comparative risk of developing a disease or condition. Statistically, relative risk is the chance that a person receiving an exposure (statins) will develop a condition (cancer) compared with the chance that a non-exposed person will develop the same condition.

HYPERCHOLESTEROLAEMIA

Increased cholesterol in the blood, associated with heart disease and stroke.

ODDS RATIO

The odds ratio is a way of comparing whether the probability of a certain event is the same for two groups, and is calculated using a 2×2 table. An odds ratio of one implies that an event is equally likely in both groups. An odds ratio greater than one implies that an event is more likely in the first group. An odds ratio less than one implies that the event is less likely in the first group.

META-ANALYSIS

A statistical practice of combining the results of a number of studies to overcome the problem of reduced statistical power in studies with small sample sizes; analysing the results from a group of studies can allow a more accurate estimation of effects.

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Demierre, MF., Higgins, P., Gruber, S. et al. Statins and cancer prevention. Nat Rev Cancer 5, 930–942 (2005). https://doi.org/10.1038/nrc1751

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