Opinion
Do the cholesterol-lowering properties of statins affect cancer risk?

https://doi.org/10.1016/j.tem.2007.12.004Get rights and content

The potential of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (‘statins’) to reduce the incidence and/or progression of certain malignancies remains uncertain. Some investigators have concluded that statins have no effects on malignancies of any kind. However, results of several epidemiologic studies, including four recent prospective cohort studies, suggest that long-term statin therapy inhibits the progression of prostate cancer. We argue that the principal mechanism of any anticancer effects from statin use arises from prolonged lowering of circulating cholesterol. Evidence suggests that prostate cancer might be particularly sensitive to this intervention. Our hypothesis provides a perspective from which mechanistic studies of cholesterol-lowering drugs and cancer, in addition to prospective trials in patients, might be designed.

Section snippets

The probable basis for statin effects on solid tumors

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, known generically as ‘statins’, are cholesterol-lowering agents widely prescribed for cardiovascular health. Statins inhibit the conversion of HMG-CoA to mevalonate, an early, rate-limiting step in cholesterol synthesis (Figure 1). Inhibition of HMG-CoA reductase is the only known mechanism of bioactivity of these agents. The similarity in structure between HMG-CoA and the open, hydroxyacid form of simvastatin is shown in

Cholesterol regulation in the prostate

If statin drugs affect solid tumors principally by reducing circulating cholesterol, what is the mechanism of any prophylactic efficacy, as might be the case with prostate cancer? In 1942, Swyer [33] reported that benign human prostate tissue has a high cholesterol content. In the 1960s and 1970s, Schaffner and coworkers 34, 35, 36, 37, 38, 39, 40 provided the first evidence that lowering cholesterol levels systemically alters prostate cell growth and/or survival. These investigators

Evidence from randomized trials

Although statins have been proposed as potential chemopreventive or therapeutic agents, and promising preclinical findings have been reported, well-publicized claims have recently been made that statin use does not reduce cancer risk at many – and possibly all – organ sites. A recent meta-analysis by Dale et al. [57] attempted to summarize the results of placebo- or standard care-controlled statin trials in which cancer incidence or cancer-specific mortality were reported as secondary or

Statins and prostate cancer risk

What does the epidemiologic literature say about statins and prostate cancer? The Browning and Martin report [59] included observational, case-control studies with a substantial prostate cancer cohort. However, conclusions derivable from this analysis regarding the efficacy of statins in prostate cancer patients are necessarily limited. Of the 12 reports used in the meta-analysis, only five reported on prostate cancer. One study, by Coogan et al. [65], a prospective analysis, consisted of 4859

Cholesterol-sensitive signal transduction in prostate cancer cells

Recent studies point toward a potential relationship between discrete signal transduction pathways, cholesterol, and tumor cell survival and growth mechanisms in prostate cancer. Pathologic studies of prostate tumor tissues demonstrated an association between the cholesterol-binding protein caveolin-1 (Cav-1) and prostate cancer aggressiveness 72, 73, 74, 75. Cav-1 is a membrane protein that localizes to cholesterol-rich microdomains known as caveolae, a subtype of the more general

Conclusions

The possible effectiveness of statins in the context of cancer chemoprevention or therapy has not been established, and in fact the potential efficacy specifically of prolonged cholesterol lowering has not been addressed. Considering the promising results of both epidemiologic and basic science studies, and the role of circulating and tumor-resident cholesterol in the progression of certain malignancies, the potential for the clinical use of statins and other cholesterol-lowering agents is only

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