Trends in Endocrinology & Metabolism
OpinionDo the cholesterol-lowering properties of statins affect cancer risk?
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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Prostate cancer incidence and mortality among men using statins and non-statin lipid-lowering medications
2019, European Journal of CancerCitation Excerpt :Although initially intended to treat individuals with higher comparative CVD risk [1], they have been shown to reduce CVD in patients with low or moderate risk [2], with the consequence that patients without atherosclerosis or other prominent CVD risk factors have been prescribed statins for many years. This prescribing practice allows for retrospective analysis of large patient populations to evaluate possible effects of statins on risk of non-cardiovascular diseases, including prostate cancer (PC), a malignancy that has been experimentally and epidemiologically linked in several reports to cholesterol [3–7]. Prior studies investigating statins and PC incidence are somewhat equivocal.
Repurposing psychiatric drugs as anti-cancer agents
2018, Cancer LettersAtorvastatin mitigates testicular injuries induced by ionizing radiation in mice
2017, Reproductive ToxicologyThe balance between induction and inhibition of mevalonate pathway regulates cancer suppression by statins: A review of molecular mechanisms
2017, Chemico-Biological InteractionsCitation Excerpt :Therefore the activity of ARF GTPases is dependent on mevalonate/isoprenoid pathway. Because of the major uptake of statins by liver, the accessibility of most of the statins for extra-hepatic tissues is limited (see Table 1) [100]. Statins mostly through inhibition of cholesterol biosynthesis in the liver, decrease the whole body cholesterol [75] so that numerous studies have suggested that statin may induce the compensatory induction of cholesterol/mevalonate pathways in extra-hepatic tissues which in turn results in over-production of FPP and GGPP and subsequently induction of the Rho and Ras GTPases activity that induces cell proliferation and inhibits apoptosis [101,102].
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