DO STATINS PROTECT AGAINST PROSTATE CANCER?

Abbreviations

LDL

low-density lipid

HMG-CoA

3-hydroxy-3-methylglutaryl coenzyme A

cdk-2

cyclin-dependent kinase-2.

INTRODUCTION

The link between high levels of low- density lipid (LDL) cholesterol and the risk of cardiovascular disease has been established since the late 1970s, with the landmark publication of the Framington study [1]. Therapeutic options for regulating lipid levels include cholestyramine, fibrates and statins, but it is the latter that has been found to be most effective in reducing LDL cholesterol. Statins work by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting step in the biosynthesis of cholesterol. They have proven benefit in reducing serum cholesterol levels but more importantly, this reduction correlates with a reduction in the number of coronary events, all cardiovascular events and total mortality [2].

Recent work suggested that statins might also play a role in preventing the development of several different tumours, including colorectal, lung and prostate. In vitro data shows that statins induce apoptosis in cancer cell lines, but the exact mechanism of anticancer action is unclear. There are several potential hypotheses.

(i) Cholesterol is an essential component of the cell membrane and statins are thought to affect the composition of the plasma membrane, affecting discrete regions within the membrane known as lipid rafts; these are responsible for signal transduction of key events such as cell growth, cell survival and cell migration. These are essential characteristics of a cell for malignant transformation. Recent work highlighted the importance of protein kinase B, which seems to be altered by statin treatment [3]. Protein kinase B is an important intracellular signalling pathway involved in cell survival.

(ii) Inhibition of HMG-CoA reductase inhibits the conversion of HMG-CoA to mevalonate. Interruptions to mevalonate synthesis are thought to be important for several reasons: mevalonate is important for isoprenoid synthesis and isoprenylation is vital for activation of Ras-G protein, a key protein in cell survival. Other downstream targets of mevalonate include farnesyl pyrophosphate and geranylgeranyl pyrophosphate, that are responsible for the translocation of Ras and Rho to the cell membrane, a step that is necessary for the cell proliferation and migration.

(iii) Direct inhibition of cyclin-dependent kinase-2 (cdk-2) activity via inhibition of the Thr-160 phosphorylation of cdk2 results in accumulation of p21 and p27, both of which are important because of their growth-inhibitory effects, and in turn result in retarded cancer cell mitosis.

Laboratory data suggested that several different cancers respond to statin therapy. It seems that prostate cancer might be particularly sensitive and mouse models confirm the significant chemopreventative effect [4]. Recently, some clinical trials were published that add further support to the anticancer hypothesis. In a study of 100 airline pilots PSA levels were assessed over a 9-year period and those taking statin therapy were compared with those not taking statins [5]; the PSA levels were reduced by >40% in the group taking a statin over the study period, compared with a rise of nearly 40% in the other group. Obviously PSA level does not directly relate to the incidence of prostate cancer, but this was investigated by Graaf et al.[6]. They examined the overall cancer incidence in 300 000 residents of eight Dutch cities and correlated this with prescriptions for cardiovascular drugs. Interestingly, there was a 20% reduction in overall risk of cancer with statin treatment, but specifically a 63% reduction in the risk of prostate cancer [6], although this was not statistically significant. Another smaller case-controlled study of 100 men with prostate cancer recruited upon referral for biopsy shows very similar results. This noted a 65% reduction in the risk of prostate cancer [7] and further analysis identified that this reduction was in patients with the more aggressive types of prostate cancer, with Gleason scores of ≥ 7.

One potentially confounding factor for the effect of statins is that epidemiological studies suggest that dietary factors, in particular fat intake, might be important in the development of prostate cancer [8]. Therefore the anticancer effect of statins might solely relate to the treatment of uncontrolled hyperlipidaemia. However, in a comparison study using statins vs bile-acid-binding resins, there was a significant reduction in cancer risk only with the statin group [9]. Although the case is not watertight for the role of statins in prostate cancer, a large-scale trial of the chemotherapeutic effect of the statins is urgently needed. This new preliminary data highlights the need for urologists to look at all aspects of men’s health.