The balance between induction and inhibition of mevalonate pathway regulates cancer suppression by statins: A review of molecular mechanisms

Highlights

• Statins inhibit the mevalonate/isoprenoid synthesis pathway in the liver and extra-hepatic tissues.

• Statins reduce the risk of cancer developing in the liver and extra-hepatic tissues except for prostate.

• Lipophilic statins may increase the risk of prostate cancer.

• Statins with intermediate lipophilicity are the preferential statin choice in treating hypercholesterolemic men.

Abstract

Statins are widely used drugs for their role in decreasing cholesterol in hypercholesterolemic patients. Statins through inhibition of Hydroxy Methyl Glutaryl-CoA Reductase (HMGCR), the main enzyme of the cholesterol biosynthesis pathway, inhibit mevalonate pathway that provides isoprenoids for prenylation of different proteins such as Ras superfamily which has an essential role in cancer developing. Inhibition of the mevalonate/isoprenoid pathway is the cause of the cholesterol independent effects of statins or pleotropic effects. Depending on their penetrance into the extra-hepatic cells, statins have different effects on mevalonate/isoprenoid pathway. Lipophilic statins diffuse into all cells and hydrophilic ones use a variety of membrane transporters to gain access to cells other than hepatocytes.

It has been suggested that the lower accessibility of statins for extra-hepatic tissues may result in the compensatory induction of mevalonate/isoprenoid pathway and so cancer developing. However, most of the population-based studies have demonstrated that statins have no effect on cancer developing, even decrease the risk of different types of cancer.

In this review we focus on the cancer developing “potentials” and the anti-cancer “activities” of statins regarding the effects of statins on mevalonate/isoprenoid pathway in the liver and extra-hepatic tissues.

Introduction

Statins are amongst the most widely used drugs in the world for their impacts on cholesterol reduction as an effective treatment for hypercholesterolemia by inhibiting Hydroxy Methyl Glutaryl-CoA Reductase (HMGCR) and thereby reduction of cholesterol synthesis [1], [2], [3], [4]. Meanwhile some studies showed other properties of statins and their possible effects on other diseases like different types of cancer [5], [6], [7], [8].

Although several studies indicated that statins have no effect on cancer [9], [10], [11], [12], [13], [14] or proposed a lower cancer incidence among statin users [5], [15], [16], some studies suggested statins can increase the risk of some types of cancers [17], [18].

One of the main reasons of such controversial findings could be related to the type of the statin so that lipophilic and hydrophilic statins have different effects on extra-hepatic tissues [19], [20]. This difference between these two types of statins leads to the different results of the studies on the effects of statins on cancer so that some studies showed lipophilic statins have anticancer effects [5], [21], [22], [23] but not all statins [10], [15], [24]. On the other hand, the type of the cancer should be regarded as well [7], [18], [25], [26], [27], [28], [29].

Although most of the population-based case control studies have shown that statins decrease the risk of different types of cancer [16], [21], [22], [30], [31], [32], [33] such as gastrointestinal cancer [34], [35], [36], [37], [38], [39], breast cancer [5], [30], [40], hepatocellular carcinoma [41], [42], [43], prostate cancer [44], [45], [46], lung cancer [47] and pancreatic cancer [48], there are other studies that concluded statins increase the risk of some cancers such as prostate [17] and both melanoma and non-melanoma skin cancer [18].

Regarding their different levels of penetrance to extra-hepatic tissues, in this review we aim to show the mechanisms of cancer developing/prevention by statins in the liver as the main target of statins and also in the extra-hepatic tissues.