Current Perspectives on Statins as Potential Anti-Cancer Therapeutics

Clinical Outcomes and Underlying Molecular Mechanisms

Ali Fatehi Hassanabad

Disclosures

Transl Lung Cancer Res. 2019;8(5) 

In This Article

Abstract and Introduction

Abstract

Statins have been shown to inhibit cell proliferation in vitro and tumor growth in animal models. Various studies have also shown a decreased cancer-specific mortality rate in patients who were prescribed these medications. Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway. Statins induce tumour-specific apoptosis through mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate (GGPP) biosynthesis. However, there is no consensus on the molecular targets of statins for their anti-cancer effects. Several studies have been conducted to further assess the association between statin use and mortality in different types of cancer. In this review, current perspectives on clinical significance of statins in prevention and treatment of various types of cancers and proposed mechanisms are discussed.

Introduction

According to the World Health Organization (WHO) cancer is a generic term for a large group of diseases that can affect any part of the body, and metastases are a major cause of death from cancer. Based on WHO statistics, cancer is the second leading cause of death globally. The economic burden of cancer is significant as its estimated total annual cost has been over US$ 1.1 trillion over the past decade. The health and socioeconomic implications of cancer underscore an urgent need for identifying and applying successful preventative and therapeutic options.[1]

Chemotherapy is a common approach to cancer management, which is currently used in a curative, palliative, or adjuvant capacity. Several classes of chemotherapeutic medications have been used clinically, including DNA alkylating agents, platinating agents, and antimetabolites. Although these drugs have had varying degrees of success, they also possess significant undesired side effects resulting in their diminished utility. Further complicating matters, in cases where these drugs initially prove efficacious, tumours can develop mechanisms of drug resistance. Such mechanisms include increasing the expression of multidrug efflux pumps, altering the expression of the drug's target, and upregulating survival pathways. To resolve these issues and improve treatment outcomes, researchers are keen on developing tumour-specific agents.

Many current chemotherapeutics have been shown to kill tumour cells by inducing apoptosis.[2] Apoptosis which is a genetically programmed cell death is executed by two major pathways: the extrinsic pathway and the intrinsic pathway. Apoptotic pathways require an array of functional interactions that would ensure effective regulation of programmed cell death. A tumour could acquire a host of mutations or alterations in order to evade apoptosis. Although escaping programmed cell death is a pivotal characteristic for tumourigenesis, it does not seem to be a general response to all apoptotic stimuli. Paradoxically, much of the apoptotic machinery and pathways remain intact in tumours, making them attractive targets for therapeutic intervention.[3]

Statins are among drugs that have been shown to possess apoptosis-inducing effects. They were originally developed as a treatment for hypercholesterolemia in the 1970s, and shortly after the discovery of mevastatin, its analogues including simvastatin, lovastatin, and pravastatin were developed.[4] Statins target and inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the highly regulated rate-limiting enzyme in the mevalonate (MVA) pathway (Figure 1). Statins can be classified as natural or fungal-derived (lovastatin, simvastatin, pravastatin), and synthetic (fluvastatin, atorvastatin, rosuvastatin, pitavastatin, and cerivastatin). The two groups differ in their ability to inhibit HMGCR and in their lipophilicity. Among these agents, lovastatin, simvastatin, atorvastatin, and fluvastatin are lipophilic, whereas pravastatin and rosuvastatin are more hydrophilic. The pharmacological activity of statins is dictated by their different chemical structures, lipophilicity/hydrophilicity, kinetic profile, rate of metabolism, and the formation of active and inactive metabolites.[5] The most severe side effect of statins is myotoxicity and rhabdomyolysis, which appears to be associated with the presence of co-existing conditions, including hepatic insufficiency, cholestasis or renal diseases.[6]

Figure 1.

Mevalonate pathway and its downstream products with their main function in brackets.

In cancer patients, the efficacy of statins as anticancer agents has been evaluated both in monotherapy and in combination therapy with currently used chemotherapeutics.[5] Many studies have also shown that statins induce programmed cell death in a subset of cell lines derived from tumours in tissue culture, implying that the corresponding cancers could be sensitive to statin-specific apoptosis in vivo.[7–9] The objectives of this article are two-fold: (I) to review the latest preclinical and clinical literature focused on the potential utility of statins as anticancer drugs; and (II) to discuss the molecular mechanisms driving their effects.

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