Can Statins be Protagonists in Our Approach to Cancer Treatment?

Abstract

COMMENTARY Cancer is a disease in which malignant cells are thought to accumulate as a result of the acquisition of several capabilities: independence in growth signals, escaping growth inhibition signals, avoiding apoptosis, unlimited replicative capability, continued angiogenesis, and tissue invasion and metastasis.1 In 2011, Hanahan and Weinberg2 updated the original hallmarks of cancer to include deregulating cellular energetics and avoiding immune destruction as emerging hallmarks of cancer. Chemotherapy has been a common approach to cancer management. It has been leveraged in a curative, palliative, or adjuvant capacity. Over the past decades, different types of chemotherapeutic drugs have been introduced. These include DNA alkylating agents, platinating agents, and antimetabolites.3 Each of these agents has had clinical success. However, they have also posed significant issues with respect to their undesired side effect profiles, which have limited their utility.4 Broadly, many current chemotherapeutics exert their effects through activating the apoptotic pathway or affecting key steps and mediators of that pathway.4 Apoptosis, or programmed cell death, requires an array of functional interactions to ensure it is completed effectively. However, a tumor can acquire a host of mutations or alterations and evade apoptosis. Thus, a number of therapeutics specifically kill tumor cells by targeting pathways not typically associated with apoptosis. It is thought that these drugs function by exploiting abnormalities within the tumor cells themselves.5 A family of drugs that have been shown to possess apoptosis-inducing effects is statins: a class of medications which was originally developed in the 1970s to manage hypercholesterolemia.6–9 Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMGCR), the highly regulated rate-limiting enzyme of the mevalonate (MVA) pathway.10 The downstream products of this pathway are required for a variety of important cellular functions, including membrane integrity and steroid production (cholesterol), cellular respiration (ubiquinone), proper protein localization and function (farnesylpyrophosphate and geranylgeranylpyrophosphate), and glycosylation (dolichol).7,10 Many studies have shown the positive effects statins have in inducing apoptosis in a subset of cell lines derived from tumors in in vitro.9,11–20 These observations have generated a lot of excitement as they imply that the corresponding cancers could also potentially be sensitive to statin-specific apoptosis in the clinical setting. Promisingly, some of these studies have highlighted the tumor-specificity of statins in promoting apoptosis. For instance, in a study on acute myelogenous leukemia, whereas the tumor cells underwent statin-induced apoptosis, normal peripheral blood–derived progenitor cells were insensitive to statins.21–23 Clinically, the safety and efficacy of statins as possible chemotherapeutic agents has been evaluated both in monotherapy and in combination therapy.24 Studies have demonstrated the potential benefits statins have in reducing mortality rates among patients with different types of cancers. These studies have considered statin treatment in patients suffering from a variety of cancers, including esophageal, breast, lung, endometrial, pancreatic, and colorectal.20,25–34 With respect to combination therapy, a phase I clinical trial showed the safety and overall positive response of adding pravastatin to idarubicin and high-dose cytarabine in patients with acute myelogenous leukemia.35 These studies have provided the impetus for designing and conducting phase II and III clinical trials to formally assess the benefits and outcomes of statin use in cancer patients. In an attempt to optimize the anticancer effects of statins, there has been great interest in elucidating the exact mechanism by which these medications exert their tumor-specific effects. A growing number of studies suggest that the MVA pathway, and its downstream products, play an important role in cancer through the regulation of cellular proliferation and transformation.36,37 For example, deficient feedback control of HMGCR has been reported in a number of different transformed cells.13,36–38 This literature has also provided evidence in implicating HMGCR’s increased activity in tumor cells compared with normal cells. In contrast, in a xenograft mouse model, exogenously administered MVA promoted the growth of breast tumors.39 Taken together, these abnormalities are thought to promote cell growth by increasing the cellular reserves of MVA and its endproducts. The previous 2 decades have seen the scientific community advance cancer management in