Statins and Colorectal Cancer

Paul Lochhead; Andrew T. Chan

Disclosures

Clin Gastroenterol Hepatol. 2013;11(2):109-118. 

In This Article

Experimental Evidence: Anticancer Mechanisms of Statins

The interest in statins as modifiers of cancer risk spawned a large number of experimental studies examining the antineoplastic effects of statins in cellular and animal models of human cancer.[10,11] Inhibition of HMG-CoA reductase by statins leads not only to a decrease in cholesterol synthesis, but also to reduced generation of other intermediates of the mevalonate pathway, including the nonsterol isoprenoids, farnesyl pyrophosphate and geranylgeranyl pyrophosphate.[5] Farnesyl pyrophosphate and geranylgeranyl pyrophosphate are required for post-translational modification (isoprenylation), and biologic activity of a wide variety of cellular proteins, including the small guanosine triphosphatases Ras and Rho,[11] which are strongly implicated in carcinogenesis.[30,31] Modulation of isoprenylation appears to be a central mechanism through which statins exert their antiproliferative and proapoptotic effects.[7,11] In addition, dysregulation of the mevalonate pathway may be causally implicated as a driver of neoplastic transformation and tumor progression, and this may partly explain the tumor-selective effects of statins.[32,33]

A number of HMG-CoA reductase-independent mechanisms have also been proposed to account for the pleiotropic effects of statins, including antioxidant activity,[34] and effects on cell adhesion,[35,36] inflammation,[8,37] immunoregulation,[38] and angiogenesis.[39]

Experimental data support a role for statins as antineoplastic agents in the colon. Statins have been shown to exert growth-inhibitory and proapoptotic effects in several human colorectal cancer cell lines in vitro, and in tumor xenograft models.[40,41] The molecular mechanisms that account for the effect of statins on colorectal cancer cell growth and survival remain poorly understood; however, enhanced cellular oxidative stress,[42] endoplasmic reticulum stress and autophagy,[43] altered expression of apoptotic and proliferative signaling molecules,[44,45] and modulation of the bone morphogenic protein signaling pathway[46] have all been implicated by experimental studies. In rodents, statins reduce the occurrence of azoxymethane-induced colonic neoplasia.[40,47,48] Statins also appear to reduce polyp formation in the genetically predisposed multiple intestinal neoplasia (Min) mouse, either alone[49] or synergistically with celecoxib.[50] In vitro data also support a role for statins as adjuncts to chemotherapy in colorectal cancer. Recent experimental evidence suggests that simvastatin may overcome resistance to epidermal growth factor receptor inhibition with cetuximab in KRAS-mutated colon cancer cells,[51] and lovastatin has been shown to act through epigenetic mechanisms to reduce cancer cell stemness and enhance chemosensitivity to 5-fluorouracil.[52] Considered together, experimental evidence provides biologically plausible roles for statins in colorectal cancer prevention and treatment.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....