Abstract A47: The anti-inflammatory role of statins and lung cancer chemoprevention

Abstract

Abstract Recently published observational studies involving over 450,000 subjects have shown that statins confer protection from lung cancer with a risk reduction of up to 50% compared to those not taking statins (RR=0.50). Statins are known to inhibit the prenylation of GTPases (Rho, Rac, Ras), intracellular signaling molecules involved in upregulation of genes involved in inflammation, lung matrix remodeling and carcinogenic pathways. This pharmacological effect has been shown to occur at normal therapeutic doses. Lung cancer is thought to result from chronic cigarette exposure but occurs in only 10% of smokers. Chronic obstructive pulmonary disease (COPD), characterised by airflow limitation on lung function testing, is found in approximately 60–90% of lung cancer cases and is the most important risk factor for lung cancer in smokers. COPD results from smoke-induced matrix remodeling involving parenchymal destruction (emphysema), airway fibrosis (small airway narrowing) and epithelial proliferation. These processes are believed to be linked to lung cancer through epithelial-mesenchymal transition (EMT), a process whereby matrix remodeling leads to excessive growth factor mediated stimulation of epithelium and subsequent malignant transformation. These premalignant events are mediated by inflammatory cytokines (notably IL-6 and IL-8) released by bronchial epithelial cells following smoke exposure and whose matrix remodeling effects are mediated by GTPases. Statins are known to inhibit the actions of IL-6 and IL-8 by GTPase inhibition thereby inhibiting the upregulating effects of these cytokines on inflammation. Pre-clinical studies show that inhibition of the GTPases can reduce or even reverse EMT. Studies also show that IL-6 is elevated in lung cancer and that anti-IL-6 activity can prevent carcinogensis. Together these observations suggest that statin therapy could, through down regulation of GTPases, inhibit the initiation of lung cancer through inhibition of the upregulatory effects of inflammatory cytokines such as IL-6. Such a mechanism would explain the possible chemo preventive actions of statins, on the development of lung cancer. Further studies are needed to establish the role of statins in inhibiting EMT and malignant transformation leading to lung cancer. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A47.