Activation of peroxisomal proliferator activated receptor (PPAR)α is beneficial for the prevention and treatment of non-small cell lung cancer
Menée in vitro, sur un modèle murin et à l'aide de xénogreffes orthotopiques de cancer humain du poumon non à petites cellules, cette étude montre que l'activation du récepteur PPAR α par le bézafibrate, un médicament utilisé pour le traitement de l'hyperlipidémie, peut constituer une stratégie intéressante pour prévenir ou traiter la maladie
Non-small cell lung cancer (NSCLC) not amenable to surgical resection is associated with high mortality due to ineffectiveness and toxicity of chemotherapy. Thus, there is urgent need for the development of new, safer, and better-tolerated drugs to combat this disease. In this study, we show that targeting the formation of pro-angiogenic epoxyeicosatrienoic acids (EETs) by the cytochrome P450 arachidonic acid epoxygenases (Cyp2c) represents a new and safe mechanism to treat NSCLC growth and progression. Downregulation of Cyp2c44 expression via activation of the peroxisomal proliferator activated receptor (PPAR)
α with the PPARα ligands Bezafibrate and Wyeth-14,643 reduced both primary and metastatic NSCLC growth, tumor angiogenesis, endothelial Cyp2c44 expression, and circulating EET levels in the KRasLA2 mouse and human orthotopic models of NSCLC. The beneficial effects of the PPARα ligands were independent of whether their administration started before or after the onset of primary NSCLC, and persisted after withdrawal, suggesting long lasting beneficial effects. These results suggest that maneuvers designed to downregulate Cyp2c expression and/or enzymatic activity represent a new, effective, and safe strategy for the treatment of NSCLC. Moreover, as Bezafibrate is a clinically approved and well-tolerated hypolipidemic drug, these studies may serve as a prelude to future clinical studies to validate the usefulness of PPAR ligands as safe agents for the treatment of lung cancer in humans.