Combination Therapy of PPARgamma Ligands and Inhibitors of Arachidonic Acid in Lung Cancer

Abstract

Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA) metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPARgamma. Targeting LOX/COX enzymes and inducing activation of PPARgamma have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPARgamma activation through synthetic ligands (TZDs) has revealed a great mechanistic complexity since effects are produced through PPARgamma-dependent and -independent mechanisms. Furthermore, PPARgamma could also be involved in regulation of COX-2. Overexpression of PPARgamma has reported to play a role in control of invasion and differentiation. Exploring the function of PPARgamma, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.

Figure 1

Inflammatory products stimulate cPLA2α which increases levels of AA available to be metabolized by the LOX/COX pathways. LOX/COX enzymes' products, leukotrienes and prostaglandins, induce cell proliferation. Natural ligands for PPARγ are also produced by the LOX/COX pathways. Activation of PPARγ balances the effect of leukotrienes and prostaglandins inducing apoptosis through various mechanisms. However, activation of PPARγ may also induce COX-2 and IL-8 expressions. Furthermore, overexpression of PPARγ may decrease invasion and induce differentiation from a mesenchymal to an epithelial-like phenotype.