Chemotherapeutic Drugs Induce PPAR-γ Expression and Show Sequence-Specific Synergy with PPAR-γ Ligands in Inhibition of Non–Small Cell Lung Cancer

Abstract

Preclinical studies have shown that peroxisome proliferator–activated receptor γ (PPAR-γ) ligands can exert antitumor effects against non–small cell lung cancer (NSCLC) and a variety of other cancers. In this study, we investigate the potential use of a PPAR-γ ligand, troglitazone (Tro), in combination with either of two chemotherapeutic agents, cisplatin (Cis) or paclitaxel (Pac), for the treatment of NSCLC. In vitro, treatment of NSCLC cell lines with Tro potentiated Cis- or Pac-induced growth inhibition. The potentiation of growth inhibition was observed only when Cis or Pac treatment was followed by Tro and not vice versa, demonstrating a sequence-specific effect. Median effect analysis revealed a synergistic interaction between Tro and Cis in the inhibition of NSCLC cell growth and confirmed the sequence-specific effect. We also found that Cis or Pac up-regulated the expression of PPAR-γ protein, accounting for the observed sequence-specific synergy. Similarly, experiments performed using a NSCLC xenograft model demonstrated enhanced effectiveness of combined treatment with Cis and PPAR-γ ligands, Tro or pioglitazone. Tumors from Cis-treated mice also demonstrated enhanced PPAR-γ expression. Together, our data demonstrate a novel sequence-specific synergy between PPAR-γ ligands and chemotherapeutic agents for lung cancer treatment.