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 gamma (PPAR-gamma) 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-gamma 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-gamma 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-gamma ligands, Tro or pioglitazone. Tumors from Cis-treated mice also demonstrated enhanced PPAR-gamma expression. Together, our data demonstrate a novel sequence-specific synergy between PPAR-gamma ligands and chemotherapeutic agents for lung cancer treatment.

Peroxisome Proliferator-Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3-Mediated Epithelial-Mesenchymal Transition

“…Earlier trials, testing PPAR-γ ligands as mono-therapy, in a very small number of advanced stage prostate and breast cancer patients failed to show a therapeutic benefit (39-41). Interestingly, recent studies (42, 43), including ours (21), assessing the use of PPAR-γ ligands in combination with standard chemotherapeutic agents demonstrated synergistic effect. Whereas, colorectal cancer cells resistant to oxaliplatin or ovarian cancer cells resistant to paclitaxel both exhibit EMT phenotype (44, 45).…”

“…We have also shown that treatment of mice with PPAR-γ agonists inhibits tumor progression of A549 xenografts in SCID-beige mice (20). Recently we showed chemotherapeutic drugs induce PPAR-γ expression and show sequence specific synergy with PPAR-γ ligands in inhibition of NSCLC (21). In the current study we demonstrate a novel mechanism of PPAR-γ dependent inhibition of EMT in tumor cells, by antagonizing Smad3 function.…”

IUGR decreases PPARγ and SETD8 Expression in neonatal rat lung and these effects are ameliorated by maternal DHA supplementation

“…PPARγ has roles in acute and chronic inflammatory responses in the lung (57–59), pulmonary fibrosis (57, 60), lung cancer (61) and pulmonary vascular disease (62); however, specific roles of PPARγ in lung development have yet to be determined. The discovery that PPARγ regulates the expression of chromatin modifying enzymes (16) suggests that PPARγ’s role in lung development may be via the regulation of epigenetic events.…”

Peroxisome proliferator-activated receptors and cancer: challenges and opportunities

“…In vitro treatment of human non‐small‐cell lung cancer cells with PPARγ activators induced differentiation and apoptosis (Chang and Szabo, 2000; Inoue et al ., 2001; Satoh et al ., 2002), as well as potentiated the inhibitory effects of cisplatin and paclitaxel (Reddy et al ., 2008). In vivo experiments using a xenograft model showed similar results (Keshamouni et al ., 2005).…”