efatutazone and Adenocarcinoma-of-Lung

The development of acquired EGFR-TKI therapeutic resistance is still a serious clinical problem in the management of lung adenocarcinoma. Peroxisome proliferator activated receptor gamma (PPARγ) agonists may exhibit anti-tumor activity by transactivating genes which are closely associated with cell proliferation, apoptosis, and differentiation. However, it remains not clear whether efatutazone has similar roles in lung adenocarcinoma cells of gefitinib resistant such as HCC827-GR and PC9-GR. It has been demonstrated by us that efatutazone prominently increased the mRNA and protein expression of PPARγ, liver X receptor alpha (LXRα),as well as ATP binding cassette subfamily A member 1 (ABCA1). In the presence of GW9662 (a specific antagonist of PPARγ) or GGPP (a specific antagonist of LXRα), efatutazone (40 μmol/L) restored the proliferation of both HCC827-GR and PC9-GR cells and obviously inhibited the increased protein and mRNA expression of PPAR-gamma, LXR-alpha, and ABCA1 induced by efatutazone. LXRα knockdown by siRNA (si-LXRα) significantly promoted the HCC827-GR and PC9-GR cells proliferation, whereas incubation efatutazone with si-LXRα restored the proliferation ability compared with the control group. In addition, combination of efatutazone and LXRα agonist T0901317 showed a synergistic therapeutic effect on lung adenocarcinoma cell proliferation and PPAR gamma, LXR A and ABCA1 protein expression. These results indicate that efatutazone could inhibit the cells proliferation of HCC827-GR and PC9-GR through PPARγ/LXRα/ABCA1 pathway, and synergistic therapeutic effect is achieved when combined with T0901317.

Topics: Adenocarcinoma of Lung; ATP Binding Cassette Transporter 1; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; Hydrocarbons, Fluorinated; Liver X Receptors; PPAR gamma; Sulfonamides; Thiazolidinediones

Development of acquired resistance to EGFR-TKI therapy continues to be a serious clinical problem in Lung adenocarcinoma management. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists demonstrate anti-tumor activity likely via transactivating genes that regulate cell proliferation, differentiation and apoptosis. Efatutazone, a novel later generation PPARγ agonist, selectively activates PPARγ target genes and has antiproliferative effects in a range of malignancies. However, the exact function and molecular mechanism of PPARγ agonists efatutazone in EGFR-TKI gefitinib-resistance of Lung adenocarcinoma has not been determined. In this study, we studied the development of acquired resistance to an EGFR-TKI gefitinib in lung adenocarcinoma cells and investigated the antiproliferative effects of efatutazone in the acquired resistant cells. The treatment of gefitinib-resistant cells with efatutazone reduced the growth of gefitinib-resistant cells in a dose- and time-dependent manner, and facilitated the anti-proliferative effects of gefitinib. Mechanistic investigations suggested that efatutazone acted by upregulating protein expression of PPARγ, phosphatase and tensin homolog (PTEN), inactivating the Akt pathway, followed by dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional levels. Our results suggested that efatutazone, alone or in combination with gefitinib, might offer therapeutic effects in lung adenocarcinoma.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; PPAR gamma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Quinazolines; Signal Transduction; Survival Analysis; Thiazolidinediones