Efatutazone and T0901317 exert synergistically therapeutic effects in acquired gefitinib-resistant lung adenocarcinoma cells.
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.
['Ni|Jie|J|', 'Zhou|Lei-Lei|LL|', 'Ding|Li|L|', 'Zhang|Xue-Qin|XQ|', 'Zhao|Xia|X|', 'Li|Huizi|H|', 'Cao|Haixia|H|', 'Liu|Siwen|S|', 'Wang|Zhuo|Z|', 'Ma|Rong|R|', 'Wu|Jianzhong|J|', 'Feng|Jifeng|J|0000-0002-7979-2391']
D064286:ATP Binding Cassette Transporter 1 D000077192:Adenocarcinoma of Lung D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D019008:Drug Resistance, Neoplasm D004357:Drug Synergism D000077156:Gefitinib D015972:Gene Expression Regulation, Neoplastic D006801:Humans D006845:Hydrocarbons, Fluorinated D000071518:Liver X Receptors D047495:PPAR gamma D013449:Sulfonamides D045162:Thiazolidinediones
Efatutazone T0901317 gefitinib-resistance lung adenocarcinoma peroxisome proliferator-activated receptor gamma