Open AccessEfatutazone and T0901317 exert synergistically therapeutic effects in acquired gefitinib‐resistant lung adenocarcinoma cells
Author(s) -
Ni Jie,
Zhou Leilei,
Ding Li,
Zhang Xueqin,
Zhao Xia,
Li Huizi,
Cao Haixia,
Liu Siwen,
Wang Zhuo,
Ma Rong,
Wu Jianzhong,
Feng Jifeng
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1440
Subject(s) - liver x receptor , gene knockdown , peroxisome proliferator activated receptor , gefitinib , cancer research , biology , cell growth , apoptosis , endocrinology , medicine , receptor , nuclear receptor , transcription factor , epidermal growth factor receptor , biochemistry , gene
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 ( PPAR γ ) 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 HCC 827‐ GR and PC 9‐ GR . It has been demonstrated by us that efatutazone prominently increased the mRNA and protein expression of PPAR γ , liver X receptor alpha ( LXR α ),as well as ATP binding cassette subfamily A member 1 ( ABCA 1). In the presence of GW 9662 (a specific antagonist of PPAR γ ) or GGPP (a specific antagonist of LXR α ), efatutazone (40 μ mol/L) restored the proliferation of both HCC 827‐ GR and PC 9‐ GR cells and obviously inhibited the increased protein and mRNA expression of PPAR ‐gamma, LXR ‐alpha, and ABCA 1 induced by efatutazone. LXR α knockdown by si RNA (si‐ LXR α ) significantly promoted the HCC 827‐ GR and PC 9‐ GR cells proliferation, whereas incubation efatutazone with si‐ LXR α restored the proliferation ability compared with the control group. In addition, combination of efatutazone and LXR α agonist T0901317 showed a synergistic therapeutic effect on lung adenocarcinoma cell proliferation and PPAR gamma, LXR A and ABCA 1 protein expression. These results indicate that efatutazone could inhibit the cells proliferation of HCC 827‐ GR and PC 9‐ GR through PPAR γ / LXR α / ABCA 1 pathway, and synergistic therapeutic effect is achieved when combined with T0901317.