PPARα agonist fenofibrate relieves acquired resistance to gefitinib in non-small cell lung cancer by promoting apoptosis via PPARα/AMPK/AKT/FoxO1 pathway

Autor: Zhirong Jia, Xuan-sheng Ding, Chen Qiao, Yameng Zhang, Kang Xiao, Jie Wang, Qian-qian Liu, Chuan-sheng Chen, Qiu-shuang Han, Meisa Wang, Kaiwei Wang
Rok vydání: 2020
Předmět:
0301 basic medicine
Lung Neoplasms
Cell Survival
Antineoplastic Agents
Apoptosis
AMP-Activated Protein Kinases
Article
03 medical and health sciences
Structure-Activity Relationship
0302 clinical medicine
Gefitinib
Fenofibrate
Carcinoma
Non-Small-Cell Lung
medicine
Humans
heterocyclic compounds
Pharmacology (medical)
PPAR alpha
skin and connective tissue diseases
neoplasms
Protein kinase B
Cell Proliferation
Hypolipidemic Agents
Pharmacology
biology
Dose-Response Relationship
Drug
Molecular Structure
Chemistry
Forkhead Box Protein O1
Intrinsic apoptosis
AMPK
General Medicine
respiratory tract diseases
030104 developmental biology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
ABCA1
biology.protein
Cancer research
Drug Screening Assays
Antitumor
Proto-Oncogene Proteins c-akt
Intracellular
medicine.drug
Zdroj: Acta Pharmacol Sin
ISSN: 1745-7254
Popis: Recent studies show that intracellular accumulation of cholesterol leads to acquired resistance to gefitinib in non-small cell lung cancer (NSCLC) cells. In this study we investigated how to regulate the cholesterol levels in gefitinib-resistant NSCLC cells. We showed that intracellular cholesterol levels in gefitinib-resistant cell lines (PC-9/GR, H1975, H1650, and A549) were significantly higher than that in gefitinib-sensitive cell line (PC-9). Treatment with gefitinib (5 μM) significantly increased intracellular cholesterol levels in PC-9/GR, H1975, and H1650 cells. Gefitinib treatment downregulated the expression of PPARα, LXRα, and ABCA1, leading to dysregulation of cholesterol efflux pathway. We found that a lipid-lowering drug fenofibrate (20, 40 μM) dose-dependently increased the expression of PPARα, LXRα, and ABCA1, decreased the intracellular cholesterol levels, and enhanced the antiproliferative effects of gefitinib in PC-9/GR, H1975, and H1650 cells. We revealed that fenofibrate increased the gefitinib-induced apoptosis via regulating the key proteins involved in the intrinsic apoptosis pathway. In PC-9/GR, H1975 and H1650 cells, fenofibrate dose-dependently increased the expression of AMPK, FoxO1, and decreased the expression of AKT, which were remarkably weakened by knockdown of PPARα. In PC-9/GR cell xenograft mice, combined administration of gefitinib (25 mg · kg(−1) · d(−1)) and fenofibrate (100 mg · kg(−1) · d(−1)) caused remarkable inhibition on tumor growth as compared to treatment with either drug alone. All the results suggest that fenofibrate relieves acquired resistance to gefitinib in NSCLC by promoting apoptosis via regulating PPARα/AMPK/AKT/FoxO1 pathway. We propose that combination of gefitinib and fenofibrate is a potential strategy for overcoming the gefitinib resistance in NSCLC.
Databáze: OpenAIRE
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