Research Papers:
Liver X receptors agonist GW3965 re-sensitizes gefitinib-resistant human non-small cell lung cancer cell to gefitinib treatment by inhibiting NF-κB in vitro
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Abstract
Yong Hu1,*, Jialan Zang1,2,*, Haixia Cao1, Ying Wu1, Dali Yan1, Xiaobing Qin1, Leilei Zhou1, Fan Fan1, Jie Ni1, Xiaoyue Xu1, Huanhuan Sha1, Siwen Liu1, Shaorong Yu1, Zhuo Wang1, Rong Ma1, Jianzhong Wu1, Jifeng Feng1
1Department of Clinical Cancer Research Center, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu Province, China
2Department of Oncology, The First Hospital of Harbin City, Harbin, Heilongjiang Province, China
*These authors have contributed equally to this work
Correspondence to:
Jifeng Feng, email: [email protected]
Keywords: non-small cell lung cancer, liver X receptor, GW3965, gefitinib resistance, NF-κB
Received: July 04, 2016 Accepted: January 06, 2017 Published: February 02, 2017
ABSTRACT
The recent research shows that the inhibition of the nuclear factor-κB (NF-κB) pathway is a promising therapeutic option for patients who progress after treatment with the novel mutant-selective EGFR-TKIs. For propose to find a nontoxic drug to reverse the acquired gefitinib resistance, we examined whether the Liver X Receptors agonist GW3965 affect gefitinib resistance of HCC827/GR-8-2 cells. Cell viability was measured by CCK-8 assay. Levels of NF-κB, p-AKT and caspases were detected by Western blot analysis. Immunocytochemical analysis was used to detect the expression of NF-κB, p-AKT intracellularly. Induction of apoptosis and cell cycle arrest was measured by Flow cytometry assay. And results revealed that more than 90% of HCC827/GR-8-2 cells lived upon treatment with gefitinib at a dose of 5μM for 48h. However, when under the combine treatment of GW3965 (5μM) & gefitinib(5μM), cell death rate was increased observably. Co-administration of gefitinib & GW3965 induced cell apoptosis and cell cycle arrest. Additionally, we observed a dose-dependent- down-regulation of NF-κB in HCC827/GR-8-2 cells treated with gefitinib & GW3965. GW3965 and gefitinib synergistically decreased cell proliferation and induced apoptosis by inhibiting NF-κB signaling pathway in gefitinib resistant cells. These findings support our hypothesis that GW3965 could act as a useful drug to reverse the gefitinib resistance.
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PII: 15007