gw-3965 and Lung-Neoplasms

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.

Topics: Antineoplastic Agents; Apoptosis; Benzoates; Benzylamines; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Liver X Receptors; Lung Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-akt; Quinazolines; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction