Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Small molecule inhibitor azd1480 reverses radiotherapy resistance in NSCLC by targeting JAK2/STAT3 pathway

Ying Mao, Yang Yao, Li Liu

Department of Oncology, Suining Central Hospital, Suining 629000, Sichuan Province, China;

For correspondence:- Li Liu Email: 13778732794@163.com

Accepted: 3 January 2024 Published: 29 January 2024

Citation: Mao Y, Yao Y, Liu L. Small molecule inhibitor azd1480 reverses radiotherapy resistance in NSCLC by targeting JAK2/STAT3 pathway. Trop J Pharm Res 2024; 23(1):45-50 doi: 10.4314/tjpr.v23i1.6

© 2024 The authors.
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Abstract

Purpose: To investigate the effect of small molecule inhibitor AZD1480 on radiotherapy resistance in non-small cell lung cancer (NSCLC), and the involvement of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the process.

Methods: Radiation-resistant cell lines A549-20F, A549-30F, A549-40F and H460, H46040F, H460-40F, and H460-40F were established, and expressions of proteins related to JAK/STAT pathway, mitogen-activated protein (MAPK) pathway and transforming growth factor-β (TGF-β) were assayed. The JAK2V617FH460 overexpression cell line and JAK2H460 cell line were established, and expressions of ATGL and CPT1A were compared. The H460 cells and H460-40F cells were treated with JAK2 small molecule inhibitor AZD1480, and the expressions of ATGL, CPT1A and JAK2/STAT3 pathway-related proteins were compared. The survival and proliferation of cell lines were also compared.

Results: The JAK/STAT pathway was significantly enriched, and MAPK and TGF-β were up-regulated. In H460 cells, JAK2/STAT3 route was obvious, suggesting that radiotherapy activated JAK2/STAT3 pathway in NSCLC cells. Significant down-regulations of p-JAK2Y1007, JAK2, p-STAT3s727, STAT3, ATGL and CPT1A proteins expressions were seen in H460 + AZD1480 group, relative to H460 group, but protein levels of p-JAK2Y1007, JAK2, p-STAT3s727, STAT3, ATGL and CPT1A were significantly lower in H460-40F + AZD1480 group than in H460-40F group (p < 0.05). The survival and proliferation rates were significantly lower in A549 + AZD1480 group than in A549 and A549-40F groups (p < 0.05).

Conclusion: Radiotherapy up-regulates the expressions of ATGL and CPT1A in NSCLC cells by activating the JAK2/STAT3 pathway, while AZD1480, a small molecule inhibitor, reverses the radiation resistance of NSCLC by targeting JAK2/STAT3 pathway and key enzymes of lipid metabolism. Therefore, azd1480 may enhance clinical treatment efficacy in NSCLC patients by reducing radiation resistance.

Keywords: AZD1480, JAK2, STAT3, NSCLC, Radiotherapy resistance