Artesunate Improves Drug Resistance of Lung Carcinomas Via Regulation of MiR-493-5p

Abstract

Objective: The aim of this study was to explore the potential involvement of the miR-493-5p/BRCA1 pathway in the anti-cell drug resistance activity of artesunate in lung carcinomas.

Method: Two drug-resistant lung carcinoma cell lines, A549 and SBC-3, resistant to cisplatin (DDP) and adriamycin (ADM), respectively, and their parental cell lines (A549 and SBC-3) were used in this study. Cell viability was determined by an MTT assay. The relative expression of miR-493-5p and BRCA1 mRNA was analyzed by quantitative real-time PCR. The protein expression of BRCA1, breast cancer resistance protein (BCRP), and (p)PI3K/AKT was determined by a Western blot.

Results: Artesunate attenuated the viability of A549/DDP and SBC-3/ADM cells and suppressed the expression of BCRP, an important multidrug resistance protein in lung carcinoma cells, accompanied by upregulation of miR-493-5p and downregulation of BRCA1. In artesunate-treated A549/DDP and SBC-3/ADM cells, miR-493-5p silencing reversed the anti-cell drug resistance activity of artesunate and resulted in increased cell viability and BRCP expression. Simultaneously, miR-493-5p silencing contributed to BRCA1 upregulation and phosphorylation of PI3K and AKT. As shown by a luciferase reporter gene assay, BRCA1 was a target gene for miR-493-5p, and its expression was negatively regulated by miR-493-5p. miR-493-5p silencing reversed the anticell drug resistance activity of artesunate, and this finding was further supported by a murine tumor-bearing model.

Conclusion: The data support the anti-cell drug resistance activity of artesunate in lung carcinoma cells and sheds light on the role of the miR-493-5p/BRCA1 pathway in this process.