Rosmarinic acid reverses non‐small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway

Abstract

Cisplatin (DDP) is one of the first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC). However, repeated use of cisplatin in clinical practice often induces chemoresistance. The aims of this study were to investigate whether rosmarinic acid (RA) could reverse multidrug resistance (MDR) in NSCLC and to explore the underlying mechanisms. Our data demonstrated that RA significantly inhibited NSCLC cell proliferation and cell colony formation in a dose-dependent manner, induced G1 phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to DDP. Mechanistically, RA inhibited NSCLC cell growth, arrested cell cycle, and induced apoptosis by activating MAPK and inhibiting the expression of P-gp and MDR1, which correspondingly enhanced p21 and p53 expression. We observed that the growth of xenograft tumors derived from NSCLC cell lines in nude mice was significantly inhibited by combination therapy. We demonstrate that RA is a potentially effective MDR reversal agent for NSCLC, based on downregulation of MDR1 mRNA expression and P-gp. Together, these results emphasize the putative role of RA as a resistance reversal agent in NSCLC. K E Y W O R D S cisplatin, MAPK, multidrug resistance, non-small cell lung cancer, rosmarinic acid

Cordycepin Reverses Cisplatin Resistance in Non-Small Cell Lung Cancer by Activating AMPK and Inhibiting the AKT Signaling Pathway

“…mTOR inhibitor (CCI-779) appears to reverse DDP resistance by increasing the growth inhibition and enhancing the apoptotic effect in DDP resistant cells (29). Rosmarinic acid reverses NSCLC resistant to DDP by activating the MAPK signaling pathway (21). Our results indicated that AMPK and AKT signaling pathways involved in NSCLC cells resistant to DDP by GO and KEGG analysis, which provided potential targets for overcoming DDP resistance.…”

“…Previously we established A549DDP cell line with persistent DDP resistance and the resistance index (RI) value was 11.19 ± 0.50 (21). To investigate the effect of Cor on NSCLC cells, we treated A549 and A549DDP cells with various concentrations of cordycepin for 48 hr and measured cell viability by CCK-8 assay.…”

Cordycepin Reverses Cisplatin Resistance in Non-small Cell Lung Cancer by Activating AMPK and Inhibiting AKT Signaling Pathway

“…We have established the A549DDP cell line with persistent DDP resistance and the resistance index (RI) was 11.19 ± 0.50 ( Liao et al, 2020 ). To investigate the effect of Cor on NSCLC cells, we treated A549 and A549DDP cells with various concentrations of Cor for 48 h and measured cell viability by CCK-8 assay.…”

“…mTOR inhibitor (CCI-779) appears to reverse DDP resistance by increasing the growth inhibition and enhancing the apoptotic effect in DDP-resistant cells ( Wu et al, 2005 ). Rosmarinic acid reverses NSCLC resistant to DDP by activating the MAPK signaling pathway ( Liao et al, 2020 ). Our results of GO and KEGG analysis indicated that AMPK and AKT signaling pathways are involved in NSCLC cells resistant to DDP, which provided potential targets for overcoming DDP resistance.…”

Apigenin as Tumor Suppressor in Cancers: Biotherapeutic Activity, Nanodelivery, and Mechanisms With Emphasis on Pancreatic Cancer

“…Plant derived-natural compounds are able to target molecular signaling pathways involved in cancer growth and metastasis (Zhang et al, 2019;Liao et al, 2020). Accumulating data exhibit that the PI3K/Akt signaling pathway plays a significant role in cancer growth and metastasis.…”