Resveratrol reverses P-glycoprotein-mediated multidrug resistance of U2OS/ADR cells by suppressing the activation of the NF-κB and p38 MAPK signaling pathways

Abstract

Abstract. The present study aimed to investigate the reversal effect of resveratrol on the phenomenon of multidrug resistance in U2OS/adriamycin (ADR) cells and to clarify the molecular mechanisms. To examine the cell survival and half-inhibitory concentration (IC 50 ) of ADR in U2OS and U2OS/ADR cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used. The accumulation of ADR in U2OS and U2OS/ADR cells was investigated by flow cytometry. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression of multidrug resistance protein 1 (MDR1), P-glycoprotein (P-gp), p65 and p38. Compared with U2OS cells, the IC 50 value of ADR was significantly increased in U2OS/ADR cells, which exhibited high levels of MDR1/P-gp. However, resveratrol could drastically reduce the IC 50 value of ADR and the expression of MDR1/P-gp, and increased the accumulation of ADR in U2OS/ADR cells. In addition, the expression levels of p38 (phosphorylated) and p65 (acetylated and total) in U2OS/ADR cells were also significantly suppressed by resveratrol. These results suggested that the nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) signaling pathways are correlated with ADR-induced drug resistance in U2OS/ADR cells. Furthermore, resveratrol could downregulate the expression of MDR1/P-gp and reverse the drug resistance phenomenon in U2OS/ADR cells partly at least by suppressing the activation of the NF-κB and p38 MAPK signaling pathways.

Regulatory Effect of Resveratrol and Prednisolone on MDR1 Protein Expression in Acute Lymphoblastic Leukemia Cell Line (CCRF-CEM)

“…Previous studies have shown that resveratrol causes decrease in MDR1 gene expression by inhibiting NF-kB activation as well as the signaling pathway of p38 MAPK (Zhang et al, 2016).…”

Human epididymis protein 4 promotes P‑glycoprotein‑mediated chemoresistance in ovarian cancer cells through interactions with Annexin II

“…In human drug-resistant human breast cancer cells, P-gp was proposed to promote migration and invasion through its associations with ANXA2 ( 15 ). Another study on gastric cancer cells reported that ANXA2 stimulates the expression of P-gp and the development of drug resistance by activating MAPK signaling pathway ( 19 ). These findings support the theory that HE4, ANXA2 and P-gp act in concert to play significant roles in the malignant biological behavior of cancer cells.…”

“…Multiple studies have provided evidence of a significant association of ANXA2 with drug resistance in diverse malignant tumors (16)(17)(18). ANXA2 increases P-gp expression in gastric cancer cells by activating the MAPK signaling pathway, resulting in MDR of cancer cells (19).…”

Targeting CD133 reverses drug-resistance via the AKT/NF-κB/MDR1 pathway in colorectal cancer

“…After NF-κB nuclear translocation and binding to its recognition site, the promoter of the MDR1 gene is activated, and gene expression is induced. 17 , 18 , 34 , 35 Tomita et al found that CD133 regulates the level of MDR1/P-gp in glioblastoma through the PI3K/AKT-NF/κB signalling pathway, thereby promoting MDR. 36 Li et al reported that PKC DNA could regulate the expression of MDR1/P-gp in CD133-positive osteosarcoma cells through the PI3K/AKT/NF-κB pathway.…”