In vitro and in silico study of the synergistic anticancer effect of alpinumisoflavone with gemcitabine on pancreatic ductal adenocarcinoma through suppression of ribonucleotide reductase subunit-M1

Abstract

A highly aggressive neoplastic disease, pancreatic ductal adenocarcinoma (PDAC) is documented as the third chief cause of cancer-associated mortality in both sexes combined in the United States. For decades, gemcitabine-based chemotherapy has been embraced as a cornerstone drug for the treatment of PDAC. However, there have been several unsolved problems, including cytotoxicity, and chemoresistance. Gemcitabine efficacy was attributed to the attenuation of ribonucleotide reductase subunit-M1 (RRM1). Overexpression of RRM1 in PDAC is highly correlated with gemcitabine resistance and reduced gemcitabine sensitivity, resulting in a poor survival rate even after gemcitabine treatment. Moreover, the status of TP53, a tumor suppressor gene, assumes a decisive role in the response of PDAC to gemcitabine. Therefore, targeting RRM1 and P53 might be a therapeutic strategy for strengthening gemcitabine efficacy and cytotoxicity against PDAC. Alpinumisoflavone (AIF) is a prenylated isoflavone originated in Cudrania tricuspidate with versatile bioactive properties, including anticancer activity. However, there was no report whether AIF can exert anticancer effect and exhibit synergistic effect with gemcitabine against PDAC. Therefore, the anticancer properties of AIF were assessed with PANC-1 and MIA PaCa-2. In addition, synergism between AIF and gemcitabine were analyzed. Moreover, the contribution of P53 and RRM1 expression to gemcitabine resistance was assessed by comparing their protein levels in PDAC cells and normal pancreatic cells. The interactions of AIF with RRM1 protein were confirmed by molecular docking and dynamics simulation. Therefore, AIF enhances gemcitabine efficacy against PDAC through the regulation of P53 and RRM1.