N1-guanyl-1, 7-diaminoheptane enhances the sensitivity of pancreatic ductal adenocarcinoma cells to gemcitabine via the inhibition of eukaryotic translation initiation factor 5A2.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy due to its broad resistance to chemotherapy. Gemcitabine is used as a standard chemotherapeutic drug for PDAC treatment, either alone or in combination with other chemotherapeutics. However, in patients with advanced disease, survival is rarely improved. This study aimed to investigate the therapeutic efficacy of N1-guanyl-1, 7-diaminoheptane (GC7) combined with gemcitabine in PDAC therapy. We measured eukaryotic translation initiation factor 5A2 (eIF5A2) expression and gemcitabine sensitivity in different PDAC cell lines (Panc-1, BxPC-3, and T3-M4). The synergistic cytotoxic effects of gemcitabine combined with GC7 were measured using Cell Counting Kit-8 assays. Western blots were performed to measure eIF5A2 and multi-drug resistance 1 (MDR1) protein expression in PDAC cells. The present findings demonstrated that combined treatment with GC7 and gemcitabine significantly inhibited PDAC cell line viability (P<0.05). EdU incorporation assays also indicated that GC7 co-treatment remarkably enhanced gemcitabine sensitivity in PDAC cells. Furthermore, downregulation of eIF5A2 diminished the regulatory role of GC7 in gemcitabine cytotoxicity. Western blotting data indicated that GC7 downregulated the expression of MDR1 while gemcitabine induced MDR1 upregulation. These findings showed that GC7 combination therapy may enhance the therapeutic efficacy of gemcitabine in PDAC by downregulating MDR1 expression.