Synergistic Interactions between GW8510 and Gemcitabine in an In Vitro Model of Pancreatic Cancer

• Published in: Anti-cancer agents in medicinal chemistry Vol. 21; no. 16; p. 2204
• Main Authors: Rüstem, Duygu Gençalp, Atay, Sevcan, Aydin, Hikmet Hakan, Ak, Handan
• Format: Journal Article
• Language: English
• Published: Netherlands 01.11.2021
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biomarkers, Tumor - analysis; Cell Proliferation - drug effects; Cell Survival - drug effects; Computational Biology; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemistry; Deoxycytidine - pharmacology; Drug Screening Assays, Antitumor; Humans; Indoles - chemistry; Indoles - pharmacology; Pancreatic Neoplasms - diagnosis; Pancreatic Neoplasms - drug therapy; Ribonucleoside Diphosphate Reductase - analysis; Tumor Cells, Cultured; GW8510; gemcitabine; RRM2; PANC-1; survival; mRNA expression
• DOI: 10.2174/1871520621999210104201553

One of the main reasons for the poor survival rates of pancreatic cancer patients is the development of gemcitabine resistance, indicating that novel treatment strategies that have the ability to improve gemcitabine sensitivity are in need to combat this devastating disease. TCGA PAAD data was used to determine the clinicopathological significance of high RRM2 (Ribonucleotide reductase subunit M2) expression for Pancreatic Ductal Adenocarcinoma (PDAC). The effects of GW8510 and gemcitabine on PANC-1 cell viability were determined using WST-8 assay. The potential synergistic interaction between GW8510 and gemcitabine was evaluated by the Combination Index (CI) analysis. The effects of GW8510 treatment on apoptosis, cell cycle, and cell migration, either in combination with gemcitabine or alone, were investigated. The effect of GW8510 on RRM2 protein levels was evaluated using ELISA assay. RRM2 is significantly over-expressed in PDAC compared to healthy pancreatic tissues (p <0.0001). RRM2 mRNA expression was found to be significantly correlated with the overall survival rate of patients (HR=2.17 [1.44-3.27], p=0.00016) and the pathological stages of the disease (p=0.0054). GW8510 significantly decreased the RRM2 protein levels compared to the control. Cell viability analysis showed that GW8510 has a similar effect to gemcitabine in inhibiting PANC-1 cell viability. GW8510 was found to synergize with gemcitabine to inhibit PANC-1 cell viability and migration. However, the effects of GW8510 on PANC-1 cells could not be explained by induction of apoptosis or cell cycle arrest. Targeting RRM2 using GW8510 may have the potential to increase gemcitabine sensitivity in pancreatic cancer.