GW8510 与吉西他滨在体外胰腺癌模型中的协同作用。

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

机构信息

Department of Medical Biochemistry, Faculty of Medicine, Near East University, Nicosia, Cyprus.

Department of Medical Biochemistry, Ege University Faculty of Medicine, Bornova, Izmir, Turkey.

出版信息

Anticancer Agents Med Chem. 2021 Oct 28;21(16):2204-2215. doi: 10.2174/1871520621999210104201553.

DOI:10.2174/1871520621999210104201553

PMID:33397269

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

Targeting RRM2 using GW8510 may have the potential to increase gemcitabine sensitivity in pancreatic cancer.

摘要

背景

胰腺癌患者生存率低的主要原因之一是吉西他滨耐药的发展，这表明需要新的治疗策略来提高吉西他滨的敏感性，以对抗这种毁灭性的疾病。

方法

使用 TCGA PAAD 数据确定高 RRM2（核苷酸还原酶亚单位 M2）表达对胰腺导管腺癌（PDAC）的临床病理意义。使用 WST-8 测定法确定 GW8510 和吉西他滨对 PANC-1 细胞活力的影响。通过组合指数（CI）分析评估 GW8510 和吉西他滨之间潜在的协同相互作用。研究 GW8510 处理对细胞凋亡、细胞周期和细胞迁移的影响，无论是与吉西他滨联合使用还是单独使用。使用 ELISA 测定法评估 GW8510 处理对 RRM2 蛋白水平的影响。

结果

与健康胰腺组织相比，RRM2 在 PDAC 中明显过表达（p <0.0001）。RRM2 mRNA 表达与患者的总生存率（HR=2.17[1.44-3.27]，p=0.00016）和疾病的病理分期（p=0.0054）显著相关。与对照组相比，GW8510 显著降低了 RRM2 蛋白水平。细胞活力分析表明，GW8510 对 PANC-1 细胞活力的抑制作用与吉西他滨相似。GW8510 与吉西他滨协同抑制 PANC-1 细胞活力和迁移。然而，GW8510 对 PANC-1 细胞的影响不能用诱导细胞凋亡或细胞周期阻滞来解释。