Qorri Bessi, Mokhtari Reza Bayat, Harless William W, Szewczuk Myron R
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
ENCYT Technologies Inc., Membertou, NS B1S 0H1, Canada.
Cancers (Basel). 2022 Mar 8;14(6):1374. doi: 10.3390/cancers14061374.
Resistance to chemotherapeutics and high metastatic rates contribute to the abysmal survival rate in patients with pancreatic cancer. An alternate approach for treating human pancreatic cancer involves repurposing the anti-inflammatory drug, aspirin (ASA), with oseltamivir phosphate (OP) in combination with the standard chemotherapeutic agent, gemcitabine (GEM). The question is whether treatment with ASA and OP can sensitize cancer cells to the cytotoxicity induced by GEM and limit the development of chemoresistance. To assess the key survival pathways critical for pancreatic cancer progression, we used the AlamarBlue cytotoxicity assay to determine the cell viability and combination index for the drug combinations, flow cytometric analysis of annexin V apoptosis assay to detect apoptotic and necrotic cells, fluorometric QCM™ chemotaxis migration assay to assess cellular migration, fluorometric extracellular matrix (ECM) cell adhesion array kit to assess the expression of the ECM proteins, scratch wound assay using the 96-well WoundMaker™, and the methylcellulose clonogenic assay to assess clonogenic potential. The combination of ASA and OP with GEM significantly upended MiaPaCa-2 and PANC-1 pancreatic cancer cell viability, clonogenic potential, expression of critical extracellular matrix proteins, migration, and promoted apoptosis. ASA in combination with OP significantly improves the effectiveness of GEM in the treatment of pancreatic cancer and disables key survival pathways critical to disease progression.
对化疗药物的耐药性和高转移率导致胰腺癌患者的生存率极低。治疗人类胰腺癌的另一种方法是将抗炎药物阿司匹林（ASA）与磷酸奥司他韦（OP）重新组合，并与标准化疗药物吉西他滨（GEM）联合使用。问题在于，ASA和OP联合治疗是否能使癌细胞对GEM诱导的细胞毒性敏感，并限制化疗耐药性的发展。为了评估对胰腺癌进展至关重要的关键生存途径，我们使用了alamarBlue细胞毒性试验来确定药物组合的细胞活力和联合指数，通过膜联蛋白V凋亡试验的流式细胞术分析来检测凋亡和坏死细胞，使用荧光QCM™趋化迁移试验来评估细胞迁移，使用荧光细胞外基质（ECM）细胞粘附阵列试剂盒来评估ECM蛋白的表达，使用96孔伤口制作器™进行划痕试验，以及使用甲基纤维素克隆形成试验来评估克隆形成潜力。ASA、OP与GEM联合使用显著颠覆了MiaPaCa-2和PANC-1胰腺癌细胞的活力、克隆形成潜力、关键细胞外基质蛋白的表达、迁移能力，并促进了细胞凋亡。ASA与OP联合使用显著提高了GEM治疗胰腺癌的有效性，并阻断了对疾病进展至关重要的关键生存途径。
