Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies, where the 5-year survival rate is less than 4% worldwide. Successful treatment of pancreatic cancer is a challenge for today's oncology. Several studies showed that increased levels of oxidative stress may cause cancer cells damage and death. Therefore, we hypothesized that oxidative as well as nitro-oxidative stress is one of the mechanisms inducing pancreatic cancer programmed cell death. We decided to use silver nanoparticles (AgNPs) (2.6 and 18 nm) as a key factor triggering the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in pancreatic ductal adenocarcinoma cells (PANC-1). Previously, we have found that AgNPs induced PANC-1 cells death. Furthermore, it is known that AgNPs may induce an accumulation of ROS and alteration of antioxidant systems in different type of tumors, and they are indicated as promising agents for cancer therapy. Then, the aim of our study was to evaluate the implication of oxidative and nitro-oxidative stress in this cytotoxic effect of AgNPs against PANC-1 cells. We determined AgNP-induced increase of ROS level in PANC-1 cells and pancreatic noncancer cell (hTERT-HPNE) for comparison purposes. We found that the increase was lower in noncancer cells. Reduction of mitochondrial membrane potential and changes in the cell cycle were also observed. Additionally, we determined the increase in RNS level: nitric oxide (NO) and nitric dioxide (NO2) in PANC-1 cells, together with increase in family of nitric oxide synthases (iNOS, eNOS, and nNOS) at protein and mRNA level. Disturbance of antioxidant enzymes: superoxide dismutase (SOD1, SOD2, and SOD3), glutathione peroxidase (GPX-4) and catalase (CAT) were proved at protein and mRNA level. Moreover, we showed cells ultrastructural changes, characteristic for oxidative damage. Summarizing, oxidative and nitro-oxidative stress and mitochondrial disruption are implicated in AgNPs-mediated death in human pancreatic ductal adenocarcinoma cells.
Highlights
Pancreatic cancer is a very debilitating and refractory cancer
We investigated the endogenous reactive oxygen species (ROS) level in pancreatic cancer cells after 24 h exposure to AgNPs compared with nontumor cells of the same tissue, and we found increased ROS level in both cell lines
We found a significant increase in SOD3 mRNA level after treatment with 2.6 nm AgNPs in a concentration-dependent manner, while bigger AgNPs did not affect the expression of this SOD isoform
Summary
Pancreatic cancer is a very debilitating and refractory cancer. It accounts for only 3% of all cancers worldwide, it is the fourth leading cause of cancer death [1]. The most common type of pancreatic cancer is adenocarcinoma, a type of exocrine pancreatic cancer which is classified as pancreatic ductal adenocarcinoma [2,3,4]. Due to the fact that the ethology of pancreatic cancer has not been unequivocally described and an effective pancreatic cancer therapy has not been developed, successful diagnosis and treatment of pancreatic cancer are one of the greatest problems of lastday oncology [2, 3]. AgNP-induced cancer cell death by apoptosis, necroptosis, autophagy, and necrosis have been
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