Abstract
Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. Cerium oxide nanoparticles (CONPs) are currently being tested in pre-clinical trials as an adjuvant to sensitize pancreatic cancer cells to RT and protect normal tissues from the harmful side effects. CONPs were not able to significantly affect RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, activation of c-Jun terminal kinase (JNK), a key driver of RT-induced apoptosis, was significantly enhanced by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activity was associated with a marked increase in Caspase 3/7 activation, indicative of apoptosis. We have previously shown that CONPs increase reactive oxygen species (ROS) production in cancer cells. ROS has been shown to drive the oxidation of thioredoxin 1 (TRX1) which results in the activation of apoptosis signaling kinase 1 (ASK1). The increase in ASK1 activation following the co-treatment with CONPs followed by RT suggests that the increased JNK activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue or when the JNK activation was blocked by an inhibitor. Taken together, these data demonstrate an important mechanism for CONPs in specifically killing cancer cells and provide novel insights into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.
Highlights
One in two men and one in three women in the United States will develop cancer at some point in their lifetimes [1]
Cerium oxide nanoparticles (CONPs) alone did not induce any DNA damage in normal cells. These results indicate that CONPs protect the normal cell from suffering mitotic catastrophe when exposed to radiation therapy (RT)
The results described above indicate a pro-apoptotic role of thioredoxin 1 (TRX1)-Jun terminal kinase (JNK) pathway in the CONPs and TR treated cancer cells
Summary
One in two men and one in three women in the United States will develop cancer at some point in their lifetimes [1]. Cancers 2018, 10, 303 roughly 30,000 of those deaths are caused by pancreatic cancer [3]. 15–20% of pancreatic cancer patients present with surgically resectable disease and roughly 20% of patients undergoing surgical resection survive five years post-operation [3]. The main treatment suggested for patients with locally advanced, or surgically unresectable, pancreatic cancer is a combination of chemotherapy and radiation therapy [3]. Chemoradiation has been shown to both extend survival and decrease the pain commonly associated with pancreatic cancer [3]. Current chemotherapeutic and radiotherapeutic agents for advanced pancreatic cancer have shown minimal lasting impact, as most patients show signs of progression and metastatic development within only a few months of completing treatment [3]
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