Abstract
Cancer stem cells, also termed tumor initiating cells (TICs), are a rare population of cells within the tumor mass which initiate tumor growth and metastasis. In pancreatic cancer, TICs significantly contribute to tumor re-growth after therapy, due to their intrinsic resistance. Here we demonstrate that copper oxide nanoparticles (CuO-NPs) are cytotoxic against TIC-enriched PANC1 human pancreatic cancer cell cultures. Specifically, treatment with CuO-NPs decreases cell viability and increases apoptosis in TIC-enriched PANC1 cultures to a greater extent than in standard PANC1 cultures. These effects are associated with increased reactive oxygen species (ROS) levels, and reduced mitochondrial membrane potential. Furthermore, we demonstrate that CuO-NPs inhibit tumor growth in a pancreatic tumor model in mice. Tumors from mice treated with CuO-NPs contain a significantly higher number of apoptotic TICs in comparison to tumors from untreated mice, confirming that CuO-NPs target TICs in vivo. Overall, our findings highlight the potential of using CuO-NPs as a new therapeutic modality for pancreatic cancer.
Highlights
Pancreatic cancer is the fifth deadliest malignancy worldwide
Recent studies have demonstrated that pancreatic tumors are highly enriched with a tumor-initiating cells (TICs) population that is responsible for cancer initiation, progression, metastasis, and chemoresistance[23]
It has been shown that TIC characteristics such as enhanced DNA-repair capacity, quiescent properties, superior detoxifying enzymes, as well as overexpression of anti-apoptotic proteins and enhanced drug-efflux pumps contribute to drug resistance[24,25]
Summary
Pancreatic cancer is the fifth deadliest malignancy worldwide. Owing to the asymptomatic nature of the disease and late diagnosis, pancreatic cancer patients have poor prognosis and short survival. Mechanisms by which TICs resist chemotherapy include quiescent ability[4], active DNA repair mediated by P215, and increased reactive oxygen species (ROS) scavenging[6]. The latter mechanism is related to the fact that TICs usually contain lower levels of ROS compared to the corresponding differentiated cancer cells[6]. CuO-NPs are most prominent as they possess antibacterial and antifungal activity[13,14], and can serve as a contrast agent for multimodal (both MRI and UltraSound) imaging[15] It can potentially be used as a theranostic agent for the treatment of cancer. To date, the anti-tumor effects of metal oxide NPs, and in particular CuO-NP on TICs have not been studied
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