טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentBenguigui Madeleine Rose
SubjectCopper Oxide Nanoparticles Inhibit Pancreatic Tumor Growth
Primarily by Targeting Tumor Initiating Cells
DepartmentDepartment of Medicine
Supervisors Professor Yuval Shaked
Professor Haim Azhari


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. TICs have been identified in a number of cancer types and were shown to resist a spectrum of anti-cancer drugs. In pancreatic cancer, among other cancers, TICs significantly contribute to tumor re-growth after therapy, therefore research focuses on identifying treatment modalities which can specifically eradicate TICs. Metal oxide nanoparticles (NPs) and in particular copper oxide (CuO) NPs, were shown to generate cytotoxic activity in cancer cells, in part by inducing apoptosis. Yet, the anti-tumor effect of CuO-NPs on resistant TICs has not been demonstrated. Using in vitro TIC-enriched PANC1 human pancreatic adenocarcinoma culture, we demonstrated that such cells are more susceptible to CuO-NPs cytotoxicity than standard PANC1 cultures. Specifically, TIC-enriched PANC1 cells exposed to CuO-NPs exhibited decreased viability and increased apoptosis rates compared to non-TIC counterparts. Such effects are associated with increased G2 cell cycle arrest resulted in increased sub-G0 apoptotic phase. Furthermore, CuO-NPs contributed to reduced mitochondrial membrane potential and increased reactive oxygen species (ROS) levels in TIC-enriched cultures compared to standard PANC1 culture. Using an in vivo pancreatic cancer model in mice, we demonstrated that the administration of CuO-NPs significantly decreased tumor growth, by over 50%, when compared to the control untreated mice. The CuO-NP-treated tumors contained apoptotic TICs, confirming a substantial CuO-NP anti-tumor activity by killing TICs. Overall, our results suggest a possible new therapeutic modality for pancreatic cancer which mainly targets TICs, hence extending survival by delaying TIC-induced drug resistance.