Medical University of South Carolina
Hypoxia and Pancreatic Cancer
Redox Regulation of Pancreatic Cancer
Pancreatic cancer has the worst prognosis of all major cancers with an overall 5-year survival rate of 3%. First-line systemic therapy for pancreatic cancer is the antimetabolite gemcitabine. Although, tumors may initially respond to the gemcitabine treatment, survival does not improve. Numerous studies have attempted to optimize and improve the efficacy of gemcitabine therapy through combination with other agents. Recently, we showed that N-acetyl-L-cysteine (NAC), a glutathione (GSH) precursor, strikingly prevents NFkB activation and promotes hypoxic apoptosis in pancreatic cancer cells through S-glutathionylation of NFkB. Surprisingly; gemcitabine treatment alone also activates NFkB in pancreatic tumors.
Hypoxia induces translocation of NFkB into nucleus in pancreatic cancer cells.
Therefore, we hypothesize that chemoresistance against gemcitabine is due to combination of inherent and acquired resistance. Inherent resistance is due to hypoxia-induced NFκB activation and acquired resistance is due to gemcitabine-induced NFκB activation. Accordingly, we are determining whether NFkB inhibition by treatment with thiol donors enhances killing of tumor cells by gemcitabine. Gemcitabine seems to work as “a double sword”: it induces apoptosis acting as an antimetabolite, but on the other hand it activates NFκB tipping the balance towards survival. NAC also seems to work on two fronts, first by inhibiting NFκB activation arising from hypoxic regions of tumors and second by blocking gemcitabine-activated NFκB in hypoxic and normoxic regions of tumors. Inhibition of NFκB decreases expression of survival genes and sensitize cells to gemcitabine-induced killing. Our goal is to develop non-toxic strategies how to overcome the gemcitabine resistance, which should be useful for optimizing therapeutic responses. This project utilizes techniques of molecular and cell biology, biochemical assays, confocal microscopy, and proteomics in cell culture and animal models.