Presentation Title: Simultaneous inhibition of p65 (NF-κB, RelA) and PDK2 Increases Cytotoxicity and Radiation-induced Cell Killing of Pancreatic Adenocarcinoma
Author Name(s): Christina C. Huang MS1, Joseph Boone BS1, Mintare Cesiunaite2, Maria Vandevord2, Maria Khan BS1, Josh Streveler BS1, Ryan Erdwins BS1, Helen Chin-Sinex BS3, and Marc S. Mendonca PhD3, 4
Author Department and School Affiliation: 1Indiana University School of Medicine, Indianapolis, IN; 2Indiana University-Purdue University Indianapolis, Indianapolis, IN; 3Indiana University School of Medicine Department of Radiation Oncology, Indianapolis, IN; 4Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46032 USA.
Background: High treatment resistance contributes to the low overall survival rates of patients with pancreatic ductal adenocarcinoma (PDAC). Cancer cell proliferation can be increased with upregulation of the NF-B pro-cell survival pathway and by upregulation of the Warburg metabolism pathway, an alternative metabolic pathway that utilizes lactate rather than oxidative phosphorylation to outcompete normal cells. Dimethyl-amino-parthenolide (DMAPT) and dichloroacetate (DCA) are known inhibitors of p65 RelA of the NF-B signaling pathway and pyruvate dehydrogenase kinase (PDK-2), a regulator of Warburg metabolism, respectively.
Methods: Established PDAC cell lines, MIA-PaCa-2, Panc-1, and AsPc-1, were treated a combination of DMAPT, DCA, sip65, and siPDK2 with and without radiation. Clonogenic survival assays, split dose repair experiments, and gamma-H2Ax immunofluorescence were performed.
Results: We show that simultaneous treatment of PDAC cells with DMAPT and DCA in addition to siRNA directed at p65 and siRNA directed at PDK2 induces cytotoxicity and radiation-induced cell killing. Furthermore, using split dose experiments and gamma-H2Ax foci analysis, we show that treatment with DMAPT and DCA in PDAC cells inhibits double strand break repair.
Conclusion: A dual approach using simultaneous chemical and genetic inhibition of NF-kB and Warburg metabolism may have therapeutic potential in the treatment of pancreatic cancer.