Abstract 5183: Efficacy study of APX3330, a Ref-1 redox inhibitor, and Gemcitabine in a mouse pancreatic ductal adenocarcinoma model
2016
High levels of apurinic/apyrimidinic endonuclease/redox factor 1 (APE1/Ref-1 or Ref-1) expression have been reported in numerous cancers such that Ref-1 is an emerging target in a variety of cancer types. Ref-1 is a dual function protein with both DNA repair activity as well as redox activity. Ref-1 is responsible for the repair of baseless sites in DNA caused by alkylation and oxidative DNA damage as well as regulating several transcription factors including HIF-1a, NFkB, AP-1, and STAT3. Using siRNA to knockdown Ref-1 in pancreatic ductal adenocarcinoma (PDAC) cells (MIA-PaCa-2), we quantitated Ref-1 expression following transfection with scrambled control and Ref-1 siRNA using Indica Lab9s HALO CytoNuclear software. Knockdown of greater than 85% greatly decreases the proliferation of PDAC cells, and supports Ref-1 as a target in pancreatic cancer. To assess the efficacy of targeting Ref-1 in vivo, a small molecule Ref-1 redox inhibitor, APX3330, was used in combination therapy with a PDAC standard of care agent, Gemcitabine, in a PDAC xenograft mouse model. In this study, NSG mice were treated with: Gemcitabine (35mg/kg), APX3330 (12.5, 25, and 50mg/kg), and combinations of APX3330 and Gemcitabine (12.5, 25, and 50mg/kg), as well as a vehicle control group. At termination of the study, tumors were harvested, tissue sections prepared, stained for HE 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5183.
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