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Sci Rep. 2018 Sep 13;8(1):13759. doi: 10.1038/s41598-018-32034-9.

Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival.

Author information

1
Indiana University School of Medicine, Department of Pharmacology and Toxicology, Indianapolis, IN, USA.
2
Indiana University School of Medicine, Department of Pediatrics, Wells Center for Pediatric Research, Indianapolis, IN, USA.
3
University of Florence, Neurofarba Department, Section of Medicinal Chemistry, Florence, Italy.
4
Indiana University School of Medicine, Department of Nephrology, Indianapolis, IN, USA.
5
Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Indianapolis, IN, USA.
6
Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Indianapolis, IN, USA.
7
Indiana University School of Medicine, Department of Pharmacology and Toxicology, Indianapolis, IN, USA. mfishel@iu.edu.
8
Indiana University School of Medicine, Department of Pediatrics, Wells Center for Pediatric Research, Indianapolis, IN, USA. mfishel@iu.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fibrosis, inflammation, and hypoxia, which activates HIF-1α to increase tumor cell metastasis and therapeutic resistance. Carbonic anhydrase IX (CA9) stabilizes intracellular pH following induction by HIF-1α. Redox effector factor-1 (APE1/Ref-1) is a multifunctional protein with redox signaling activity that converts certain oxidized transcription factors to a reduced state, enabling them to upregulate tumor-promoting genes. Our studies evaluate PDAC hypoxia responses and APE1/Ref-1 redox signaling contributions to HIF-1α-mediated CA9 transcription. Our previous studies implicated this pathway in PDAC cell survival under hypoxia. We expand those studies, comparing drug responses using patient-derived PDAC cells displaying differential hypoxic responses in 3D spheroid tumor-stroma models to characterize second generation APE1/Ref-1 redox signaling and CA9 inhibitors. Our data demonstrates that HIF-1α-mediated CA9 induction differs between patient-derived PDAC cells and that APE1/Ref-1 redox inhibition attenuates this induction by decreasing hypoxia-induced HIF-1 DNA binding. Dual-targeting of APE1/Ref-1 and CA9 in 3D spheroids demonstrated that this combination effectively kills PDAC tumor cells displaying drastically different levels of CA9. New APE1/Ref-1 and CA9 inhibitors were significantly more potent alone and in combination, highlighting the potential of combination therapy targeting the APE1-Ref-1 signaling axis with significant clinical potential.

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