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NPJ Precis Oncol. 2017;1. pii: 19. doi: 10.1038/s41698-017-0023-0. Epub 2017 Jun 8.

Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic.

Author information

1
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202, USA.
2
Department of Pharmacology & Toxicology, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202, USA.
3
Apexian Pharmaceuticals, Indianapolis, IN 46204, USA.

Abstract

Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transcription factors to promote growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Ref-1/APE1 is activated in a variety of cancers, including prostate, colon, pancreatic, ovarian, lung and leukemias, leading to increased aggressiveness. Transcription factors downstream of Ref-1/APE1 are key contributors to many cancers, and Ref-1/APE1 redox signaling inhibition slows growth and progression in a number of tumor types. Ref-1/APE1 inhibition is also highly effective when paired with other drugs, including standard-of-care therapies and therapies targeting pathways affected by Ref-1/APE1 redox signaling. Additionally, Ref-1/APE1 plays a role in a variety of other indications, such as retinopathy, inflammation, and neuropathy. In this review, we discuss the functional consequences of activation of the Ref-1/APE1 node in cancer and other diseases, as well as potential therapies targeting Ref-1/APE1 and related pathways in relevant diseases. APX3330, a novel oral anticancer agent and the first drug to target Ref-1/APE1 for cancer is entering clinical trials and will be explored in various cancers and other diseases bringing bench discoveries to the clinic.

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