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Overview
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Background
AP endonuclease 1 (APE1) is a dual-function protein, which contains a redox domain and a DNA repair domain. APE1 is overexpressed in numerous solid cancers, including prostate and bladder cancers, non-small cell lung cancers, gliomas, medulloblastomas and primitive neurectodermal tumors, osteosarcomas, and germ cell tumors. E3330 is a small molecule inhibitor of redox activity of APE1 protein.In vitro: E3330 significantly reduces the growth of human pancreatic cancer cells in vitro. This phenomenon was further confirmed by a small interfering RNA experiment to knockdown APE1 expression in pancreatic cancer cells. Furthermore, the growth-inhibitory effects of E3330 are accentuated by hypoxia, and this is accompanied by striking inhibition in the DNA binding ability of hypoxia-inducible factor-1α [1]. In vivo: Oral pretreatment with E3330 attenuated the elevation of plasma tumor necrosis factor activity and protected micefrom liver injury. Furthermore, E3330 inhibited the production of tumor necrosis factor from cultured Propionibacterium acnes-elicited murine peritoneal macrophages on stimulation with lipopolysaccharide in vitro [2]. Clinical trial: Up to now, E3330 is still in the preclinical development stage.
[1] Gang-Ming Zou and Anirban Maitra. Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration. Mol Cancer Ther. 2008 Jul; 7(7): 2012–2021.
[2] Nagakawa J, Hishinuma I, Miyamoto K, Hirota K, Abe S, Yamanaka T, Katayama K, Yamatsu I. Protective effects of (2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4- benzoquinoyl)]-2-nonyl-2-propenoic acid on endotoxin-mediated hepatitis in mice. J Pharmacol Exp Ther. 1992 Jul;262(1):145-50.
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