E3330

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.

Reference:
[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.


The Ape-1/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells: therapeutic implications in tumor angiogenesis.[Pubmed:19097035]

J Cell Physiol. 2009 Apr;219(1):209-18.

The apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape-1/Ref-1) is a multi-functional protein, involved in DNA repair and the activation of redox-sensitive transcription factors. The Ape-1/Ref-1 redox domain acts as a cytoprotective element in normal endothelial cells, mitigating the deleterious effects of apoptotic stimuli through induction of survival signals. We explored the role of the Ape-1/Ref-1 redox domain in the maintenance of tumor-associated endothelium, and of endothelial progenitor cells (EPCs), which contribute to tumor angiogenesis. We demonstrate that E3330, a small molecule inhibitor of the Ape-1/Ref-1 redox domain, blocks the in vitro growth of pancreatic cancer-associated endothelial cells (PCECs) and EPCs, which is recapitulated by stable expression of a dominant-negative redox domain mutant. Further, E3330 blocks the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into CD31(+) endothelial progeny. Exposure of PCECs to E3330 results in a reduction of H-ras expression and intracellular nitric oxide (NO) levels, as well as decreased DNA-binding activity of the hypoxia-inducible transcription factor, HIF-1alpha. E3330 also reduces secreted and intracellular vascular endothelial growth factor expression by pancreatic cancer cells, while concomitantly downregulating the cognate receptor Flk-1/KDR on PCECs. Inhibition of the Ape-1/Ref-1 redox domain with E3330 or comparable angiogenesis inhibitors might be a potent therapeutic strategy in solid tumors.

Functional analysis of novel analogues of E3330 that block the redox signaling activity of the multifunctional AP endonuclease/redox signaling enzyme APE1/Ref-1.[Pubmed:20874257]

Antioxid Redox Signal. 2011 Apr 15;14(8):1387-401.

APE1 is a multifunctional protein possessing DNA repair and redox activation of transcription factors. Blocking these functions leads to apoptosis, antiangiogenesis, cell-growth inhibition, and other effects, depending on which function is blocked. Because a selective inhibitor of the APE redox function has potential as a novel anticancer therapeutic, new analogues of E3330 were synthesized. Mass spectrometry was used to characterize the interactions of the analogues (RN8-51, 10-52, and 7-60) with APE1. RN10-52 and RN7-60 were found to react rapidly with APE1, forming covalent adducts, whereas RN8-51 reacted reversibly. Median inhibitory concentration (IC(50) values of all three compounds were significantly lower than that of E3330. EMSA, transactivation assays, and endothelial tube growth-inhibition analysis demonstrated the specificity of E3330 and its analogues in blocking the APE1 redox function and demonstrated that the analogues had up to a sixfold greater effect than did E3330. Studies using cancer cell lines demonstrated that E3330 and one analogue, RN8-51, decreased the cell line growth with little apoptosis, whereas the third, RN7-60, caused a dramatic effect. RN8-51 shows particular promise for further anticancer therapeutic development. This progress in synthesizing and isolating biologically active novel E3330 analogues that effectively inhibit the APE1 redox function validates the utility of further translational anticancer therapeutic development.

Specific inhibition of the redox activity of ape1/ref-1 by e3330 blocks tnf-alpha-induced activation of IL-8 production in liver cancer cell lines.[Pubmed:23967134]

PLoS One. 2013 Aug 15;8(8):e70909.

APE1/Ref-1 is a main regulator of cellular response to oxidative stress via DNA-repair function and co-activating activity on the NF-kappaB transcription factor. APE1 is central in controlling the oxidative stress-based inflammatory processes through modulation of cytokines expression and its overexpression is responsible for the onset of chemoresistance in different tumors including hepatic cancer. We examined the functional role of APE1 overexpression during hepatic cell damage related to fatty acid accumulation and the role of the redox function of APE1 in the inflammatory process. HepG2 cells were stably transfected with functional and non-functional APE1 encoding plasmids and the protective effect of APE1 overexpression toward genotoxic compounds or FAs accumulation, was tested. JHH6 cells were stimulated with TNF-alpha in the presence or absence of E3330, an APE1 redox inhibitor. IL-8 promoter activity was assessed by a luciferase reporter assay, gene expression by Real-Time PCR and cytokines (IL-6, IL-8, IL-12) levels measured by ELISA. APE1 over-expression did not prevent cytotoxicity induced by lipid accumulation. E3330 treatment prevented the functional activation of NF-kappaB via the alteration of APE1 subcellular trafficking and reduced IL-6 and IL-8 expression induced by TNF-alpha and FAs accumulation through blockage of the redox-mediated activation of NF-kappaB. APE1 overexpression observed in hepatic cancer cells may reflect an adaptive response to cell damage and may be responsible for further cell resistance to chemotherapy and for the onset of inflammatory response. The efficacy of the inhibition of APE1 redox activity in blocking TNF-alpha and FAs induced inflammatory response opens new perspectives for treatment of inflammatory-based liver diseases.

The APE1 redox inhibitor E3330 reduces collective cell migration of human breast cancer cells and decreases chemoinvasion and colony formation when combined with docetaxel.[Pubmed:28303665]

Chem Biol Drug Des. 2017 Oct;90(4):561-571.

The human apurinic/apyrimidinic endonuclease 1 (APE1) is an ubiquitous multifunctional DNA repair enzyme and a redox signalling protein. Our work addressed the inhibition of APE1 redox function using E3330, as single agent or in combination with docetaxel (DTX), in human breast cancer MDA-MB-231 cells. E3330 decreased the colony formation of DTX-treated cells. In addition, E3330 alone significantly reduced the collective cell migration as assessed by the wound-healing assay, whereas the combined treatment decreased chemoinvasion. These results suggest that the inhibition of APE1 redox function might have therapeutic potential by modulating cell migration and invasion in metastatic breast cancer.

E3330 (APX-3330) is a direct, orally active AP endonuclease 1 (APE1; also known as REF-1) inhibitor, which suppresses NF-κB DNA-binding activity. E3330 (APX-3330) blocks TNF-α-induced activation of IL-8 production in liver cancer cell lines. E3330 (APX-3330) shows anticancer properties, such as inhibition of cancer cell growth and migration[1-4].

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