Small-Molecule Inhibitors of APE1 DNA Repair Function: An Overview

Al-Safi, Rasha I.; Odde, Srinivas; Shabaik, Yumna; Neamati, Nouri

doi:10.2174/1874467211205010014

Cited by 44 publications

(22 citation statements)

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“…In this assay, APE1-mediated cleavage of the AP site generates a 20-mer 32P-end-labeled product that can be separated from uncleaved substrate on a polyacrylamide gel. Myricetin was used as a positive control, as it was previously identified as an APE1 endonuclease activity inhibitor 23. In the presence of 300 pg recombinant APE1 protein, gossypol inhibited APE1 endonuclease activity starting at 0.001 μM, with a half maximal inhibitory concentration (IC50) of 0.036 μM.…”

Section: Resultsmentioning

confidence: 99%

“…E3330, for example, inhibits the APE1 redox function, while CRT0044876 blocks its repair function 19,23. Importantly, gossypol inhibits both the redox and repair functions of APE1.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the dual functions of APE1, several inhibitors have been discovered that selectively inhibit either its DNA repair or redox function. DNA repair inhibitors include the indirect inhibitor methoxamine and the direct/indirect inhibitors such as lucanthone and CRT0044876 23. The redox function inhibitors are soy isoflavones, resveratrol,24 E3330,25,26 and its benzoquinone and naphthoquinone analogs 27…”

Section: Introductionmentioning

confidence: 99%

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Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor

Qian¹,

Li²,

Sui³

et al. 2014

DDDT

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The human apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (APE1/Ref-1), an essential multifunctional protein involved in the repair of oxidative deoxyribonucleic acid (DNA) damage and transcriptional regulation, is often overexpressed in tumor tissues and cancer cells. Moreover, APE1/Ref-1 (APE1) overexpression has been linked to chemoresistance in human tumors. Thus, inhibiting APE1 function in cancer cells is considered a promising strategy to overcome resistance to therapeutic agents. Gossypol is a Bcl-2 homology 3 (BH3)-mimetic agent and is able to bind to the BH3 domain of B-cell lymphoma 2 (Bcl-2) family members. Other studies demonstrated that Bcl-2 directly interacted with APE1 via its BH domains. Using apurinic/apyrimidinic (AP) endonuclease assays, we found that gossypol inhibits the repair activity of APE1. Electrophoretic mobility shift assays and dual luciferase assays showed that gossypol could also inhibit the redox function of APE1. Using dual polarization interferometry technology, we show that gossypol can directly interact with APE1. Furthermore, addition of gossypol, in conjunction with APE1 overexpression, leads to cancer cell death. The addition of gossypol also enhances the cell killing effect of the laboratory alkylating agent methyl methanesulfonate and the clinical agent cisplatin (DDP). Administration of gossypol significantly inhibited the growth of xenografts. Furthermore, the combined treatment of gossypol and DDP resulted in a statistically higher antitumor activity compared with DDP alone in vivo. In conclusion, we have demonstrated that gossypol effectively inhibits the repair and redox activity of APE1 through a direct interaction.

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Section: Resultsmentioning

confidence: 99%

“…E3330, for example, inhibits the APE1 redox function, while CRT0044876 blocks its repair function 19,23. Importantly, gossypol inhibits both the redox and repair functions of APE1.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor

Qian¹,

Li²,

Sui³

et al. 2014

DDDT

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“…MX is currently used in combination with pemetrexed and temozolomide in clinical trials sponsored by CTEP and Tracon Pharmaceuticals to treat advanced solid cancers. In addition, discovery of direct APE1 inhibitors have also been reported recently, but none of them have to date been successfully used in either cell or animal models [28]. Inhibitors of Pol β have also been developed but demonstrated only mild preclinical efficacy, and new compounds suffer from the fear of toxicity due to overlapping specificity with additional DNA polymerases [29].…”

Section: Introductionmentioning

confidence: 99%

Advances in therapeutic targeting of the DNA damage response in cancer

2018

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The DNA damage response (DDR) is a series of pathways and processes required to repair lesions to DNA. These pathways range from repairing strand breaks to the double helix, damaged bases formed after oxidation or deamination, inaccurate DNA replication resulting in mispaired base alignment, intrastrand crosslinks that trigger cell death, and a plethora of other genomic insults. The DDR is believed to be a critical component of radio and chemoresistance in many cancers as well, with the tumor’s ability to repair therapy induced damage being an important tool used to survive traditional chemotherapeutic agents. Here we summarize advances made in specifically targeting DDR proteins in cancer therapy and project on the potential breakthroughs and pitfalls to arise as the field progresses.

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“…5–8 Additionally, Ape1 expression in GBM cell lines is predictive of their radiosensitivity. 9 However, no Ape1 inhibitors are approved for clinical use, 10–15 with only one, methylamine, making it to Phase I and II clinical trials. 16 As opposed to these small molecule Ape1 inhibitors, delivery of antisense oligonucleotides such as short interfering RNAs (siRNA) is advantageous because of the potency and efficiency of the RNA interference (RNAi) pathway.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle-mediated knockdown of DNA repair sensitizes cells to radiotherapy and extends survival in a genetic mouse model of glioblastoma

Kievit

Wang

Ozawa

et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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Glioblastoma (GBM) remains incurable, and recurrent tumors that rarely respond to standard-of-care radiation and chemo therapies. Therefore, strategies that enhance the effects of these therapies should provide significant benefits to GBM patients. We have developed a nanoparticle delivery vehicle that can stably bind and protect nucleic acids for specific delivery into brain tumor cells. These nanoparticles can deliver therapeutic siRNAs to sensitize GBM cells to radiotherapy and improve GBM treatment via systemic administration. We show that nanoparticle-mediated knockdown of the DNA repair protein apurinic endonuclease 1 (Ape1) sensitizes GBM cells to radiotherapy and extend survival in a genetic mouse model of GBM. Specific knockdown of Ape1 activity by 30% in brain tumor tissue doubled the extended survival achieved with radiotherapy alone. Ape1 is a promising target for increasing the effectiveness of radiotherapy, and nanoparticle-mediated delivery of siRNA is a promising strategy for tumor specific knockdown of Ape1.

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Small-Molecule Inhibitors of APE1 DNA Repair Function: An Overview

Cited by 44 publications

References 0 publications

Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor

Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor

Advances in therapeutic targeting of the DNA damage response in cancer

Nanoparticle-mediated knockdown of DNA repair sensitizes cells to radiotherapy and extends survival in a genetic mouse model of glioblastoma

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