Human AP endonuclease 1 (APE1): from mechanistic insights to druggable target in cancer.
DNA base excision repair (BER) is critically involved in the processing of DNA base damage induced by alkylating agents. Pharmacological inhibition of BER (using PARP inhibitors), either alone or in combination with chemotherapy has recently shown promise in clinical trials. Human apurinic/apyrimidinic endonuclease 1(APE1) is an essential BER protein that is involved in the processing of potentially cytotoxic abasic sites that are obligatory intermediates in BER. Here we provide a summary of the basic mechanistic role of APE1 in DNA repair and redox regulation and highlight preclinical and clinical data that confirm APE1 as a valid anticancer drug target. Development of small molecule inhibitors of APE1 is an area of intense research and current evidence using APE1 inhibitors has demonstrated potentiation of cytotoxicity of alkylating agents in preclinical models implying translational applications in cancer patients.
Abbotts
Rachel
R
Translational DNA Repair Group, Laboratory of Molecular Oncology, Academic Unit of Oncology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Madhusudan
Srinivasan
S
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase