Repurposing\nthe Antihypertensive Agent Hydralazine\nAs an Inhibitor of the Base Excision Repair Enzyme APE1

Apurinic/apyrimidinic endonuclease 1 (APE1) is a central enzyme in the base excision\nrepair (BER)\npathway. APE1 catalyzes incision of the phosphodiester linkage on\nthe 5′-side of apurinic/apyrimidinic (AP) sites during the\nrepair of damaged nucleobases in cellular DNA. Inhibition of this\nenzyme can potentiate the action of DNA-damaging chemotherapeutic\nagents. The antihypertensive drug hydralazine generates covalent AP\nadducts that block the catalytic action of APE1. Hydralazine was found\nto be superior to the investigational drug methoxyamine in its capacity\nto covalently capture AP sites in duplex DNA and inhibit the action\nof APE1. It was further shown that hydralazine sensitized SF295 glioblastoma\ncells to the cytotoxic action of the anticancer drug Temozolomide,\nwhich generates alkylpurine residues requiring APE1 for repair. The\nresults suggest that the FDA-approved drug hydralazine might be repurposed\nin oncology to potentiate the activity of existing chemotherapeutic\nagents that induce AP sites in cellular DNA.