Repurposing the Antihypertensive Agent Hydralazine As an Inhibitor of the Base Excision Repair Enzyme APE1

Abstract

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