Islam Tanhaul, Nunna Venkatrao, Liyanarachchi Don Pivithuru, Melton Douglas, Lewis Calvin D, Gates Kent S
University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, Missouri 65211, United States.
Washington University School of Medicine Department of Radiation Oncology, Box 8224, 4921 Parkview Place, St. Louis, Missouri 63110, United States.
Chem Res Toxicol. 2025 Jan 20;38(1):42-45. doi: 10.1021/acs.chemrestox.4c00445. Epub 2024 Dec 24.
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.
脱嘌呤/脱嘧啶内切酶1（APE1）是碱基切除修复（BER）途径中的关键酶。在细胞DNA中受损核碱基的修复过程中，APE1催化脱嘌呤/脱嘧啶（AP）位点5'侧磷酸二酯键的切割。抑制这种酶可增强DNA损伤化疗药物的作用。抗高血压药物肼屈嗪会生成共价AP加合物，从而阻断APE1的催化作用。研究发现，肼屈嗪在共价捕获双链DNA中的AP位点并抑制APE1作用的能力方面优于研究药物甲氧基胺。进一步研究表明，肼屈嗪使SF295胶质母细胞瘤细胞对抗癌药物替莫唑胺的细胞毒性作用敏感，替莫唑胺会产生需要APE1进行修复的烷基嘌呤残基。结果表明，美国食品药品监督管理局（FDA）批准的药物肼屈嗪可能可用于肿瘤学领域，以增强现有能在细胞DNA中诱导AP位点的化疗药物的活性。
