NAT2 activity increases cytotoxicity of anthracycline antibiotics and HDAC inhibitors

The Arylamine-N-acetyltransferase-2, or NAT2, enzyme plays a role in the body’s processing of many commonly prescribed medications, leading to variations in how well these treatments work and how well they are tolerated among individuals. To address the current lack of comprehensive understanding regarding the metabolism of cytotoxic, or cell-killing, drugs by NAT2 and to pinpoint anticancer agents whose effects are influenced by NAT2 activity, we conducted an evaluation of 147 drugs that are used clinically.

Compounds that showed initial promise were further examined for their metabolic conversion through acetylation in the presence of purified NAT2 enzyme. Our investigation of these 147 drugs revealed that doxorubicin, daunorubicin, epirubicin, valrubicin, teniposide, afatinib, carmustine, vincristine, panobinostat, and vorinostat exhibited increased toxicity to cancer cells that expressed the rapid NAT2 gene variant.

Furthermore, we report that NAT2 mediates the acetylation of idarubicin, daunorubicin, doxorubicin, vorinostat, and CUDC-101. These discoveries carry significant implications for the field of pharmacogenomics, which studies how genes affect a person’s response to drugs, and for the advancement of precision medicine in cancer treatment using conventional chemotherapy.

Improving the effectiveness and safety of these drugs based on an individual’s NAT2 profile could potentially benefit over four million cancer patients globally who receive these agents as part of their standard care.