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NAT2 activity increases cytotoxicity of anthracycline antibiotics and HDAC inhibitors

Natallia Rameika1, Ioanna Tsiara2, Xiaonan Zhang1

  • 1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|March 13, 2025
PubMed

Insights

The Arylamine-N-acetyltransferase-2 (NAT2) enzyme affects cancer drug efficacy. Rapid NAT2 activity increases toxicity for certain chemotherapy drugs, impacting precision medicine for millions of patients.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Oncology

Background:

  • The Arylamine-N-acetyltransferase-2 (NAT2) enzyme plays a crucial role in drug metabolism, influencing treatment outcomes.
  • Variations in NAT2 activity can lead to significant differences in drug efficacy and tolerability.
  • Understanding NAT2's role in the metabolism of cytotoxic drugs is essential for optimizing cancer therapy.

Purpose of the Study:

  • To investigate the metabolism of 147 clinically used drugs by the NAT2 enzyme.
  • To identify anticancer agents whose efficacy and toxicity are dependent on NAT2 activity.
  • To bridge the knowledge gap regarding NAT2-mediated metabolism of cytotoxic chemotherapy drugs.

Main Methods:

  • Assessed 147 clinically used drugs for their interaction with NAT2.
  • Evaluated metabolic conversion of hit compounds via acetylation using recombinant NAT2.
  • Compared the toxicity of drugs in cancer cells expressing different NAT2 alleles.

Main Results:

  • Identified 10 drugs (doxorubicin, daunorubicin, epirubicin, valrubicin, teniposide, afatinib, carmustine, vincristine, panobinostat, and vorinostat) with increased toxicity in cancer cells expressing the rapid NAT2 allele.
  • Reported NAT2-mediated acetylation for idarubicin, daunorubicin, doxorubicin, vorinostat, and CUDC-101.
  • Demonstrated that NAT2 activity influences the toxicity of several conventional chemotherapeutic agents.

Conclusions:

  • NAT2 genotype is a significant factor in the efficacy and safety of certain anticancer drugs.
  • These findings support the application of pharmacogenomics in cancer precision medicine.
  • Optimizing chemotherapy based on NAT2 activity could improve outcomes for millions of cancer patients worldwide.
Keywords:
AcetylationAnthracyclinesCancerChemotherapyDrug metabolismHDAC inhibitorsNAT2

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