Spotlight: NAT2 Activity Increases Cytotoxicity of Anthracycline Antibiotics and HDAC Inhibitors
Increasing importance of NAT2 acetylator status in therapeutic drug metabolism
Introduction
N-acetyltransferase2 (NAT2) is a phase II drug metabolic enzyme with many reported SNPs that affect its catalytic activity. Depending upon the combination of alleles present a subject could have slow, intermediate or rapid acetylator status. Most studies on NAT2-related toxicity have focussed on the anti-TB drug isoniazid, which has been shown to cause hepatotoxicity in patients that harbour two slow acetylator alleles. Other drugs known to be metabolised by NAT2 include the hydralazine (Hypotensive), procainamide (Hypotensive), clonazepam (Epilepsy), sulfasalazine (Inflammatory Bowel Disease), nitrazepam (Insomia) and amonafide (AML, Cancers). In this study the authors highlight the lack of studies addressing NAT2-dependent metabolism of anti-cancer agents and how this can influence efficacy and toxicity. Allelic status can therefore predict the response and doses tailored accordingly.
Main Points
- 147 FDA approved cancer drugs were assessed for cytotoxicity in RKO cell lines expressing rapid (NAT2”13) or slow (NAT2*6) acetylator status. 40 compounds had a 20% difference in growth inhibition between the 2 cell lines.
- A similar result was observed n DLD-1 CRC cells expressing the same NAT2 haplotypes.
- Further analysis identified 10 drugs that were more toxic in the cell lines with the rapid NAT2 mutations, no drugs had increased toxicity in cell lines with the slow NAT2 allele. These drugs were afatinib, carmustine, daunorubicin, doxorubicin, epirubicin, panobinostat, teniposide, valrubicin, vincristine and vorinostat.
- 4 of these drugs were anthracycline-based antibiotics with valrubicin having a 4.8-fold difference in toxicity, doxorubicin a 3.3-fold, epirubicin a 3.1-fold and daunorubicin a 1.8-fold.
- The rapid allele also increased toxicity for other drug classes such as the vinca alkaloid vincristine, the ErbB kinase covalent blocker afatini, the topioisomerase inhibitor teniposide and HDAC inhibitors vorinostat and Panobinostat.
- This led the authors to test HDAC inhibitors CUDC-101, pracinostat, belinostat and trichostatin A and all showed selective toxicity when the rapid NAT2 allele was present in both RKO and DLD-1 models.
- Acetylated vorinostat demonstrated higher toxicity levels than native vorinostat in the RKO cell line model described above. This is the likely cause of the increased toxicity of agents in cells that express the rapid NAT2 alleles.
Conclusion
NAT2 polymorphisms results in three types of acetylator status, slow intermediate and rapid. In this study the authors demonstrated that the rapid allele could increase the toxicity of a number of commonly used anti-cancer therapies including doxorubicin and vincristine. They also demonstrated that anthracycline antibiotics and HDAC inhibitors were substrates for NAT2. In the 1000 genomes project the estimated prevalence of the rapid allele was ~0.5 and hence the authors estimate that over 4 million patients per year globally are being treated with agents metabolised by NAT2 leading to variations in toxicity and efficacy.
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