A possible link to uracil DNA glycosylase in the synergistic action of HDAC inhibitors and thymidylate synthase inhibitors

Meredith S Showler,Brian P Weiser

doi:10.1186/s12967-020-02555-x

Meredith S Showler, Brian P Weiser

Open Access

https://doi.org/10.1186/s12967-020-02555-x

Copy DOI

Abstract

It is well established that thymidylate synthase inhibitors can cause cellular toxicity through uracil DNA glycosylase (UNG2)-dependent pathways. Additionally, thymidylate synthase inhibitors and HDAC inhibitors are known to act synergistically in a variety of cancer types. A recent article from J. Transl. Med. links these together by demonstrating widespread depletion of UNG2 levels across a variety of cell lines treated with HDAC inhibitors. Recent findings suggest that UNG2 depletion by HDAC inhibitors would likely be an effective method to sensitize cells to thymidylate synthase inhibitors. This is particularly important for cancer types that are typically resistant to thymidylate synthase inhibitors, such as cells that are deficient in p53 activity.

Highlights

Med., Iveland et al showed that Histone deacetylase (HDAC) inhibitors caused a comprehensive and widespread depletion of Uracil DNA Glycosylase (UNG2) protein levels in a variety of cancer cell lines [1]
This work has implications for cancer treatments that can be affected by Uracil DNA glycosylase (UNG2) activity, namely thymidylate synthase (TS) inhibitors, which include 5-fluorouracil, pemetrexed, and raltitrexed
We propose that Iveland et al may have uncovered a novel approach to re-sensitize other cancers to TS inhibitors by targeting UNG2-dependent pathways with HDAC inhibitors

Summary

Introduction

Med., Iveland et al showed that HDAC inhibitors caused a comprehensive and widespread depletion of Uracil DNA Glycosylase (UNG2) protein levels in a variety of cancer cell lines [1]. We propose that Iveland et al may have uncovered a novel approach to re-sensitize other cancers to TS inhibitors by targeting UNG2-dependent pathways with HDAC inhibitors. *Correspondence: weiser@rowan.edu 2 Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA Full list of author information is available at the end of the article generations of molecules continue to be developed.

Results

Conclusion