Henriksson, S.; Calderón-Montaño, J.M.; Solvie, D.; Warpman Berglund, U.; Helleday, T. Overexpressed c-Myc Sensitizes Cells to TH1579, a Mitotic Arrest and Oxidative DNA Damage Inducer. Biomolecules2022, 12, 1777.
Henriksson, S.; Calderón-Montaño, J.M.; Solvie, D.; Warpman Berglund, U.; Helleday, T. Overexpressed c-Myc Sensitizes Cells to TH1579, a Mitotic Arrest and Oxidative DNA Damage Inducer. Biomolecules 2022, 12, 1777.
Henriksson, S.; Calderón-Montaño, J.M.; Solvie, D.; Warpman Berglund, U.; Helleday, T. Overexpressed c-Myc Sensitizes Cells to TH1579, a Mitotic Arrest and Oxidative DNA Damage Inducer. Biomolecules2022, 12, 1777.
Henriksson, S.; Calderón-Montaño, J.M.; Solvie, D.; Warpman Berglund, U.; Helleday, T. Overexpressed c-Myc Sensitizes Cells to TH1579, a Mitotic Arrest and Oxidative DNA Damage Inducer. Biomolecules 2022, 12, 1777.
Abstract
Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras expressing or transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Oncogenes induce replication stress, re-sulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment cause toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overex-pressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but interestingly not by nucleoside supplementation. This suggest that cancer selectivity is unrelated oncogene-induced replication stress. We conclude that the molecular toxi-cological mechanisms how TH588 and TH1579 kill c-Myc overexpressing cells have several com-ponents and involves MTH1-independent proteosomal degradation of c-Myc itself, c-Myc driven transcription and CDK activation, and is likely unrelated to oncogene-induced replication stress.
Keywords
MTH1; TH588; TH1579; c-Myc; replication stress; DNA damage; cell death; cancer
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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