Investigation of the DNA damage response to SFOM-0046, a new small-molecule drug inducing DNA double-strand breaks

2-Ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) is a novel anticancer agent that arrests cell cycle in S-phase and causes DNA replication stress leading to the phosphorylation of H2AX into γ-H2AX. First, using the M21, HT29, HT-1080 and HeLa cell lines, we confirmed that S-phase cell cyc...

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Bibliographic Details
Published in:Scientific reports 2016-03, Vol.6 (1), p.23302-23302, Article 23302
Main Authors: Pauty, Joris, Côté, Marie-France, Rodrigue, Amélie, Velic, Denis, Masson, Jean-Yves, Fortin, Sébastien
Format: Article
Language:English
Subjects:
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Antineoplastic Agents - pharmacology
Benzenesulfonates - pharmacology
Cell cycle
Cell Line, Tumor
Deoxyribonucleic acid
DNA
DNA Damage
DNA Repair
DNA Replication
Humanities and Social Sciences
Humans
multidisciplinary
Phenylurea Compounds - pharmacology
Science
Signal transduction
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Summary:2-Ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) is a novel anticancer agent that arrests cell cycle in S-phase and causes DNA replication stress leading to the phosphorylation of H2AX into γ-H2AX. First, using the M21, HT29, HT-1080 and HeLa cell lines, we confirmed that S-phase cell cycle arrest and γ-H2AX foci induction by SFOM-0046 is a general mechanism occurring in diverse cancer cell lines. In addition to γ-H2AX, SFOM-0046 activates preferentially ATR-Chk1 in M21 and HT29 cells while both ATR-Chk1 and ATM-Chk2 pathways are activated in HCT116 cells. Co-localization of SFOM-0046-induced 53BP1 foci with γ-H2AX foci validates that the DNA damage generated corresponds to double-strand-breaks (DSBs). Consistent with an S-phase arrest, SFOM-0046 treatment induces RAD51 foci formation but not DNA-PKcs foci, confirming that homologous recombination is the major DSB repair pathway targeted by the drug. Furthermore, using isogenic HCT116 p53+/+ and HCT116 p53−/− cells, we showed that p53 plays a key role in the survival mechanism to SFOM-0046. Finally, SFOM-0046 exhibits a dose-dependent antitumor activity on human fibrosarcoma HT-1080 tumours grafted onto chick chorioallantoic membranes without showing embryo toxicity even at high doses. Altogether, our results highlight SFOM-0046 as a very promising drug that induces a replication stress response.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep23302