title: Investigation of the DNA damage response to SFOM-0046, a new small-molecule drug inducing DNA double-strand breaks.
abstract: 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.
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, Oncology Axis, Hôtel-Dieu-de-Québec, 9 McMahon, Quebec City, QC, G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, G1V 0A6, Canada.
authors.forename: Joris
authors.initials: J
authors.lastname: Pauty
authors.affiliation: CHU de Québec Research Center, Oncology Axis, Hôpital Saint-François d'Assise, 10 de l'Espinay, Quebec City, QC, G1L 3L5, Canada.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Côté
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, Oncology Axis, Hôtel-Dieu-de-Québec, 9 McMahon, Quebec City, QC, G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, G1V 0A6, Canada.
authors.forename: Amélie
authors.initials: A
authors.lastname: Rodrigue
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, Oncology Axis, Hôtel-Dieu-de-Québec, 9 McMahon, Quebec City, QC, G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, G1V 0A6, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Velic
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, Oncology Axis, Hôtel-Dieu-de-Québec, 9 McMahon, Quebec City, QC, G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, G1V 0A6, Canada.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Masson
authors.affiliation: CHU de Québec Research Center, Oncology Axis, Hôpital Saint-François d'Assise, 10 de l'Espinay, Quebec City, QC, G1L 3L5, Canada.|Faculty of Pharmacy, Laval University, Quebec City, QC, G1V 0A6, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fortin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D006801:Humans; D010671:Phenylurea Compounds / Q000494:pharmacology*
chemical_list: C575267:2-ethylphenyl 4-(3-ethylureido)benzenesulfonate; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds