Velic, Denis; Charlier, Cathy; Popova, Milena; Jaunet-Lahary, Titouan; Bouchouireb, Zakaria; Henry, Sébastien; Weigel, Pierre; Masson, Jean-Yves; Laurent, Adèle D; Nabiev, Igor; Fleury, Fabrice Interactions of the Rad51 inhibitor DIDS with human and bovine serum albumins: Optical spectroscopy and isothermal calorimetry approaches Article Biochimie, 167 , p. 187–197, 2019, ISSN: 0300-9084. Résumé | Liens | BibTeX @article{VELIC2019187,
title = {Interactions of the Rad51 inhibitor DIDS with human and bovine serum albumins: Optical spectroscopy and isothermal calorimetry approaches},
author = {Denis Velic and Cathy Charlier and Milena Popova and Titouan Jaunet-Lahary and Zakaria Bouchouireb and Sébastien Henry and Pierre Weigel and Jean-Yves Masson and Adèle D Laurent and Igor Nabiev and Fabrice Fleury},
url = {http://www.sciencedirect.com/science/article/pii/S0300908419302743},
doi = {https://doi.org/10.1016/j.biochi.2019.09.016},
issn = {0300-9084},
year = {2019},
date = {2019-01-01},
journal = {Biochimie},
volume = {167},
pages = {187--197},
abstract = {Rad51 is a key protein in DNA repair by homologous recombination and an important target for development of drugs in cancer therapy. 4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) has been used in clinic during the past 30 years as an inhibitor of anion transporters and channels. Recently DIDS has been demonstrated to affect Rad51-mediated homologous pairing and strand exchange, key processes in homologous recombination. Consequently, DIDS has been considered as a potential revertant of radio- and chemo-resistance of cancer cells, the major causes of therapy failure. Here, we have investigated the behavior of DIDS towards serum albumins. The effects of environmental factors, primarily, solvent polarity, on DIDS stability were evaluated, and the mechanisms of interaction of DIDS with human or bovine serum albumin were analyzed using isothermal calorimetry, circular dichroism and fluorescence spectroscopies. DIDS interaction with both serum albumins have been demonstrated, and the interaction characteristics have been determined. By comparing these characteristics for several DIDS derivatives, we have identified the DIDS moiety essential for the interaction. Furthermore, site competition data indicate that human albumin has two DIDS-binding sites: a high-affinity site in the IIIA subdomain and a low-affinity one in the IB subdomain. Molecular docking has revealed the key molecular moieties of DIDS responsible for its interactions in each site and shown that the IB site can bind two ligands. These findings show that binding of DIDS to serum albumin may change the balance between the free and bound DIDS forms, thereby affecting its bioavailability and efficacy against Rad51.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Rad51 is a key protein in DNA repair by homologous recombination and an important target for development of drugs in cancer therapy. 4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) has been used in clinic during the past 30 years as an inhibitor of anion transporters and channels. Recently DIDS has been demonstrated to affect Rad51-mediated homologous pairing and strand exchange, key processes in homologous recombination. Consequently, DIDS has been considered as a potential revertant of radio- and chemo-resistance of cancer cells, the major causes of therapy failure. Here, we have investigated the behavior of DIDS towards serum albumins. The effects of environmental factors, primarily, solvent polarity, on DIDS stability were evaluated, and the mechanisms of interaction of DIDS with human or bovine serum albumin were analyzed using isothermal calorimetry, circular dichroism and fluorescence spectroscopies. DIDS interaction with both serum albumins have been demonstrated, and the interaction characteristics have been determined. By comparing these characteristics for several DIDS derivatives, we have identified the DIDS moiety essential for the interaction. Furthermore, site competition data indicate that human albumin has two DIDS-binding sites: a high-affinity site in the IIIA subdomain and a low-affinity one in the IB subdomain. Molecular docking has revealed the key molecular moieties of DIDS responsible for its interactions in each site and shown that the IB site can bind two ligands. These findings show that binding of DIDS to serum albumin may change the balance between the free and bound DIDS forms, thereby affecting its bioavailability and efficacy against Rad51. |
Pauty, Joris; Côté, Marie-France; Rodrigue, Amélie; Velic, Denis; Masson, Jean-Yves; Fortin, Sébastien Investigation of the DNA damage response to SFOM-0046, a new small-molecule drug inducing DNA double-strand breaks Article Scientific reports, 6 (1), p. 1–11, 2016. Résumé | Liens | BibTeX @article{pauty2016investigation,
title = {Investigation of the DNA damage response to SFOM-0046, a new small-molecule drug inducing DNA double-strand breaks},
author = {Joris Pauty and Marie-France Côté and Amélie Rodrigue and Denis Velic and Jean-Yves Masson and Sébastien Fortin},
url = {https://www.nature.com/articles/srep23302},
doi = {10.1038/srep23302},
year = {2016},
date = {2016-01-01},
journal = {Scientific reports},
volume = {6},
number = {1},
pages = {1--11},
publisher = {Nature Publishing Group},
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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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. |
Velic, Denis; Couturier, Anthony M; Ferreira, Maria Tedim; Rodrigue, Amélie; Poirier, Guy G; Fleury, Fabrice; Masson, Jean-Yves DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer Article Biomolecules, 5 (4), p. 3204–3259, 2015, ISSN: 2218-273X. Résumé | Liens | BibTeX @article{biom5043204,
title = {DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer},
author = {Denis Velic and Anthony M Couturier and Maria Tedim Ferreira and Amélie Rodrigue and Guy G Poirier and Fabrice Fleury and Jean-Yves Masson},
url = {https://www.mdpi.com/2218-273X/5/4/3204},
doi = {10.3390/biom5043204},
issn = {2218-273X},
year = {2015},
date = {2015-01-01},
journal = {Biomolecules},
volume = {5},
number = {4},
pages = {3204--3259},
abstract = {For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use. |