Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition
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Stéphanie Arnould1,2,3,4, Geneviève Rodier1,2,3,4, Gisèle Matar1,2,3,4, Charles Vincent1,2,3,4, Nelly Pirot1,2,3,4,5, Yoann Delorme1,2,3,4, Charlène Berthet1,2,3,4,5, Yoan Buscail1,2,3,4,5, Jean Yohan Noël1,2,3,4,5, Simon Lachambre6, Marta Jarlier1,2,3,4, Florence Bernex1,2,3,4,5, Hélène Delpech1,2,3,4, Pierre Olivier Vidalain7, Yves L. Janin8, Charles Theillet1,2,3,4 and Claude Sardet1,2,3,4
1Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
2INSERM U1194, Montpellier, France
3Université de Montpellier, Montpellier, France
4Institut Régional du Cancer de Montpellier, Montpellier, France
5Réseau d'Histologie Expérimentale de Montpellier, BioCampus, UMS3426 CNRS-US009 INSERM-UM, Montpellier, France
6Montpellier RIO Imaging, BioCampus, UMS3426 CNRS-US009 INSERM-UM, Montpellier, France
7Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Equipe Chimie and Biologie, Modélisation et Immunologie pour la Thérapie, CNRS UMR 8601 CNRS-Université Paris Descartes, Paris, France
8Institut Pasteur, Unité de Chimie et Biocatalyse, CNRS UMR3523, Paris, France
Claude Sardet, email: [email protected]
Stéphanie Arnould, email: [email protected]
Keywords: DHODH, Chk1, cytotoxicity, triple negative breast cancer, DNA damage
Received: December 20, 2016 Accepted: June 17, 2017 Published: July 12, 2017
Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalised counterparts, and this effect was amplified when cells were subsequently exposed to PF477736 Chk1 inhibitor. Flow cytometry analyses revealed substantial accumulations of cells in S and G2/M phases, followed by increased cytotoxicity which was characterised by caspase 3-dependent induction of cell death. Associating PF477736 with teriflunomide also significantly sensitised SUM159 and HCC1937 human triple negative breast cancer cell lines to dihydroorotate dehydrogenase inhibition. The main characteristic of this effect was the sustained accumulation of teriflunomide-induced DNA damage as cells displayed increased phospho serine 139 H2AX (γH2AX) levels and concentration-dependent phosphorylation of Chk1 on serine 345 upon exposure to the combination as compared with either inhibitor alone. Importantly a similar significant increase in cell death was observed upon dual siRNA mediated depletion of Chk1 and DHODH in both murine and human cancer cell models. Altogether these results suggest that combining DHODH and Chk1 inhibitions may be a strategy worth considering as a potential alternative to conventional chemotherapies.
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