Chloroquine-Induced DNA Damage Synergizes with Nonhomologous End Joining Inhibition to Cause Ovarian Cancer Cell Cytotoxicity |
| |
Authors: | María Ovejero-Snchez Jorge Rubio-Heras María del Carmen Vicente de la Pea Laura San-Segundo Jesús Prez-Losada Rogelio Gonzlez-Sarmiento Ana Beln Herrero |
| |
Affiliation: | 1.Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (M.O.-S.); (L.S.-S.); (J.P.-L.);2.Molecular Medicine Unit, Department of Medicine, University of Salamanca, 37007 Salamanca, Spain; (J.R.-H.); (M.d.C.V.d.l.P.);3.Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, 37007 Salamanca, Spain |
| |
Abstract: | Ovarian cancer (OC) is the most lethal gynecological malignancy; therefore, more effective treatments are urgently needed. We recently reported that chloroquine (CQ) increased reactive oxygen species (ROS) in OC cell lines (OCCLs), causing DNA double-strand breaks (DSBs). Here, we analyzed whether these lesions are repaired by nonhomologous end joining (NHEJ), one of the main pathways involved in DSB repair, and if the combination of CQ with NHEJ inhibitors (NHEJi) could be effective against OC. We found that NHEJ inhibition increased the persistence of γH2AX foci after CQ-induced DNA damage, revealing an essential role of this pathway in the repair of the lesions. NHEJi decreased the proliferation of OCCLs and a strong in vitro synergistic effect on apoptosis induction was observed when combined with CQ. This effect was largely abolished by the antioxidant N-Acetyl-L-cysteine, revealing the critical role of ROS and DSB generation in CQ/NHEJi-induced lethality. We also found that the NHEJ efficiency in OCCLs was not affected by treatment with Panobinostat, a pan-histone deacetylase inhibitor that also synergizes with CQ in OCCLs by impairing homologous recombination. Accordingly, the triple combination of CQ-NHEJi-Panobinostat exerted a stronger in vitro synergistic effect. Altogether, our data suggest that the combination of these drugs could represent new therapeutic strategies against OC. |
| |
Keywords: | chloroquine panobinostat DNA damage and repair nonhomologous end joining KU-57788 NU-7026 SCR7 |
|
|