Chloroquine-Induced DNA Damage Synergizes with Nonhomologous End Joining Inhibition to Cause Ovarian Cancer Cell Cytotoxicity
María Ovejero-Sánchez 1 2 3, Jorge Rubio-Heras 2, María Del Carmen Vicente de la Peña 2, Laura San-Segundo 1 3, Jesús Pérez-Losada 1 3, Rogelio González-Sarmiento 1 2 3, Ana Belén Herrero 1 2 3
Ovarian cancer (OC) is easily the most lethal gynecological malignancy therefore, more efficient remedies are urgently needed. We lately reported that chloroquine (CQ) elevated reactive oxygen species (ROS) in OC cell lines (OCCLs), causing DNA double-strand breaks (DSBs). Here, we examined whether these lesions are repaired by nonhomologous finish joining (NHEJ), among the primary pathways involved with DSB repair, and when the mixture of CQ with NHEJ inhibitors (NHEJi) might be effective against OC. We discovered that NHEJ inhibition elevated the persistence of |?H2AX foci after CQ-caused DNA damage, revealing an important role of the path within the repair from the lesions. NHEJi decreased the proliferation of OCCLs along with a strong in vitro synergistic impact on apoptosis induction was observed when coupled with CQ. This effect was largely abolished through the antioxidant N-Acetyl-L-cysteine, revealing the critical role of ROS and DSB generation in CQ/NHEJi-caused lethality. We discovered that the NHEJ efficiency in OCCLs wasn’t impacted by treatment with Panobinostat, a pan-histone deacetylase inhibitor which synergizes with CQ in OCCLs by impairing homologous recombination. Accordingly, the triple mixture of CQ-NHEJi-Panobinostat exerted a more powerful in vitro synergistic effect. Altogether, our data claim that the mixture of those drugs could represent new therapeutic strategies against OC.KU-57788