Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
[EN]Ovarian cancer (OC) is the deadliest gynecologic malignancy, which is mainly due to late-stage diagnosis and chemotherapy resistance. Therefore, new and more effective treatments are urgently needed. The in vitro effects of Panobinostat (LBH), a histone deacetylase inhibitor that exerts pleiotro...
| Autores: | , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Salamanca (USAL) |
| Repositorio: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/164471 |
| Acceso en línea: | http://hdl.handle.net/10366/164471 |
| Access Level: | acceso abierto |
| Palabra clave: | Antineoplastic agents Cell line Cancer DNA damage DNA repair Drug synergism Cloroquine Panobinostat Chloroquine Reactive Oxygen Species Drug Synergism Humans DNA Damage Cell Line Antineoplastic Agents Autophagy DNA Repair Cell Cycle Checkpoints Cell Survival Apoptosis Ovarian Neoplasms DNA Breaks Recombinational DNA Repair apoptosis daño del ADN humanos línea celular autofagia reparación del ADN por recombinación cloroquina neoplasias ováricas antineoplásicos roturas del ADN puntos de comprobación del ciclo celular reparación del ADN especies reactivas de oxígeno sinergismo farmacológico supervivencia celular |
| Sumario: | [EN]Ovarian cancer (OC) is the deadliest gynecologic malignancy, which is mainly due to late-stage diagnosis and chemotherapy resistance. Therefore, new and more effective treatments are urgently needed. The in vitro effects of Panobinostat (LBH), a histone deacetylase inhibitor that exerts pleiotropic antitumor effects but induces autophagy, in combination with Chloroquine (CQ), an autophagy inhibitor that avoid this cell survival mechanism, were evaluated in 4 OC cell lines. LBH and CQ inhibited ovarian cancer cell proliferation and induced apoptosis, and a strong synergistic effect was observed when combined. Deeping into their mechanisms of action we show that, in addition to autophagy modulation, treatment with CQ increased reactive oxygen species (ROS) causing DNA double strand breaks (DSBs), whereas LBH inhibited their repair by avoiding the correct recruitment of the recombinase Rad51 to DSBs. Interestingly, CQ-induced DSBs and cell death caused by CQ/LBH combination were largely abolished by the ROS scavenger N-Acetylcysteine, revealing the critical role of DSB generation in CQ/LBH-induced lethality. This role was also manifested by the synergy found when we combined CQ with Mirin, a well-known homologous recombination repair inhibitor. Altogether, our results provide a rationale for the clinical investigation of CQ/LBH combination in ovarian cancer. |
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