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...

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Authors: Ovejero-Sánchez, María, González Sarmiento, Rogelio, Herrero Hernández, Ana Belén
Format: article
Status:Published version
Publication Date:2021
Country:España
Institution:Universidad de Salamanca (USAL)
Repository:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/164471
Online Access:http://hdl.handle.net/10366/164471
Access Level:Open access
Keyword: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
id ES_fb0f84f6b0a8036023a291f5e6fea8a1
oai_identifier_str oai:gredos.usal.es:10366/164471
network_acronym_str ES
network_name_str España
repository_id_str
spelling Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repairOvejero-Sánchez, MaríaGonzález Sarmiento, RogelioHerrero Hernández, Ana BelénAntineoplastic agentsCell lineCancerDNA damageDNA repairDrug synergismCloroquinePanobinostatChloroquineReactive Oxygen SpeciesDrug SynergismHumansDNA DamageCell LineAntineoplastic AgentsAutophagyDNA RepairCell Cycle CheckpointsCell SurvivalApoptosisOvarian NeoplasmsDNA BreaksRecombinational DNA Repairapoptosisdaño del ADNhumanoslínea celularautofagiareparación del ADN por recombinacióncloroquinaneoplasias ováricasantineoplásicosroturas del ADNpuntos de comprobación del ciclo celularreparación del ADNespecies reactivas de oxígenosinergismo farmacológicosupervivencia celular[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.Elsevier202520252021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10366/164471reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésPI20/01589info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1644712026-06-07T06:28:51Z
dc.title.none.fl_str_mv Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
title Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
spellingShingle Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
Ovejero-Sánchez, María
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
title_short Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
title_full Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
title_fullStr Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
title_full_unstemmed Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
title_sort Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
dc.creator.none.fl_str_mv Ovejero-Sánchez, María
González Sarmiento, Rogelio
Herrero Hernández, Ana Belén
author Ovejero-Sánchez, María
author_facet Ovejero-Sánchez, María
González Sarmiento, Rogelio
Herrero Hernández, Ana Belén
author_role author
author2 González Sarmiento, Rogelio
Herrero Hernández, Ana Belén
author2_role author
author
dc.subject.none.fl_str_mv 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
topic 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
description [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.
publishDate 2021
dc.date.none.fl_str_mv 2021
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/164471
url http://hdl.handle.net/10366/164471
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PI20/01589
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425294645919744
score 15,198674

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