2. Academic Validation
  3. Synergistic effect of Chloroquine and Panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair

Synergistic effect of Chloroquine and Panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair

  • Neoplasia. 2021 May;23(5):515-528. doi: 10.1016/j.neo.2021.04.003.
María Ovejero-Sánchez 1,  Rogelio González-Sarmiento 2,  Ana Belén Herrero 3
Affiliations

Affiliations

  • 1 Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain.
  • 2 Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain. Electronic address: gonzalez@usal.es.
  • 3 Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain. Electronic address: anah@usal.es.
PMID: 33930758 DOI: 10.1016/j.neo.2021.04.003
Abstract

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.

Keywords

Chloroquine; DNA damage andrepair; Panobinostat; ROS; autophagy; homologous recombination.

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