Simultaneous targeting of DNA replication and homologous recombination in glioblastoma with a polyether ionophore

Yi Chieh Lim, Kathleen S. Ensbey, Carolin Offenhäuser, Rochelle C.J. D'souza, Jason K. Cullen, Brett W. Stringer, Hazel Quek, Zara C. Bruce, Amanda Kijas, Valentina Cianfanelli, Bijan Mahboubi, Fiona Smith, Rosalind L. Jeffree, Lisa Wiesmüeller, Adrian P. Wiegmans, Amanda Bain, Fanny J. Lombard, Tara L. Roberts, Kum Kum Khanna, Martin F. LavinBaek Kim, Petra Hamerlik, Terrance G. Johns, Mark J. Coster, Andrew W. Boyd, Bryan W. Day

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Background: Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair. Methods: In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships. Results: Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell-like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action. Conclusion: Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents.

Original languageEnglish
Pages (from-to)216-228
Number of pages13
JournalNeuro-Oncology
Volume22
Issue number2
DOIs
Publication statusPublished - Feb 2020
Externally publishedYes

Bibliographical note

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Keywords

  • DNA damage
  • drug discovery
  • glioblastoma
  • homologous recombination

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