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

• Type of Material: Article
• Authors: B Mahboubi, Emory University; Baek Kim, Emory University; Yi Chieh Lim, QIMR Berghofer Medical Research Institute; Kathleen Ensbey, QIMR Berghofer Medical Research Institute; Carolin Offenhäuser, QIMR Berghofer Medical Research Institute; Rochelle C.J. D'souza, QIMR Berghofer Medical Research Institute; Jason K. Cullen, QIMR Berghofer Medical Research Institute; Brett W. Stringer, QIMR Berghofer Medical Research Institute; Hazel Quek, QIMR Berghofer Medical Research Institute; Zara C. Bruce, QIMR Berghofer Medical Research Institute; Amanda Kijas, University of Queensland; Valentina Cianfanelli, Danish Cancer Society Research Center; Fiona Smith, QIMR Berghofer Medical Research Institute; Rosalind L. Jeffree, Royal Brisbane and Women’s Hospital Campus; Lisa Wiesmüeller, University of Ulm; Adrian P. Wiegmans, QIMR Berghofer Medical Research Institute; Amanda Bain, QIMR Berghofer Medical Research Institute; Fanny J. Lombard, University of Queensland; Tara L. Roberts, Ingham Institute; Kum Kum Khanna, QIMR Berghofer Medical Research Institute; Martin F. Lavin, QIMR Berghofer Medical Research Institute; Petra Hamerlik, Danish Cancer Society Research Center; Terrance G. Johns, Telethon Kids Institute; Mark J. Coster, Griffith University; Andrew W. Boyd, QIMR Berghofer Medical Research Institute; Bryan W. Day, QIMR Berghofer Medical Research Institute
• Language: English
• Date: 2020-02-01
• Publisher: OXFORD UNIV PRESS INC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2019
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/neuonc/noz159
• Title of Journal or Parent Work: NEURO-ONCOLOGY
• Volume: 22
• Issue: 2
• Start Page: 216
• End Page: 228
• Grant/Funding Information: This work was supported by Cancer Council QLD (1061216 and 1098841), Rio Tinto Ride to Conquer Cancer, Brain Cancer Discovery Collaborative, Novo Nordisk Foundation (NNF16OC0023146 and NNF17OC0026056), and the National Institute of Health (AI136581 and AI150451 to B.K).
• Keywords: REPAIR; DNA damage; TEMOZOLOMIDE; Neurosciences & Neurology; GLIOMA-CELLS; Oncology; drug discovery; RADIATION; glioblastoma; Life Sciences & Biomedicine; homologous recombination; STEM-CELLS; Clinical Neurology; DEGRADATION; DOWN-REGULATION; PATHWAY; AUTOPHAGY; SALINOMYCIN; Science & Technology
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology

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.