Abstract
Although cancer cell genetic instability contributes to characteristics that mediate tumorigenicity, it also contributes to the tumor-selective toxicity of some chemotherapy drugs. This synthetic lethality can be enhanced by inhibitors of DNA repair. To exploit this potential Achilles heel, we tested the ability of a RAD51 inhibitor to potentiate the cytotoxicity of chemotherapy drugs. 2-(Benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) inhibits RAD51-mediated DNA double-strand break repair but also enhances cytotoxicity of the Bcr-Abl inhibitor imatinib. The potential for synergy between IBR2 and more drugs was examined in vitro across a spectrum of cancer cell lines from various tissues. Cells were exposed to IBR2 simultaneously with inhibitors of receptor tyrosine kinases, DNA-damaging agents, or microtubule disruptors. IBR2, at concentrations that inhibited proliferation between 0% and 75%, enhanced toxicity by up to 80% of imatinib and regorafenib (targets RAF and kit); epidermal growth factor receptor inhibitors erlotinib, gefitinib, afatinib, and osimertinib; and vincristine, an inhibitor of microtubule function. However, IBR2 antagonized the action of olaparib, cisplatin, melphalan, and irinotecan. A vincristine-resistant squamous cell line was not cross resistant to imatinib, but IBR2 and another RAD51 inhibitor (B02) enhanced imatinib toxicity in this cell line, its HN-5a parent, and the colon cancer line HT-29 by up to 60% and much better than verapamil, a P-glycoprotein inhibitor (P < 0.05). Given the disparate agents the functions of which are enhanced by IBR2, the mechanisms of enhancement may be multimodal. Whether RAD51 is common to these mechanisms remains to be elucidated, but it provides the potential for selectivity to tumor cells.
Footnotes
- Received March 24, 2017.
- Accepted October 20, 2017.
This work was supported by a grant from the Medical Oncology Research Fund, London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 4L6, Canada.
Portions of this work were presented in abstract form: Ferguson PJ, Vincent MD, and Koropatnick J (2016) Synergistic anticancer activity of the targeted drugs imatinib, regorafenib, and gefitinib with the RAD51 inhibitor IBR2, in Proceedings of 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; 29 November-2 December, Munich, Germany.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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