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Synergistic antiproliferative activity of the RAD51 inhibitor IBR2 with inhibitors of receptor tyrosine kinases and microtubule protein.

著者 Ferguson PJ , Vincent MD , Koropatnick J
J Pharmacol Exp Ther.2017 Oct 23 ; ():.
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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, regorafenib (targets RAF, kit), EGFR 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.
PMID: 29061656 [PubMed - as supplied by publisher]
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