PMID- 29061656
OWN - NLM
STAT- MEDLINE
DCOM- 20171220
LR  - 20190127
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 364
IP  - 1
DP  - 2018 Jan
TI  - Synergistic Antiproliferative Activity of the RAD51 Inhibitor IBR2 with 
      Inhibitors of Receptor Tyrosine Kinases and Microtubule Protein.
PG  - 46-54
LID - 10.1124/jpet.117.241661 [doi]
AB  - 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.
CI  - Copyright (c) 2017 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Ferguson, Peter J
AU  - Ferguson PJ
AD  - London Regional Cancer Program and Lawson Health Research Institute, London, 
      Ontario, Canada (P.J.F., M.D.V., J.K.); and Departments of Microbiology and 
      Immunology (J.K.), Pathology (J.K.), Physiology and Pharmacology (J.K.), and 
      Oncology (P.J.F., M.D.V., J.K.), University of Western Ontario, London, Ontario, 
      Canada peter.ferguson@uwo.ca.
FAU - Vincent, Mark D
AU  - Vincent MD
AD  - London Regional Cancer Program and Lawson Health Research Institute, London, 
      Ontario, Canada (P.J.F., M.D.V., J.K.); and Departments of Microbiology and 
      Immunology (J.K.), Pathology (J.K.), Physiology and Pharmacology (J.K.), and 
      Oncology (P.J.F., M.D.V., J.K.), University of Western Ontario, London, Ontario, 
      Canada.
FAU - Koropatnick, James
AU  - Koropatnick J
AD  - London Regional Cancer Program and Lawson Health Research Institute, London, 
      Ontario, Canada (P.J.F., M.D.V., J.K.); and Departments of Microbiology and 
      Immunology (J.K.), Pathology (J.K.), Physiology and Pharmacology (J.K.), and 
      Oncology (P.J.F., M.D.V., J.K.), University of Western Ontario, London, Ontario, 
      Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171023
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 ((R)-1-(1H-indol-3-yl)-2-phenylmethanesulfonyl-1,2,3,4-tetrahydroisoquinoline)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Indoles)
RN  - 0 (Microtubule Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Tetrahydroisoquinolines)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.7.- (RAD51 protein, human)
RN  - EC 2.7.7.- (Rad51 Recombinase)
SB  - IM
MH  - A549 Cells
MH  - Antineoplastic Agents/administration & dosage
MH  - Cell Proliferation/*drug effects/physiology
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - HEK293 Cells
MH  - HT29 Cells
MH  - Humans
MH  - Indoles/*administration & dosage
MH  - K562 Cells
MH  - MCF-7 Cells
MH  - Microtubule Proteins/*antagonists & inhibitors/metabolism
MH  - Protein Kinase Inhibitors/*administration & dosage
MH  - Rad51 Recombinase/*antagonists & inhibitors/metabolism
MH  - Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism
MH  - Tetrahydroisoquinolines/*administration & dosage
EDAT- 2017/10/25 06:00
MHDA- 2017/12/21 06:00
CRDT- 2017/10/25 06:00
PHST- 2017/03/24 00:00 [received]
PHST- 2017/10/20 00:00 [accepted]
PHST- 2017/10/25 06:00 [pubmed]
PHST- 2017/12/21 06:00 [medline]
PHST- 2017/10/25 06:00 [entrez]
AID - jpet.117.241661 [pii]
AID - 10.1124/jpet.117.241661 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2018 Jan;364(1):46-54. doi: 10.1124/jpet.117.241661. Epub 
      2017 Oct 23.