A novel small molecule RAD51 inactivator overcomes imatinib‐resistance in chronic myeloid leukaemia

RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug‐resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic mye...

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Published in:EMBO molecular medicine 2013-03, Vol.5 (3), p.353-365
Main Authors: Zhu, Jiewen, Zhou, Longen, Wu, Guikai, Konig, Heiko, Lin, Xiaoqin, Li, Guideng, Qiu, Xiao‐Long, Chen, Chi‐Fen, Hu, Chun‐Mei, Goldblatt, Erin, Bhatia, Ravi, Chamberlin, A. Richard, Chen, Phang‐Lang, Lee, Wen‐Hwa
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
BCR protein
Benzamides - pharmacology
Binding Sites
Bone marrow
Breast cancer
cancer
Cancer therapies
CD34 antigen
Cell cycle
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
Cell survival
Chronic myeloid leukemia
CML
Deoxyribonucleic acid
DNA
DNA damage
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm - genetics
Experiments
Female
Fusion Proteins, bcr-abl - antagonists & inhibitors
Fusion Proteins, bcr-abl - genetics
Gene Expression Regulation, Neoplastic - drug effects
Granulocytes
Homologous recombination
Homologous Recombination - drug effects
Humans
Imatinib
Imatinib Mesylate
Indoles - metabolism
Indoles - pharmacology
inhibitor
Ionizing radiation
Kinases
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Medical research
Mice
Mice, Inbred NOD
Mice, SCID
Molecular Docking Simulation
Mutation
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - pathology
Piperazines - pharmacology
Progenitor cells
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors - metabolism
Proteasome Inhibitors - pharmacology
Proteasomes
Protein Kinase Inhibitors - pharmacology
Protein Multimerization
Protein Processing, Post-Translational
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - genetics
Pyrimidines - pharmacology
RAD51
Rad51 protein
Rad51 Recombinase - antagonists & inhibitors
Rad51 Recombinase - chemistry
Rad51 Recombinase - genetics
Rad51 Recombinase - metabolism
Recombinase
RNA Interference
small molecule
Stem cells
Survival analysis
Tetrahydroisoquinolines - metabolism
Tetrahydroisoquinolines - pharmacology
Time Factors
Transfection
Tumor Burden - drug effects
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Summary:RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug‐resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome‐mediated RAD51 protein degradation, reduces ionizing radiation‐induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib‐resistant CML model bearing the T315I Bcr‐abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34+ progenitor cells from CML patients resistant to known BCR‐ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad‐spectrum therapeutics for difficult‐to‐treat cancers. A newly identified RAD51 inhibitor leading to degradation of RAD51 via the proteasome pathway inhibits cancer cell survival and greatly increases life spans in a mouse chronic myeloid leukaemia model.
ISSN:1757-4676
1757-4684
DOI:10.1002/emmm.201201760