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

Jiewen Zhu, Longen Zhou, Guikai Wu, Heiko Konig, Xiaoqin Lin, Guideng Li, Xiao‐Long Qiu, Chi‐Fen Chen, Chun‐Mei Hu, Erin Goldblatt, Ravi Bhatia, A. Richard Chamberlin, Phang‐Lang Chen, Wen‐Hwa Lee

Author Affiliations

  1. Jiewen Zhu1,,
  2. Longen Zhou1,,
  3. Guikai Wu1,,
  4. Heiko Konig2,
  5. Xiaoqin Lin1,
  6. Guideng Li1,
  7. Xiao‐Long Qiu1,4,
  8. Chi‐Fen Chen1,
  9. Chun‐Mei Hu1,
  10. Erin Goldblatt1,
  11. Ravi Bhatia2,
  12. A. Richard Chamberlin3,
  13. Phang‐Lang Chen (plchen{at}uci.edu) *,1 and
  14. Wen‐Hwa Lee (whlee{at}uci.edu) *,1
  1. 1Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA
  2. 2Division of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA, USA
  3. 3Department of Chemistry, University of California, Irvine, CA, USA
  4. 4Current address: Wisdom Pharmaceutical Co., Ltd., 601 East, Xiu‐shan Road, Haimen, Jiangsu Province, P.R. China, 226100
  1. * Phang‐Lang Chen, Tel: +1 949 8244008; Fax: +1 949 8242688

    Wen‐Hwa Lee, Tel: +1 949 8244492; Fax: +1 949 8244493

  1. These authors contributed equally to this work.

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Abstract

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.

  • Received July 19, 2012.
  • Revision received November 27, 2012.
  • Accepted November 27, 2012.
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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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