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Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia

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Summary

Due to the poor prognosis and limited therapeutic options for adult patients with acute lymphoblastic leukemia (ALL), development of novel therapies is much needed to prolong patient survival and increase the efficacy of their treatment. Malignant T cells need high levels of nutrients to maintain their proliferation rate. Borrelidin, a small molecule nitrile-containing macrolide, is an inhibitor of bacterial and eukaryal threonyl-tRNA synthetase. Borrelidin-mediated inhibition of aminoacyl-tRNA synthesis, leads to an induction in the levels of uncharged tRNA, nutritional stress and ultimately inhibition of protein synthesis. The aim of the present study was to investigate whether borrelidin treatment inhibits the proliferation of malignant ALL cell lines, Jurkat and CEM cells, and study the mechanism by which this drug acts. Our results show that borrelidin was able to potently inhibit the proliferation of ALL cell lines with a half maximal inhibitory concentration of 50 ng/ml. Borrelidin showed a greater inhibitory effect on ALL cell lines compared to primary fibroblasts. Flow cytometry and western blot analysis indicated that borrelidin was able to increase the level of apoptosis and cause G1 arrest in ALL cell lines. Activation of the general control nonderepressible-2 (GCN2) kinase stress responsive pathway and induction of CHOP protein was significantly higher in ALL cell lines treated with borrelidin. These findings collectively suggest for the first time that borrelidin targets ALL cell lines by inducing apoptosis and mediating G1 arrest and that borrelidin treatment in ALL cell lines is correlated with activation of the GCN2 kinase pathway.

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Acknowledgements

Contact grant sponsors: The Canadian Cancer Society Research Institute (CCSRI), The Cancer Research Society (CRS). Darya Habibi held University Graduate Fellowships from the University of British Columbia, CIHR/MSFHR Training Award in Transplant Research and is holding CIHR Skin Research Training Centre (SRTC) Award as well as the Roman M. Babicki Fellowship in Medical Research.

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The authors state no conflict of interest.

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Authors and Affiliations

  1. Vancouver Prostate Centre, Department of Surgery, University of British Columbia, Rm 241, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada

    Darya Habibi, Nadya Ogloff & Christopher J. Ong

  2. Department of Surgery, University of British Columbia, Vancouver, BC, Canada

    Darya Habibi, Reza B. Jalili & Aziz Ghahary

  3. Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada

    Arla Yost & Andrew P. Weng

Authors
  1. Darya Habibi
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  2. Nadya Ogloff
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  3. Reza B. Jalili
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  4. Arla Yost
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  5. Andrew P. Weng
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  6. Aziz Ghahary
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  7. Christopher J. Ong
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Correspondence to Christopher J. Ong.

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Habibi, D., Ogloff, N., Jalili, R.B. et al. Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia. Invest New Drugs 30, 1361–1370 (2012). https://doi.org/10.1007/s10637-011-9700-y

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  • DOI: https://doi.org/10.1007/s10637-011-9700-y

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