title: Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia.
abstract: 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 G(1) 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 G(1) arrest and that borrelidin treatment in ALL cell lines is correlated with activation of the GCN2 kinase pathway.
authors.affiliation: Vancouver Prostate Centre, Department of Surgery, University of British Columbia, Rm 241, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Darya
authors.initials: D
authors.lastname: Habibi
authors.forename: Nadya
authors.initials: N
authors.lastname: Ogloff
authors.forename: Reza B
authors.initials: RB
authors.lastname: Jalili
authors.forename: Arla
authors.initials: A
authors.lastname: Yost
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ong
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005233:Fatty Alcohols / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013914:Threonine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051742:Transcription Factor CHOP
chemical_list: D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D018942:Macrolides; D009570:Nitriles; D054852:Small Molecule Libraries; D051742:Transcription Factor CHOP; C005066:borrelidin; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D013914:Threonine-tRNA Ligase