title: Leukaemic cells from chronic lymphocytic leukaemia patients undergo apoptosis following microtubule depolymerization and Lyn inhibition by nocodazole.
abstract: Functional abnormalities of chronic lymphocytic leukaemia (CLL) cells may be related to the microtubular network of cell cytoskeleton; specifically tubulin involvement in cells after B-cell receptor engagement. As microtubule inhibitors could represent a therapeutic strategy for CLL, this study investigated the capability of nocodazole, a synthetic depolymerizing agent, to kill CLL leukaemic cells. We demonstrated that nocodazole was highly specific for the in vitro induction of apoptosis in leukaemic cells from 90 CLL patients, without affecting the viability of T-cells and/or mesenchymal stromal cells (MSCs) recovered from the same patients. Nocodazole was observed to overcome the pro-survival signals provided by MSCs. Competing with ATP for the nucleotide-binding site, nocodazole has been observed to turn off the high basal tyrosine phosphorylation of leukaemic cells mediated by the Src-kinase Lyn. Considering that most anti-microtubule drugs have limited clinical use because of their strong toxic effects, the high selectivity of nocodazole for leukaemic cells in CLL and its capability to bypass microenvironmental pro-survival stimuli, suggests the use of this inhibitor for designing new therapeutic strategies in CLL treatment.
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Centro di Eccellenza per la Ricerca Biomedica, Padova, Italy; Department of Medicine, Haematology and Clinical Immunology Branch, Padova University School of Medicine, Padova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Frezzato
authors.forename: Valentina
authors.initials: V
authors.lastname: Trimarco
authors.forename: Veronica
authors.initials: V
authors.lastname: Martini
authors.forename: Cristina
authors.initials: C
authors.lastname: Gattazzo
authors.forename: Elisa
authors.initials: E
authors.lastname: Ave
authors.forename: Andrea
authors.initials: A
authors.lastname: Visentin
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.forename: Valeria
authors.initials: V
authors.lastname: Olivieri
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
authors.forename: Monica
authors.initials: M
authors.lastname: Facco
authors.forename: Francesca
authors.initials: F
authors.lastname: Zonta
authors.forename: Andrea
authors.initials: A
authors.lastname: Cristiani
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Brunati
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D018920:Coculture Techniques; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology; D018613:Microscopy, Confocal; D008870:Microtubules / Q000187:drug effects*; D008875:Middle Aged; D015739:Nocodazole / Q000378:metabolism / Q000494:pharmacology*; D011379:Prognosis; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D050257:Tubulin Modulators / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D050257:Tubulin Modulators; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051562:Proto-Oncogene Proteins c-bcr; D015739:Nocodazole
keywords: Lyn; apoptosis; chronic lymphocytic leukaemia; inhibitor; nocodazole