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Br J Haematol. 2014 Jun;165(5):659-72. doi: 10.1111/bjh.12815. Epub 2014 Mar 7.

Leukaemic cells from chronic lymphocytic leukaemia patients undergo apoptosis following microtubule depolymerization and Lyn inhibition by nocodazole.

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  • 1Venetian 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.

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.

KEYWORDS:

Lyn; apoptosis; chronic lymphocytic leukaemia; inhibitor; nocodazole

PMID:
24606526
DOI:
10.1111/bjh.12815
[PubMed - indexed for MEDLINE]
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