Nocodazole, a microtubule de-polymerising agent, induces apoptosis of chronic lymphocytic leukaemia cells associated with changes in Bcl-2 phosphorylation and expression.
Microtubule active drugs are used in the treatment of malignancies and their mechanism of action in cycling cells is to produce mitotic arrest followed by apoptosis. In this study, we investigate in detail the specificity and mechanism by which a microtubule de-polymerising agent, nocodazole, induces apoptosis in non-cyclingm, i.e. G(0)/G(1), chronic lymphocytic leukaemia (CLL) B-cells. The majority of cases of CLL are sensitive (IC(50)<or=16 microM) but normal peripheral blood B-cells, which are also in G(0)/G(1), are resistant to the maximum in vitro concentration of this agent. Taxol, a microtubule stabilising drug does not kill CLL cells suggesting a specific effect of nocodazole. The mechanism of apoptosis involves mitochondrial membrane depolarisation, activation of caspases and cleavage of PARP. Nocodazole causes two patterns of change to Bcl-2 expression. In one there is increase in expression of the serine-70 phosphorylated form of Bcl-2 and in the other total Bcl-2 expression is reduced. Collectively the data shows that sensitivity to nocodazole-induced apoptosis is a feature of chronic lymphocytic leukaemia and suggests that newer microtubule active agents be systematically investigated for their effectiveness in this condition.
Beswick
Richard W
RW
Division of Investigative Sciences, Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Ambrose
Helen E
HE
Wagner
Simon D
SD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008870:Microtubules / Q000187:drug effects*; D015739:Nocodazole / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017239:Paclitaxel; D015739:Nocodazole