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CLL

Farnesyltransferase inhibitor BMS-214662 induces apoptosis in B-cell chronic lymphocytic leukemia cells

Leukemia volume 18, pages 1599–1604 (2004)Cite this article

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) cells develop resistance to nucleoside analogs over time. This chemoresistance may be caused by selection for B-CLL cells with defects in the particular apoptosis pathway triggered by these drugs. Therefore, anticancer agents that induce apoptosis through alternative pathways might be useful in treating chemoresistant B-CLL. Farnesyltransferase inhibitors (FTIs) are a class of synthetic drugs with definite molecular targets, which have demonstrated cytotoxicity against leukemic cell lines. We have studied the ex vivo effect of the FTI BMS-214662 on cells from 18 patients with B-CLL. Low concentrations (<1 μ M) of BMS-214662 prevented farnesylation of the chaperone marker HDJ-2 and had no effect on Akt activation. BMS-214662 induced apoptosis in B-CLL cells from all patients studied, including those showing resistance to cladribine and fludarabine ex vivo and in vivo. Treatment with BMS-214662 induced loss of mitochondrial membrane potential (ΔΨm), phosphatidylserine exposure, proapoptotic conformational changes of Bax and Bak, reduction in Mcl-1 levels and activation of caspases 9 and 3. The general caspase inhibitor Z-VAD-fmk did not prevent BMS-214662-induced cell death. These results indicate that BMS-214662 may be a useful drug for treating B-CLL and, in particular, an alternative for the therapy of purine analog-resistant or relapsed B-CLL.

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Acknowledgements

We thank Dr Veeraswamy Manne (Bristol-Myers Squibb) for providing us with BMS-214662. This work was supported in part by grants PIO20065 and G03/136 Thematic Network from Fondo de Investigaciones Sanitarias (Ministerio de Sanidad, Spain) and P24/2000 from Diputación General de Aragón.

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Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain

    I Marzo, P Pérez-Galán, N López-Royuela, M Gómez-Benito, A Anel & J Naval

  2. Servicio de Inmunología, Hospital Clínico Universitario, Zaragoza, Spain

    L Larrad & P Lasierra

  3. Servicio de Hematología, Hospital Universitario Miguel Servet, Zaragoza, Spain

    P Giraldo & D Rubio-Félix

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  1. I Marzo
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  2. P Pérez-Galán
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Correspondence to I Marzo.

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Marzo, I., Pérez-Galán, P., Giraldo, P. et al. Farnesyltransferase inhibitor BMS-214662 induces apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia 18, 1599–1604 (2004). https://doi.org/10.1038/sj.leu.2403469

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