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Inhibition of Apoptosis by Endogenous Nitric Oxide in Chronic Lymphocytic Leukaemia

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Nitric Oxide (NO) and Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Chronic lymphocytic leukaemia (CLL) is a malignant lymphoproliferative disease characterized by a dramatic resistance to spontaneous and drug-induced apoptosis. In the present review the role of endogenous nitric oxide (NO) in this resistance has been analysed. Although a contribution of NOS3 cannot be excluded, NO is mainly produced by an inducible NOS (NOS2) that is constitutively expressed by the leukaemia cells, at variance with normal B lymphocytes. The expression of this enzyme in the tumour cells appears to be regulated by engagement of the toll-like receptor-7 (TLR-7) and is modulated by the ligation of the low-affinity IgE receptor/CD23 and by various cytokines such as interleukin-4 (IL-4) and IFN-γ.

According to its concentration, flux, cell type and redox state, NO exerts contrasting effects on apoptosis, activating transduction pathways leading to apoptosis, whereas in other cases protecting cells against spontaneous or induced apoptosis. In CLL cells, the level of endogenous NO is correlated with the abundance of mitochondria and resistance to apoptosis. NO inactivates caspase(s) through oxidation and S-nitrosylation of a cysteine present in their active site, providing an efficient means to block apoptosis. Conversely, a caspase-sensitive down-regulation of iNOS expression and of NO production appears to be associated with the induction of apoptosis by a variety of reagents. Other protective effects of NO on apoptosis probably rely on the modulation through S-nitrosylation-dependent and S-nitrosylation-independent pathways of members of the Bcl-2/Bax family that control the release of apoptogenic factors by mitochondria. If appropriately targeted, NOS inhibitors would provide an efficient mean to reinduce apoptosis in CLL cells and to allow the development of a new therapeutic approach.

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Acknowledgments

This work was supported by INSERM, University Pierre et Marie Curie and Canceropole Ile-de-France.

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Authors and Affiliations

  1. Centre de Recherche des Cordeliers, UMRS 872 INSERM/University Pierre et Marie Curie/University Paris Descartes, Paris, France

    Christian Billard

  2. Tumor Biology Labs, Biochemistry Department, UCC, Cork, Ireland

    Claire Quiney

  3. Centre de Recherche des Cordeliers, UMRS 872 INSERM/University Pierre et Marie Curie/University Paris Descartes, 15 rue de l’Ecole de Médecine, 75270, Paris cedex 06, France

    Jean-Pierre Kolb

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Correspondence to Jean-Pierre Kolb .

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  1. Dept. Microbiology, Immunology &, Molecular Genetics, University of California, Los Angeles, Charles E. Young Dr. E. 609, Los Angeles, 90095, California, USA

    Benjamin Bonavida

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Billard, C., Quiney, C., Kolb, JP. (2010). Inhibition of Apoptosis by Endogenous Nitric Oxide in Chronic Lymphocytic Leukaemia. In: Bonavida, B. (eds) Nitric Oxide (NO) and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1432-3_9

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