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B-CLL

AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells: interference with the Akt/NF-κB survival pathway

Leukemia volume 19, pages 572–579 (2005)Cite this article

Abstract

Clinical treatment of B-cell chronic lymphocytic leukemia (B-CLL) is limited by the progressive drug resistance and nonselectivity of most drugs towards malignant cells. Depsipeptides are present in certain bacteria and display potent antitumor activity. We have studied the effect of the novel cyclodepsipeptide AT514 (serratamolide) from Serratia marcescens on B-CLL cell viability. AT514 induced apoptosis of B-CLL cells from the 21 patients studied, as confirmed by Annexin-V binding and nuclei condensation, with an average IC50 of 13 μ M. AT514 was effective in those B-CLL cases resistant to fludarabine, but had no effect on normal PBL. AT514 preferentially activated the intrinsic apoptotic pathway, as evidenced by loss of mitochondrial membrane potential, release of cytochrome c and activation of caspase-9 and -3, but not of caspase-8. Importantly, AT514 interfered with phosphatidylinositol-3 kinase and protein kinase C survival signals since it increased the apoptotic effect of LY294002 and BisI inhibitors, and induced Akt dephosphorylation at Ser 473. AT514 also decreased NF-κB activity by dramatically reducing the levels of p65 in B-CLL. This was confirmed on functional assays using NF-κB-luc-transfected Raji cells and transgenic mice. Our results establish that AT514 induces apoptosis of primary B-CLL cells and could be useful for clinical treatment of this malignancy.

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Acknowledgements

We thank the B-CLL patients who donated blood samples for this research and Dr Maria José Terol (Hospital Clínico, Valencia, Spain) for providing some of these samples. Drs Angel Corbí and José L Rodríguez-Fernández for valuable help and advice with the NF-κB studies and for reviewing the manuscript, and Dr Pedro Lastres for help with the flow cytometry analyses. This work was supported by grants 08.3/0030.1/2003 from the Comunidad Autónoma de Madrid, SAF2003-00824 from the Ministerio de Ciencia y Tecnología (MCyT), and 01/1183 from Fondo de Investigación Sanitaria (to AGP); and CIDEM Grant 301888 (Generalitat de Catalunya)/Fundació Bosch i Gimpera, to RPT). E Escobar and E López-Martín were supported by fellowships from MCyT.

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Authors and Affiliations

  1. Departamento de Inmunología, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain

    E Escobar-Díaz, E M López-Martín, M Hernández del Cerro, A Puig-Kroger & A Garcia-Pardo

  2. Departament de Biologia Cel.lular i Anatomia Patològica, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

    V Soto-Cerrato, B Montaner & R Pérez-Tomás

  3. Departament de Química Orgànica, IRBB-PCB Universitat de Barcelona, Barcelona

    E Giralt

  4. Servicio de Hematología, Hospital Universitario Puerta de Hierro, Madrid

    J A García-Marco

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  1. E Escobar-Díaz
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Correspondence to A Garcia-Pardo.

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Escobar-Díaz, E., López-Martín, E., Hernández del Cerro, M. et al. AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells: interference with the Akt/NF-κB survival pathway. Leukemia 19, 572–579 (2005). https://doi.org/10.1038/sj.leu.2403679

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