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Myeloma

Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I

Leukemia volume 19, pages 2324–2331 (2005)Cite this article

Abstract

The proteasome inhibitor PSI is potently cytotoxic in vitro against human chronic myeloid leukemia (CML) and acute myeloid leukemias (AML). Here, we have tested proteasome inhibitor I (PSI) in a panel of 11 human multiple myeloma (MM) cell lines and found that it has antiproliferative activity, with an IC50 between 4.5 and 557 nM at 48 h. PSI potentiated the toxicity of a number of chemotherapeutic agents in myeloid leukemia but not in MM cell lines, while in combination with therapeutic proteasome inhibitor PS-341 (Bortezomib) it had a synergistic effect. PSI suppressed the growth of AML cell lines more effectively than PS-341. CFU-GM colony assays revealed that CD34+ bone marrow progenitors from CML and AML patients were more sensitive to PSI than those from normal subjects (IC50: 5, 15 and 50 nM for AML, CML and normal, respectively). Moreover, the growth of normal primitive progenitors (LTC-IC) was unaffected by 15 nM PSI (P=0.576). PSI-induced cell death required RNA transcription and protein synthesis, but not DNA replication, was accompanied by the upregulation of Bcl-2 and modest reduction of Bax and Bcl-XL proteins, and involved the activation of caspases 2, 3, 7 and 8. These findings lend additional support to preclinical investigations with PSI.

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Acknowledgements

This work was financially supported by grants of the Italian Association for Cancer Research (AIRC), National Research Council (CNR, Grant CU03.00416) and the Italian Ministry of Health (Ricerca Finalizzata).

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Authors and Affiliations

  1. Fondazione Matarelli, Ospedale Fatebenefratelli e Oftalmico, Milan, Italy

    F Servida, D Soligo & G Lambertenghi Deliliers

  2. U.O. Ematologia 1-Centro Trapianto di Midollo, Fondazione IRCCS Ospedale Maggiore and Université di Milano, Milan, Italy

    D Soligo, L Lombardi & G Lambertenghi Deliliers

  3. Istituto Nazionale dei Tumori, Milan, Italy

    D Delia

  4. Dipartimento di Scienze e Tecnologie Biomediche Universita’ degli Studi di Udine, Udine, Italy

    C Henderson & C Brancolini

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  1. F Servida
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Correspondence to D Soligo.

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Servida, F., Soligo, D., Delia, D. et al. Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I. Leukemia 19, 2324–2331 (2005). https://doi.org/10.1038/sj.leu.2403987

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