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

F. Servida, Davide Soligo, D. Delia, C. Henderson, C. Brancolini, L. Lombardi, G. Lambertenghi Deliliers

Research output: Contribution to journalArticle

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 IC 50 between 4.5 and 557nM at 48h. 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 (IC 50: 5, 15 and 50nM for AML, CML and normal, respectively). Moreover, the growth of normal primitive progenitors (LTC-IC) was unaffected by 15nM 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-X L proteins, and involved the activation of caspases 2, 3, 7 and 8. These findings lend additional support to preclinical investigations with PSI.

Original languageEnglish
Pages (from-to)2324-2331
Number of pages8
JournalLeukemia
Volume19
Issue number12
DOIs
Publication statusPublished - Dec 2005

Keywords

  • CD34
  • Hematopoitic progenitors
  • Multiple myeloma
  • Myeloid leukemia
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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    Servida, F., Soligo, D., Delia, D., Henderson, C., Brancolini, C., Lombardi, L., & Deliliers, G. L. (2005). Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I. Leukemia, 19(12), 2324-2331. https://doi.org/10.1038/sj.leu.2403987