The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI

Davide Soligo, Federica Servida, Domenico Delia, Enrico Fontanella, Giuseppe Lamorte, Lorenza Caneva, Rossella Fumiatti, Giorgio Lambertenghi Deliliers

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Degradation of several intracellular proteins involved in cell cycle control and tumour growth is regulated by the ubiquitin-dependent multicatalytic protease complex (proteasome). We report that proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leucinal (PSI) was cytotoxic on most human myeloid leukaemia cell lines at IC 50 doses ranging from 5 to 25 nmol/l. Additionally, PSI pretreatment enhanced cytotoxicity by taxol and cisplatinum. PSI was more active on leukaemic than on normal CD34 + bone marrow progenitors because the 50% growth inhibition of colony-forming unit granulocyte macrophage (CFU-GM) from cases of chronic myelogenous leukaemia (CML) and normal subjects was achieved by 15 nmol/l and 50 nmol/l PSI respectively. PSI killed cells by apoptosis as revealed by ultrastructural changes, nuclear DNA fragmentation, cleavage of poly (ADP-ribose) polymerase (PARP) and of β-catenin, and was antagonized by ectopic expression of Bcl-2 but not by inactivating mutations of p53. This event was associated with a slight accumulation of Bcl-2, a decrease of Bax but no changes in Bcl-X L protein expression at any time point. In Ph + cell lines BCR-ABL protein was only down-regulated after 48 h of treatment with 10 nmol/l PSI. Altogether, these results indicate that PSI, alone or in association with other cytotoxic agents, has anti-tumour activity against myeloid malignancies and is more effective on leukaemic than on normal haematopoietic progenitor cells.

Original languageEnglish
Pages (from-to)126-135
Number of pages10
JournalBritish Journal of Haematology
Volume113
Issue number1
DOIs
Publication statusPublished - 2001

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Myeloid Leukemia
Myeloid Cells
Hematopoietic Stem Cells
Protease Inhibitors
Cell Line
bcl-X Protein
Catenins
Neoplasms
Granulocyte-Macrophage Progenitor Cells
DNA Cleavage
Poly(ADP-ribose) Polymerases
Cytotoxins
DNA Fragmentation
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Growth
Ubiquitin
Paclitaxel
Cell Cycle Checkpoints
Proteins
Peptide Hydrolases

Keywords

  • Apoptosis
  • CD34 haematopoietic progenitors
  • Cytotoxic agent
  • Myelogenous leukaemia
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Hematology

Cite this

The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI. / Soligo, Davide; Servida, Federica; Delia, Domenico; Fontanella, Enrico; Lamorte, Giuseppe; Caneva, Lorenza; Fumiatti, Rossella; Deliliers, Giorgio Lambertenghi.

In: British Journal of Haematology, Vol. 113, No. 1, 2001, p. 126-135.

Research output: Contribution to journalArticle

Soligo, Davide ; Servida, Federica ; Delia, Domenico ; Fontanella, Enrico ; Lamorte, Giuseppe ; Caneva, Lorenza ; Fumiatti, Rossella ; Deliliers, Giorgio Lambertenghi. / The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI. In: British Journal of Haematology. 2001 ; Vol. 113, No. 1. pp. 126-135.
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AU - Lamorte, Giuseppe

AU - Caneva, Lorenza

AU - Fumiatti, Rossella

AU - Deliliers, Giorgio Lambertenghi

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