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

Br J Haematol. 2001 Apr;113(1):126-35. doi: 10.1046/j.1365-2141.2001.02683.x.


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 IC50 doses ranging from 5 to 25 nmol/l. Additionally, PSI pre-treatment 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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Line, Transformed
  • Cisplatin / administration & dosage
  • Cytoskeletal Proteins / analysis
  • Dose-Response Relationship, Drug
  • Fusion Proteins, bcr-abl
  • Gene Expression / drug effects
  • Genes, bcl-2
  • Genes, p53
  • HL-60 Cells / drug effects
  • HL-60 Cells / ultrastructure
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / ultrastructure
  • Humans
  • Leucine / analogs & derivatives*
  • Leucine / therapeutic use*
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / pathology
  • Membrane Glycoproteins / analysis
  • Microscopy, Electron
  • Paclitaxel / administration & dosage
  • Protease Inhibitors / therapeutic use*
  • Time Factors
  • Trans-Activators*
  • beta Catenin


  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Membrane Glycoproteins
  • Protease Inhibitors
  • Trans-Activators
  • beta Catenin
  • leucinal
  • Fusion Proteins, bcr-abl
  • Leucine
  • Paclitaxel
  • Cisplatin