title: The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI.
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 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.
authors.affiliation: Bone Marrow Transplantation Unit, I.R.C.C.S., Ospedale Maggiore and University of Milan, Italy. dsoligo@galactica.it
authors.forename: D
authors.initials: D
authors.lastname: Soligo
authors.forename: F
authors.initials: F
authors.lastname: Servida
authors.forename: D
authors.initials: D
authors.lastname: Delia
authors.forename: E
authors.initials: E
authors.lastname: Fontanella
authors.forename: G
authors.initials: G
authors.lastname: Lamorte
authors.forename: L
authors.initials: L
authors.lastname: Caneva
authors.forename: R
authors.initials: R
authors.lastname: Fumiatti
authors.forename: G
authors.initials: G
authors.lastname: Lambertenghi Deliliers
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000008:administration & dosage; D003598:Cytoskeletal Proteins / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2; D016158:Genes, p53; D018922:HL-60 Cells / Q000187:drug effects / Q000648:ultrastructure; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000648:ultrastructure; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000032:analysis; D008854:Microscopy, Electron; D017239:Paclitaxel / Q000008:administration & dosage; D011480:Protease Inhibitors / Q000627:therapeutic use*; D013997:Time Factors; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D015534:Trans-Activators; D051176:beta Catenin; C035766:leucinal; D016044:Fusion Proteins, bcr-abl; D007930:Leucine; D017239:Paclitaxel; D002945:Cisplatin