title: Herbimycin A accelerates the induction of apoptosis following etoposide treatment or gamma-irradiation of bcr/abl-positive leukaemia cells.
abstract: Philadelphia chromosome (Ph)-positive leukaemia cells express the chimeric bcr/abl oncoprotein, whose deregulated protein tyrosine kinase (PTK) activity antagonizes the induction of apoptosis by DNA damaging agents. Treatment of Ph-positive K562, TOM 1 and KCL-22 cells with etoposide for 2d induced cytosolic vacuolation, but not nuclear condensation or DNA fragmentation. The bcr/abl kinase-selective inhibitor herbimycin A increased the induction of nuclear apoptosis by etoposide or gamma-radiation. The concentration of herbimycin required to synergize with etoposide was similar to that required to decrease the level of tyrosine phosphorylated proteins or of the protein tyrosine kinase activity of anti-abl immune complexes in K562 cells. The ability of herbimycin A to sensitize K562, TOM 1 or KCL-22 cells to apoptosis induction correlated with its ability to decrease the cellular content of phosphotyrosyl proteins in these Philadelphia-positive lines. Enhancement of nuclear apoptosis by herbimycin was not attributable to downregulation of the bcl-2 or bcl-XL anti-apoptotic proteins. In contrast, herbimycin protected Philadelphia-negative HL60 cells from apoptosis induction by etoposide and did not affect killing of NC37 and CEM cells. The data suggest that the induction of apoptosis is blocked in cells expressing the bcr/abl oncoprotein and that herbimycin A increases induction of programmed cell death following DNA damage. Selective PTK inhibitors may therefore be of value in securing the genetic death of Ph-positive leukaemia cells.
authors.affiliation: Department of Hematology, Royal Free Hospital School of Medicine, London, UK.
authors.forename: F A
authors.initials: FA
authors.lastname: Riordan
authors.forename: C A
authors.initials: CA
authors.lastname: Bravery
authors.forename: K
authors.initials: K
authors.lastname: Mengubas
authors.forename: N
authors.initials: N
authors.lastname: Ray
authors.forename: N J
authors.initials: NJ
authors.lastname: Borthwick
authors.forename: A N
authors.initials: AN
authors.lastname: Akbar
authors.forename: S M
authors.initials: SM
authors.lastname: Hart
authors.forename: A V
authors.initials: AV
authors.lastname: Hoffbrand
authors.forename: A B
authors.initials: AB
authors.lastname: Mehta
authors.forename: R G
authors.initials: RG
authors.lastname: Wickremasinghe
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D016227:Benzoquinones; D005047:Etoposide / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000032:analysis* / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D018922:HL-60 Cells; D006801:Humans; D047029:Lactams, Macrocyclic; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology*; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D011809:Quinones; D051020:bcl-X Protein; D017828:Rifabutin; D005047:Etoposide; C020754:herbimycin; D016044:Fusion Proteins, bcr-abl