Article: Enhancement of stress-induced apoptosis in B-lineage cells by caspase-9 inhibitor.
2004 Volume 104, Issue 9, Page(s) 2873–2878
Abstract: We have established human B-lineage (BLIN) acute lymphoblastic leukemia cell lines that retain a dependency on fibroblast monolayers for survival and proliferation. Eight hours following removal from adherent cell contact BLIN cells undergo a decrease in ...
| Abstract | We have established human B-lineage (BLIN) acute lymphoblastic leukemia cell lines that retain a dependency on fibroblast monolayers for survival and proliferation. Eight hours following removal from adherent cell contact BLIN cells undergo a decrease in mitochondrial transmembrane potential and an increase in annexin V binding. Unexpectedly, the caspase-9 inhibitor (C9i) benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethylketone enhanced the appearance of apoptotic cells within 8 hours following removal of BLIN cells from fibroblast monolayers. C9i enhancement of apoptosis was dose dependent and did not occur with irreversible inhibitors of caspases-2, -3, -6, and -8. C9i also enhanced apoptosis in cord blood-derived CD19(+) B-lineage cells (but not myeloid cells) removed from murine stromal cells. Longer exposure (> 18 hours) to C9i culminated in apoptosis in a panel of B-lineage acute lymphoblastic leukemia (ALL) cell lines in the presence or absence of fibroblast monolayers, as well as in 2 proliferating leukemic cell lines (RAMOS and CEM). BLIN-4L cells made deficient in caspase-9 by RNA interference exhibited no resistance to apoptotic signals and actually showed increased apoptotic sensitivity to staurosporine. These collective results suggest that a 4-amino acid caspase inhibitor of caspase-9 can promote apoptosis and that at least some types of apoptotic pathways in B-lineage ALL do not require caspase-9. |
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| MeSH term(s) | Animals ; Apoptosis/drug effects ; B-Lymphocytes/drug effects ; B-Lymphocytes/pathology ; Burkitt Lymphoma/pathology ; Caspase 9 ; Caspase Inhibitors ; Cell Line, Tumor ; Coculture Techniques ; Cysteine Proteinase Inhibitors/pharmacology ; Fibroblasts/cytology ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Humans ; Mice ; Oligopeptides/pharmacology ; Stress, Physiological/pathology | ||||||||||
| Chemical Substances | Caspase Inhibitors ; Cysteine Proteinase Inhibitors ; Oligopeptides ; benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone ; CASP9 protein, human (EC 3.4.22.-) ; Casp9 protein, mouse (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2004-07-08 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. | ||||||||||
| ZDB-ID | 80069-7 | ||||||||||
| ISSN | 1528-0020 ; 0006-4971 | ||||||||||
| ISSN (online) | 1528-0020 | ||||||||||
| ISSN | 0006-4971 | ||||||||||
| DOI | 10.1182/blood-2003-10-3720 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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