In vivo suppression of Bcl-XL expression facilitates chemotherapy-induced leukaemia cell death in a SCID/NOD-Hu model.
Br J Haematol
; 112(3): 706-13, 2001 Mar.
Article
en En
| MEDLINE
| ID: mdl-11260076
Bcl-XL, a member of the Bcl-2-related anti-apoptosis protein family, antagonizes a diverse range of apoptosis-inducing stimuli by preventing mitochondrial permeability transition, release of apoptogenic factors including cytochrome C, and caspase activation. We have tested the hypothesis that the susceptibility of Bcl-XL-expressing leukaemic cells to apoptosis induced by VP16 (etoposide) can be enhanced by pharmacological downregulation of Bcl-XL in vivo. Two subcutaneous xenograft models of B-cell leukaemia-employing SEMK-2 and BV173 cell lines were established in severe combined immunodeficient/non-obese diabetic mice followed by 14 d of continuous subcutaneous administration of Bcl-XL-specific second generation oligonucleotides ISIS 16009 or ISIS 15999. Tumours were disaggregated, enabling investigation of Bcl-XL expression and apoptosis susceptibility at single-cell resolution using cytofluorimetry. Marked sequence-specific reduction of Bcl-XL was associated with sequence-specific enhancement of VP16-induced mitochondrial permeability transition, caspase-3 activation and loss of membrane asymmetry. A negative correlation between Bcl-XL expression and apoptosis susceptibility was observed, together with a positive correlation with respect to a reduced redox state. Bcl-XL downregulation reduces the threshold for VP16-induced apoptosis by potentiating mitochondrial dysfunction and its sequelae, and therefore presents a novel therapeutic strategy for reversing chemoresistance.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Terapia Genética
/
Oligonucleótidos Antisentido
/
Inmunodeficiencia Combinada Grave
/
Resistencia a Antineoplásicos
/
Proteínas Proto-Oncogénicas c-bcl-2
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Br J Haematol
Año:
2001
Tipo del documento:
Article
Pais de publicación:
Reino Unido