Cannabinoids induce cell death in leukaemic cells through Parthanatos and PARP-related metabolic disruptions.
Br J Cancer
; 130(9): 1529-1541, 2024 May.
Article
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| MEDLINE
| ID: mdl-38461169
ABSTRACT
BACKGROUND:
Several studies have described a potential anti-tumour effect of cannabinoids (CNB). CNB receptor 2 (CB2) is mostly present in hematopoietic stem cells (HSC). The present study evaluates the anti-leukaemic effect of CNB.METHODS:
Cell lines and primary cells from acute myeloid leukaemia (AML) patients were used and the effect of the CNB derivative WIN-55 was evaluated in vitro, ex vivo and in vivo.RESULTS:
We demonstrate a potent antileukemic effect of WIN-55 which is abolished with CB antagonists. WIN-treated mice, xenografted with AML cells, had better survival as compared to vehicle or cytarabine. DNA damage-related genes were affected upon exposure to WIN. Co-incubation with the PARP inhibitor Olaparib prevented WIN-induced cell death, suggesting PARP-mediated apoptosis which was further confirmed with the translocation of AIF to the nucleus observed in WIN-treated cells. Nicotinamide prevented WIN-related apoptosis, indicating NAD+ depletion. Finally, WIN altered glycolytic enzymes levels as well as the activity of G6PDH. These effects are reversed through PARP1 inhibition.CONCLUSIONS:
WIN-55 exerts an antileukemic effect through Parthanatos, leading to translocation of AIF to the nucleus and depletion of NAD+, which are reversed through PARP1 inhibition. It also induces metabolic disruptions. These effects are not observed in normal HSC.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
/
Parthanatos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Br J Cancer
Año:
2024
Tipo del documento:
Article
País de afiliación:
España