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Canna~Fangled Abstracts

Cannabinoids induce cell death in leukaemic cells through Parthanatos and PARP-related metabolic disruptions

By March 9, 2024March 11th, 2024No Comments

. 2024 Mar 9.

doi: 10.1038/s41416-024-02618-6.

Online ahead of print.
M Medrano 1, M Contreras 1, T Caballero-Velázquez 1 2, L Martínez 3 4, J A Bejarano-García 1, R Calderón-Ruiz 1, C B García-Calderón 1, I V Rosado 4, J A Pérez-Simón 5 6
Affiliations 

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.

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