Medrano, M.Contreras, M.Caballero Velázquez, TeresaMartínez, L.Bejarano-García, J. A.Calderón Ruiz, RocíoGarcía-Calderón, C. B.Valle Rosado, IvánPérez Simón, José Antonio2024-04-112024-04-112024Medrano, M., Contreras, M., Caballero Velázquez, T., Martínez, L., Bejarano-García, J.A., Calderón Ruiz, R.,...,Pérez Simón, J.A. (2024). Cannabinoids induce cell death in leukaemic cells through Parthanatos and PARP-related metabolic disruptions. British Journal of Cancer. https://doi.org/10.1038/s41416-024-02618-6.0007-0920https://hdl.handle.net/11441/156813BACKGROUND: 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 PARPmediated 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.application/pdf13 p.engAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.1038/s41416-024-02618-6