PDF(Pubmed)
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.
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.
摘要：
背景：一些研究已经描述了大麻素（CNB）的潜在抗肿瘤作用。CNB受体2(CB2)主要存在于造血干细胞(HSC)中。本研究评估了CNB的抗白血病作用。
方法：使用来自急性髓系白血病（AML）患者的细胞系和原代细胞，并在体外评估CNB衍生物WIN-55的作用，离体和体内。
结果：我们证明了WIN-55的有效抗白血病作用，该作用被CB拮抗剂消除。胜利治疗的小鼠，与AML细胞异种移植，与媒介物或阿糖胞苷相比，存活率更好。DNA损伤相关基因在暴露于WIN时受到影响。与PARP抑制剂Olaparib共同孵育可防止WIN诱导的细胞死亡，提示PARP介导的细胞凋亡，在WIN处理的细胞中观察到AIF易位到细胞核进一步证实。烟酰胺可预防WIN相关细胞凋亡，表示NAD+耗尽。最后,WIN改变了糖酵解酶水平以及G6PDH的活性。这些作用通过PARP1抑制而逆转。
结论：WIN-55通过Parthanatos发挥抗白血病作用，导致AIF易位到细胞核和NAD+耗尽，通过PARP1抑制逆转。它还诱导代谢破坏。在正常HSC中未观察到这些作用。
方法：使用来自急性髓系白血病（AML）患者的细胞系和原代细胞，并在体外评估CNB衍生物WIN-55的作用，离体和体内。
结果：我们证明了WIN-55的有效抗白血病作用，该作用被CB拮抗剂消除。胜利治疗的小鼠，与AML细胞异种移植，与媒介物或阿糖胞苷相比，存活率更好。DNA损伤相关基因在暴露于WIN时受到影响。与PARP抑制剂Olaparib共同孵育可防止WIN诱导的细胞死亡，提示PARP介导的细胞凋亡，在WIN处理的细胞中观察到AIF易位到细胞核进一步证实。烟酰胺可预防WIN相关细胞凋亡，表示NAD+耗尽。最后,WIN改变了糖酵解酶水平以及G6PDH的活性。这些作用通过PARP1抑制而逆转。
结论：WIN-55通过Parthanatos发挥抗白血病作用，导致AIF易位到细胞核和NAD+耗尽，通过PARP1抑制逆转。它还诱导代谢破坏。在正常HSC中未观察到这些作用。
