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.
Leukemia, Myeloid, Acute , Parthanatos , Humans , Animals , Mice , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Parthanatos/drug effects , Cell Line, Tumor , Xenograft Model Antitumor Assays , Apoptosis/drug effects , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Piperazines/pharmacology , Poly (ADP-Ribose) Polymerase-1/metabolism , Cannabinoids/pharmacology , Phthalazines/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , DNA Damage/drug effects , Cell Death/drug effects , Antineoplastic Agents/pharmacology
The use of nanovectors in several medicinal treatments has reached a great importance in the last decade. Some drugs need to be protected to increase their lifetimes in the blood flow, to avoid degradation, to be delivered into target cells or to decrease their side effects. The goal of this work was to design and prepare nanovectors formed by novel surfactants derived from the [Ru(bpy)3]2+ complex. These amphiphilic molecules are assembled to form metallomicelles which can act as pharmaceutical agents and, at the same time, as nanovectors for several drugs. TEM images showed a structural transition from spherical to elongated micelles when the surfactant concentration increased. Fluorescence microscopy confirmed the internalization of these metallomicelles into diverse cell lines and cytotoxicity assays demonstrated specificity for some human cancer cells. The encapsulation of various antibiotics was carried out as well as a thorough study about the DNA condensation by the metallomicelles. To the best of our knowledge, applications of these metallomicelles have not been shown in the literature yet.
Coordination Complexes/chemistry , Micelles , Nanoparticles/chemistry , Ruthenium/chemistry , A549 Cells , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/pharmacology , Drug Compounding , Hep G2 Cells , Humans , MCF-7 Cells , Microscopy, Atomic Force , Microscopy, Confocal , Microscopy, Electron, Transmission , Nanoparticles/ultrastructure , Ruthenium/pharmacology
