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(Chalcogen)semicarbazones and their cobalt complexes differentiate HL-60 myeloid leukaemia cells and are cytotoxic towards tumor cell lines.

ABSTRACT: Cobalt complexes with semi- and thiosemicarbazones of 8-quinolinecarboxaldehyde have been synthesized and characterized by X-ray diffraction analysis. These novel complexes and a previously synthesized cobalt complex with a selenium-based selenosemicarbazone ligand showed myeloid differentiation activity on all trans retinoic acid resistant HL-60 acute myeloid leukaemia cells. They also showed varying levels of cytotoxicity on five human tumor cell lines: cervix carcinoma cells (HeLa), lung adenocarcinoma cells (A549), colorectal adenocarcinoma cells (LS-174), breast carcinoma cells (MDA-MB-361), and chronic myeloid leukaemia (K562) as well as one normal human cell line: fetal lung fibroblast cells (MRC-5). Leukaemia differentiation was most strongly induced by a metal-free oxygen ligand and the selenium ligand, whilst the latter and the cobalt(ii) complex with an oxygen ligand showed the strongest dose-dependent cytotoxic activity. In four out of five investigated tumor cell lines, it was of the same order of magnitude as cisplatin. These best compounds, however, had lower toxicity on non-transformed MRC-5 cells than cisplatin.

SUBMITTER: Todorovic TR

PROVIDER: S-EPMC6071924 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundT cell immunoglobulin and mucin-domain containing-3 (TIM-3) is a cell surface molecule that was first discovered on T cells. However, recent studies revealed that it is also highly expressed in acute myeloid leukemia (AML) cells and it is related to AML progression. As, Glutamine appears to play a prominent role in malignant tumor progression, especially in their myeloid group, therefore, in this study we aimed to evaluate the relation between TIM-3/Galectin-9 axis and glutamine metabolism in two types of AML cell lines, HL-60 and THP-1.MethodsCell lines were cultured in RPMI 1640 which supplemented with 10% FBS and 1% antibiotics. 24, 48, and 72 h after addition of recombinant Galectin-9 (Gal-9), RT-qPCR analysis, RP-HPLC and gas chromatography techniques were performed to evaluate the expression of glutaminase (GLS), glutamate dehydrogenase (GDH) enzymes, concentration of metabolites; Glutamate (Glu) and alpha-ketoglutarate (α-KG) in glutaminolysis pathway, respectively. Western blotting and MTT assay were used to detect expression of mammalian target of rapamycin complex (mTORC) as signaling factor, GLS protein and cell proliferation rate, respectively.ResultsThe most mRNA expression of GLS and GDH in HL-60 cells was seen at 72 h after Gal-9 treatment (p = 0.001, p = 0.0001) and in THP-1 cell line was observed at 24 h after Gal-9 addition (p = 0.001, p = 0.0001). The most mTORC and GLS protein expression in HL-60 and THP-1 cells was observed at 72 and 24 h after Gal-9 treatment (p = 0.0001), respectively. MTT assay revealed that Gal-9 could promote cell proliferation rate in both cell lines (p = 0.001). Glu concentration in HL-60 and α-KG concentration in both HL-60 (p = 0.03) and THP-1 (p = 0.0001) cell lines had a decreasing trend. But, Glu concentration had an increasing trend in THP-1 cell line (p = 0.0001).ConclusionTaken together, this study suggests TIM-3/Gal-9 interaction could promote glutamine metabolism in HL-60 and THP-1 cells and resulting in AML development.

Project description:Combined bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) exert unexpected antileukaemic activities against acute myeloid leukaemia (AML) and these activities are associated with the generation of reactive oxygen species (ROS) within the tumor cells. Although the generation of ROS by these drugs is supported by preceding studies including our own, the interrelationship between the cellular effects of the drugs and ROS generation is not well understood. Here we report the use of NMR metabolomic profiling to further study the effect of BEZ and MPA on three AML cell lines and to shed light on the underlying mechanism of action. For this we focused on drug effects induced during the initial 24 hours of treatment prior to the onset of overt cellular responses and examined these in the context of basal differences in metabolic profiles between the cell lines. Despite their ultimately profound cellular effects, the early changes in metabolic profiles engendered by these drugs were less pronounced than the constitutive metabolic differences between cell types. Nonetheless, drug treatments engendered common metabolic changes, most markedly in the response to the combination of BEZ and MPA. These responses included changes to TCA cycle intermediates consistent with recently identified chemical actions of ROS. Notable amongst these was the conversion of alpha-ketoglutarate to succinate which was recapitulated by the treatment of cell extracts with exogenous hydrogen peroxide. These findings indicate that the actions of combined BEZ and MPA against AML cells are indeed mediated downstream of the generation of ROS rather than some hitherto unsuspected mechanism. Moreover, our findings demonstrate that metabolite profiles represent highly sensitive markers for genomic differences between cells and their responses to external stimuli. This opens new perspectives to use metabolic profiling as a tool to study the rational redeployment of drugs in new disease settings.

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(Chalcogen)semicarbazones and their cobalt complexes differentiate HL-60 myeloid leukaemia cells and are cytotoxic towards tumor cell lines.

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