Design, Synthesis of Amide Derivatives of Scutellarin And Their Anti-Leukemia And Neuroprotective Activities

A unique series of amide-scutellarin derivatives were designed and synthesized in order to develop the function of scutellarin further. The antiproliferative activity of all target compounds against two human leukaemia cell lines were evaluated. Among them, compounds 6g and 7c displayed the most antitumor activities against HL-60 and THP-1. Moreover, all compounds were also assayed for their neuroprotective activity against hydrogen peroxide (H2O2)-induced PC-12 cell injury, and the majority of the compounds had moderate to good neuroprotective properties. These findings confirmed that these target compounds could be used as anti-leukaemia and neuroprotective candicates in the future.

Ablation of MYB-dependent leukaemia phenotype in MLL-driven AML correlates with increased expression of MAFB

ABSTRACTThe transcription factor MYB plays a pivotal role in haematopoietic homeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). Our previous work has demonstrated that not all AML types display the same dependency on MYB expression and that MYB dependence is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML still remains to be further elucidated. In this study, we investigate the importance of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-fusion-driven leukaemia upon MYB suppression is not seen in AML cells with a complex karyotype. By performing transcriptome analysis, we demonstrate that a strong activation of MAFB expression driven by MYB ablation is restricted to MYB-dependent cells. In line with these observations, stratification of publicly available patient data reveals a reciprocal relationship between the expression of MYB and MAFB, highlighting a novel connection between those two factors in AML.

Apoptotic Effects on HL60 Human Leukaemia Cells Induced by Lavandin Essential Oil Treatment

Recent scientific investigations have reported a number of essential oils to interfere with intracellular signalling pathways and to induce apoptosis in different cancer cell types. In this paper, Lavandin Essential Oil (LEO), a natural sterile hybrid obtained by cross-breeding L. angustifolia × L. latifolia, was tested on human leukaemia cells (HL60). Based on the MTT results, the reduced cell viability of HL60 cells was further investigated to determine whether cell death was related to the apoptotic process. HL60 cells treated for 24 h with LEO were processed by flow cytometry, and the presence of Annexin V was measured. The activation of caspases-3 was evaluated by western blot and immunofluorescence techniques. Treated cells were also examined by scanning and transmission electron microscopy to establish the possible occurrence of morphological alterations during the apoptotic process. LEO main compounds, such as linalool, linalyl acetate, 1,8-cineole, and terpinen-4-ol, were also investigated by MTT and flow cytometry analysis. The set of obtained results showed that LEO treatments induced apoptosis in a dose-dependent, but not time-dependent, manner on HL60 cells, while among LEO main compounds, both terpinen-4-ol and linalyl acetate were able to induce apoptosis.

Quantitative structure-activity relationship (QSAR) investigation on 2-arylideneaminobenzimidazole derivatives as anti-proliferative activity against mv4-11 human leukaemia cells

This undertaking involves QSAR investigations on the use of 28 2-arylideneaminobenzimidazole derivatives, for curbing the proliferative activity of cells in the mv4-11 human leukaemia cell line. The geometries of the compounds under investigation were initially optimized at level (PM3) in accordance to the semi-empirical theory, and subsequently through the B3LYP procedure at the 6-31G(d) basis set in accordance to the DFT theory. The multiple regression procedure was employed for the construction of two QSAR equations, to assess the anti-proliferative activity of these compounds (Equations 1 and 2). The values of R2 extended from 0.792 to 0.812, those of S from 0.187 to 0.193, and those of F from 24.897 to 30.429. According to the results attained, the use of four parameters in Equation 2[(N5), (N10), r(C1=N2) andLUMO+4] led to raised R2 values and minimized S values. This suggests that these parameters are significant for identifying the anti-proliferative effectiveness of the compounds, in the context of mv4-11 human leukaemia cell line cells. This revelation is also an indication that QSAR can be successfully applied for a broad range of compounds.Â

Augmentation of Saporin-Based Immunotoxins for Human Leukaemia and Lymphoma Cells by Triterpenoid Saponins: The Modifying Effects of Small Molecule Pharmacological Agents

Triterpenoid saponins from Saponinum album (SA) significantly augment the cytotoxicity of saporin-based immunotoxins but the mechanism of augmentation is not fully understood. We investigated the effects of six small molecule pharmacological agents, which interfere with endocytic and other processes, on SA-mediated augmentation of saporin and saporin-based immunotoxins (ITs) directed against CD7, CD19, CD22 and CD38 on human lymphoma and leukaemia cell lines. Inhibition of clathrin-mediated endocytosis or endosomal acidification abolished the SA augmentation of saporin and of all four immunotoxins tested but the cytotoxicity of each IT or saporin alone was largely unaffected. The data support the hypothesis that endocytic processes are involved in the augmentative action of SA for saporin ITs targeted against a range of antigens expressed by leukaemia and lymphoma cells. In addition, the reactive oxygen species (ROS) scavenger tiron reduced the cytotoxicity of BU12-SAP and OKT10-SAP but had no effect on 4KB128-SAP or saporin cytotoxicity. Tiron also had no effect on SA-mediated augmentation of the saporin-based ITs or unconjugated saporin. These results suggest that ROS are not involved in the augmentation of saporin ITs and that ROS induction is target antigen-dependent and not directly due to the cytotoxic action of the toxin moiety.