hymecromone and Leukemia--Myeloid--Acute

Despite continuous improvement in the treatment of acute leukemia, new therapies are still needed to overcome resistance and reduce adverse effects. The aim of this work was to study the tumor-suppressive effects of 4-methylumbelliferone (4MU) in human acute leukemia cell lines. In addition, we aimed to address the extent of these effects in relation to the inhibition of hyaluronic acid (HA) synthesis.. 4MU reduced metabolic activity and inhibited cell proliferation in all leukemia cells, and these effects were explained by the induction of senescence or cell death depending on the cell line evaluated. Exogenous HA failed to prevent most of the tumor-suppressive effects observed. Results from this work suggest that the tumor-suppressive effects exerted by 4MU would be explained by HA-synthesis-independent mechanisms.. These findings broaden the knowledge of 4MU as a potential treatment in acute leukemia. We report for the first time the existence of tumor-suppressive effects of 4MU on human acute leukemia cell lines that are independent of its role as HA-synthesis inhibitor.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Hyaluronic Acid; Hymecromone; Jurkat Cells; Leukemia, Myeloid, Acute; U937 Cells

A method is described for the detection of Escherichia coli beta-galactosidase-expressing leukemic cells in ex vivo bone marrow samples. 4-Methylumbelliferyl-beta-D-galactopyranoside is used as a substrate in a kinetic assay. D-Galactose is used to suppress endogenous lysosomal beta-galactosidase activity, yielding a sixfold increase in sensitivity. With this assay, the detection limit is one leukemic cell per 10(4) normal bone marrow cells.

Topics: Animals; beta-Galactosidase; Disease Models, Animal; Escherichia coli; Galactose; Galactosides; Genetic Markers; Hydrogen-Ion Concentration; Hymecromone; In Vitro Techniques; Kinetics; Leukemia, Myeloid, Acute; Lysosomes; Rats; Rats, Inbred BN; Sensitivity and Specificity; Substrate Specificity

Glycosaminoglycans, mainly chondroitin 4-sulfate, are located in the primary granules of human myeloid cells. These polyanionic carbohydrates are believed to play an important role in leukocyte maturation and function. To study the effect of altered chondroitin sulfate metabolism on human promyelocytic leukemia cells, we have treated HL-60 cells with 4-methylumbelliferyl-beta-D-xyloside. beta-D-Xylosides initiate the synthesis of free chondroitin sulfate chains. Cytochemical studies of treated cells demonstrated a marked increase in cytoplasmic granules stained with cationic dyes. This was confirmed by radiolabeled precursor incorporation studies that demonstrated a 344% increase in 35S-sulfate uptake into glycosaminoglycans associated with the cells and a 39% increase in incorporation into glycosaminoglycans released into the media. Chromatographic analyses of these glycosaminoglycans from treated cells demonstrated that the newly formed chondroitin sulfate chains were not attached to protein core and were of shorter length, but of greater charge density than chondroitin sulfate produced by control cells. Thus, beta-D-xyloside appears to alter the protein linkage, chain length, and sulfation of chondroitin sulfate produced by HL-60 cells, and these changes are morphologically evident. These biochemically altered cells may provide important information concerning the role of these macromolecules in myeloid development.

Topics: Cell Division; Cells, Cultured; Cytoplasmic Granules; Glycosaminoglycans; Humans; Hymecromone; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Sulfates; Sulfur Radioisotopes; Umbelliferones