chrysin and Leukemia

Chrysin is a natural flavonoid currently under investigation due to its important biological anti-cancer properties. In most of the cancer cells tested, chrysin has shown to inhibit proliferation and induce apoptosis, and is more potent than other tested flavonoids in leukemia cells, where chrysin is likely to act via activation of caspases and inactivation of Akt signaling in the cells. Moreover, structure-activity relationships have revealed that the chemical structure of chrysin meets the key structural requirements of flavonoids for potent cytotoxicity in leukemia cells. It is possible that combination therapy or modified chrysin could be more potent than single-agent use or administration of unmodified chrysin. This study may help to develop ways of improving the effectiveness of chrysin in the treatment of leukemia and other human cancers in vitro.

Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Enzyme Activation; Flavonoids; Humans; Leukemia; Neoplasm Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; Structure-Activity Relationship

We isolated the 4 kinds of flavonoids from strawberry 'Nohime' and examined the effect of these flavonoids on the degranulation in RBL-2H3 cells. The flavonoids were found to suppress the degranulation from Ag-stimulated RBL-2H3 cells to different extents. To disclose the inhibitory mechanism of degranulation by flavonoids, we examined their effects on the intracellular free Ca(2+) concentration ([Ca(2+)]i) and the intracellular signaling pathway such as Lyn, Syk, and PLCgammas. The intracellular free Ca(2+) concentration ([Ca(2+)]i) was elevated by Fc epsilonRI activation, but these flavonoid treatments reduced the elevation of [Ca(2+)]i by suppressing Ca(2+) influx. Kaempferol strongly suppressed the activation of Syk and PLCgammas. It was thus suggested that suppression of Ag-stimulated degranulation by the flavonoids is mainly due to suppression of [Ca(2+)]i elevation and Syk activation. These results suggested that strawberry would be of some ameliorative benefit for the allergic symptoms.

Topics: Animals; Anti-Allergic Agents; Basophil Degranulation Test; Basophils; beta-N-Acetylhexosaminidases; Calcium; Cell Degranulation; Cell Line, Tumor; Flavonoids; Fragaria; Fruit; Immunoglobulin E; Intracellular Signaling Peptides and Proteins; Leukemia; Molecular Structure; Protein-Tyrosine Kinases; Rats; Reactive Oxygen Species; Receptors, IgE; Signal Transduction; Syk Kinase

Arsenic trioxide (ATO) is an effective therapeutic agent for the treatment of acute promyelocytic leukemia, but successful application of this agent may occasionally require the use of sensitizing strategies. The present work demonstrates that the flavonoids quercetin and chrysin cooperate with ATO to induce apoptosis in U937 promonocytes and other human leukemia cell lines (THP-1, HL-60). Co-treatment with ATO plus quercetin caused mitochondrial transmembrane potential dissipation, stimulated the mitochondrial apoptotic pathway, as indicated by cytochrome c and Omi/Htra2 release, XIAP and Bcl-X(L) down-regulation, and Bax activation, and caused caspase-8/Bid activation. Bcl-2 over-expression abrogated cytochrome c release and apoptosis, and also blocked caspase-8 activation. Quercetin and chrysin, alone or with ATO, decreased Akt phosphorylation as well as intracellular GSH content. GSH depletion was regulated at the level of L-buthionine-(S,R)-sulfoximine (BSO)-sensitive enzyme activity, and N-acetyl-L-cysteine failed both to restore GSH content and to prevent apoptosis. Treatment with BSO caused GSH depletion and potentiated ATO-provoked apoptosis, but did not affect apoptosis induction by ara-C and cisplatin. As an exception, ATO plus quercetin failed to elicit Akt de-phosphorylation and GSH depletion in NB4 acute promyelocytic leukemia cells, and correspondingly exhibited low cooperative effect in inducing apoptosis in this cell line. It is concluded that GSH depletion explains at least in part the selective potentiation of ATO toxicity by quercetin, and that this flavonoid might be used to increase the clinical efficacy of the antileukemic drug.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; bcl-2-Associated X Protein; Cell Line, Tumor; Drug Synergism; Flavonoids; Glutathione; Humans; Leukemia; Membrane Potential, Mitochondrial; Oxides; Protein Kinases; Quercetin

The bioassay-guided separation of a Malagasy plant, Agelaea pentagyna, led to the isolation of a flavonoid, tricin (1), with potent inhibitory activity toward exocytosis from antigen-stimulated rat leukemia basophils (RBL-2H3). The structure-activity relationships among structurally related natural and synthetic flavonoids are also discussed.

Topics: Animals; Basophils; Connaraceae; Flavonoids; Histamine H1 Antagonists; Leukemia; Molecular Structure; Plants, Medicinal; Rats; Structure-Activity Relationship