title: 5,7,3'-Trihydroxy-3,4'-dimethoxyflavone inhibits the tubulin polymerization and activates the sphingomyelin pathway.
abstract: Flavonoids are polyphenolic compounds which display a vast array of biological activities and are among the most promising anti-cancer agents. The derivative of quercetin, 5,7,3'-trihydroxy-3,4'-dimethoxyflavone (THDF), is a natural flavonoid that inhibits cell proliferation and induces apoptosis in human leukemia cells. Here we show that THDF induces cell-cycle arrest in the M phase and inhibits tubulin polymerization. This was associated with the accumulation of cyclin B1 and p21(Cip1) , changes in the phosphorylation status of cyclin B1, Cdk1, Cdc25C, and MPM-2, and activation of the acidic sphingomyelinase (ASMase). Moreover, desipramine attenuated THDF-mediated cell death, indicating a crucial role of ASMase in the mechanism of cell death. In vivo studies on the athymic nude mouse xenograft model also confirmed that THDF inhibits growth of human leukemia cells and suggest that this compound may have therapeutic value.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Torres
authors.forename: José
authors.initials: J
authors.lastname: Quintana
authors.forename: Francisco
authors.initials: F
authors.lastname: Estévez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D005260:Female; D047309:Flavones / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D058105:Polymerization / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000032:analysis; D013109:Sphingomyelins / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays; D020687:cdc25 Phosphatases / Q000032:analysis
chemical_list: C549753:5,7,3'-trihydroxy-3,4'-dimethoxyflavone; D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D056744:Cyclin B1; D047309:Flavones; D013109:Sphingomyelins; D014404:Tubulin; D050257:Tubulin Modulators; D016203:CDC2 Protein Kinase; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D013108:Sphingomyelin Phosphodiesterase; D003891:Desipramine