title: 3-(Iodoacetamido)-benzoylurea: a novel cancericidal tubulin ligand that inhibits microtubule polymerization, phosphorylates bcl-2, and induces apoptosis in tumor cells.
abstract: 3-(Iodoacetamido)-benzoylurea (3-IAABU) is a newly synthesized antitubulin compound with a molecular weight of 347. 3-IAABU exhibited anticancer activity in a variety of tumor cell lines with ID90 in the range of 0.015-0.29 microM for leukemic cells and 0.06-0.92 microM for solid tumors. Higher selectivity against malignant cells was observed with 3-IAABU than that with vinblastine and paclitaxel. It inhibits microtubule assembly in tubulin systems either with or without microtubule-associated proteins (ID50 was 0.1 microM and 1.2 microM, respectively) and microtubule depolymerization was not affected, indicating an inhibition of polymerization by binding of 3-IAABU to the heterodimeric subunit of tubulin. 3-IAABU was shown to inhibit the binding of colchicine, a subunit binding compound, but did not inhibit binding of vinblastine and guanosine 5'-triphosphate/guanosine 5'-diphosphate, indicating that colchicine site corresponds to the site that 3-IAABU locates. Tumor cells treated with 3-IAABU showed scattered chromosomes in metaphase. Normal microtubule architecture or spindle apparatus was absent in these cells; instead, punctuated aggregates of tubulin were found by an immunofluorescent staining. Cell cycle analyses showed an accumulation of tumor cells at M phase after a 4-h treatment with 3-IAABU. The phosphorylated bcl-2 representative of an inactivated form of the oncoprotein was found in the cells 12 h after treatment with 3-IAABU. These cells progressed to apoptosis within 16 h. As a new tubulin ligand, 3-IAABU could be a promising agent in cancer chemotherapy.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Jiang
authors.forename: A S
authors.initials: AS
authors.lastname: Davis
authors.forename: K
authors.initials: K
authors.lastname: Middleton
authors.forename: Y H
authors.initials: YH
authors.lastname: Ling
authors.forename: R
authors.initials: R
authors.lastname: Perez-Soler
authors.forename: J F
authors.initials: JF
authors.lastname: Holland
authors.forename: J G
authors.initials: JG
authors.lastname: Bekesi
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D008941:Spindle Apparatus / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin