title: A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma.
abstract: Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma.
authors: Department of Biosciences and Informatics, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Japan.
authors: Hirokazu
authors: H
authors: Shiheido
authors: Fukiko
authors: F
authors: Terada
authors: Noriko
authors: N
authors: Tabata
authors: Ichigo
authors: I
authors: Hayakawa
authors: Nobutaka
authors: N
authors: Matsumura
authors: Hideaki
authors: H
authors: Takashima
authors: Yoko
authors: Y
authors: Ogawa
authors: Wenlin
authors: W
authors: Du
authors: Taketo
authors: T
authors: Yamada
authors: Mitsuru
authors: M
authors: Shoji
authors: Takeshi
authors: T
authors: Sugai
authors: Nobuhide
authors: N
authors: Doi
authors: Shiro
authors: S
authors: Iijima
authors: Yutaka
authors: Y
authors: Hattori
authors: Hiroshi
authors: H
authors: Yanagawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D018385:Centrosome / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D044085:Microfluidics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D010797:Phthalimides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C579116:2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3-dione; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D010797:Phthalimides; D012333:RNA, Messenger; D000090243:Nucleophosmin