A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma

Hirokazu Shiheido, Fukiko Terada, Noriko Tabata, Ichigo Hayakawa, Nobutaka Matsumura, Hideaki Takashima, Yoko Ogawa, Wenlin Du, Taketo Yamada, Mitsuru Shoji, Takeshi Sugai, Nobuhide Doi, Shiro Iijima, Yutaka Hattori, Hiroshi Yanagawa

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Article numbere38878
JournalPLoS One
Volume7
Issue number6
DOIs
Publication statusPublished - 2012 Jun 25

Fingerprint

phthalimide
myeloma
Multiple Myeloma
Cluster Analysis
Derivatives
drugs
Tumors
apoptosis
Cells
cell lines
Apoptosis
surface plasmon resonance
Protein Array Analysis
Inbred ICR Mouse
Microfluidics
SCID Mice
Surface Plasmon Resonance
Caspase 9
Caspase 8
Cell proliferation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Shiheido, H., Terada, F., Tabata, N., Hayakawa, I., Matsumura, N., Takashima, H., ... Yanagawa, H. (2012). A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. PLoS One, 7(6), [e38878]. https://doi.org/10.1371/journal.pone.0038878

A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. / Shiheido, Hirokazu; Terada, Fukiko; Tabata, Noriko; Hayakawa, Ichigo; Matsumura, Nobutaka; Takashima, Hideaki; Ogawa, Yoko; Du, Wenlin; Yamada, Taketo; Shoji, Mitsuru; Sugai, Takeshi; Doi, Nobuhide; Iijima, Shiro; Hattori, Yutaka; Yanagawa, Hiroshi.

In: PLoS One, Vol. 7, No. 6, e38878, 25.06.2012.

Research output: Contribution to journalArticle

Shiheido, H, Terada, F, Tabata, N, Hayakawa, I, Matsumura, N, Takashima, H, Ogawa, Y, Du, W, Yamada, T, Shoji, M, Sugai, T, Doi, N, Iijima, S, Hattori, Y & Yanagawa, H 2012, 'A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma', PLoS One, vol. 7, no. 6, e38878. https://doi.org/10.1371/journal.pone.0038878
Shiheido H, Terada F, Tabata N, Hayakawa I, Matsumura N, Takashima H et al. A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. PLoS One. 2012 Jun 25;7(6). e38878. https://doi.org/10.1371/journal.pone.0038878
Shiheido, Hirokazu ; Terada, Fukiko ; Tabata, Noriko ; Hayakawa, Ichigo ; Matsumura, Nobutaka ; Takashima, Hideaki ; Ogawa, Yoko ; Du, Wenlin ; Yamada, Taketo ; Shoji, Mitsuru ; Sugai, Takeshi ; Doi, Nobuhide ; Iijima, Shiro ; Hattori, Yutaka ; Yanagawa, Hiroshi. / A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. In: PLoS One. 2012 ; Vol. 7, No. 6.
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