A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma.
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 deriv...
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2012-01-01
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doaj-39b2b178d8884a0d95e69700689dc38f2020-11-25T02:20:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0176e3887810.1371/journal.pone.0038878A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma.Hirokazu ShiheidoFukiko TeradaNoriko TabataIchigo HayakawaNobutaka MatsumuraHideaki TakashimaYoko OgawaWenlin DuTaketo YamadaMitsuru ShojiTakeshi SugaiNobuhide DoiShiro IijimaYutaka HattoriHiroshi YanagawaDespite 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.http://europepmc.org/articles/PMC3382596?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. PLoS ONE |
author_facet |
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 |
author_sort |
Hirokazu Shiheido |
title |
A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. |
title_short |
A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. |
title_full |
A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. |
title_fullStr |
A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. |
title_full_unstemmed |
A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. |
title_sort |
phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3382596?pdf=render |
work_keys_str_mv |
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