A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts

A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts

Despite the recent advances in the treatment of multiple myeloma (MM), MM patients with high-risk cytogenetic changes such as t(4;14) translocation or deletion of chromosome 17 still have extremely poor prognoses. With the goal of helping these high-risk MM patients, we previously developed a novel...

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Main Authors: Matsushita, Maiko, Ozaki, Yoshie, Hasegawa, Yuka, Terada, Fukiko, Tabata, Noriko, Shiheido, Hirokazu, Yanagawa, Hiroshi, Oikawa, Tsukasa, Matsuo, Koichi, Du, Wenlin, Yamada, Taketo, Hozumi, Masashi, Ichikawa, Daiju, Hattori, Yutaka
Format: Online
Language:English
Published: Public Library of Science 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305313/
id pubmed-4305313
recordtype oai_dc
spelling pubmed-43053132015-01-30 A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts Matsushita, Maiko Ozaki, Yoshie Hasegawa, Yuka Terada, Fukiko Tabata, Noriko Shiheido, Hirokazu Yanagawa, Hiroshi Oikawa, Tsukasa Matsuo, Koichi Du, Wenlin Yamada, Taketo Hozumi, Masashi Ichikawa, Daiju Hattori, Yutaka Research Article Despite the recent advances in the treatment of multiple myeloma (MM), MM patients with high-risk cytogenetic changes such as t(4;14) translocation or deletion of chromosome 17 still have extremely poor prognoses. With the goal of helping these high-risk MM patients, we previously developed a novel phthalimide derivative, TC11. Here we report the further characterization of TC11 including anti-myeloma effects in vitro and in vivo, a pharmacokinetic study in mice, and anti-osteoclastogenic activity. Intraperitoneal injections of TC11 significantly delayed the growth of subcutaneous tumors in human myeloma-bearing SCID mice. Immunohistochemical analyses showed that TC11 induced apoptosis of MM cells in vivo. In the pharmacokinetic analyses, the Cmax was 2.1 μM at 1 h after the injection of TC11, with 1.2 h as the half-life. TC11 significantly inhibited the differentiation and function of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts in mouse osteoclast cultures using M-CSF and RANKL. We also revealed that TC11 induced the apoptosis of myeloma cells accompanied by α-tubulin fragmentation. In addition, TC11 and lenalidomide, another phthalimide derivative, directly bound to nucleophosmin 1 (NPM1), whose role in MM is unknown. Thus, through multiple molecular interactions, TC11 is a potentially effective drug for high-risk MM patients with bone lesions. The present results suggest the possibility of the further development of novel thalidomide derivatives by drug designing. Public Library of Science 2015-01-24 /pmc/articles/PMC4305313/ /pubmed/25617756 http://dx.doi.org/10.1371/journal.pone.0116135 Text en © 2015 Matsushita et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Matsushita, Maiko
Ozaki, Yoshie
Hasegawa, Yuka
Terada, Fukiko
Tabata, Noriko
Shiheido, Hirokazu
Yanagawa, Hiroshi
Oikawa, Tsukasa
Matsuo, Koichi
Du, Wenlin
Yamada, Taketo
Hozumi, Masashi
Ichikawa, Daiju
Hattori, Yutaka
spellingShingle Matsushita, Maiko
Ozaki, Yoshie
Hasegawa, Yuka
Terada, Fukiko
Tabata, Noriko
Shiheido, Hirokazu
Yanagawa, Hiroshi
Oikawa, Tsukasa
Matsuo, Koichi
Du, Wenlin
Yamada, Taketo
Hozumi, Masashi
Ichikawa, Daiju
Hattori, Yutaka
A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts
author_facet Matsushita, Maiko
Ozaki, Yoshie
Hasegawa, Yuka
Terada, Fukiko
Tabata, Noriko
Shiheido, Hirokazu
Yanagawa, Hiroshi
Oikawa, Tsukasa
Matsuo, Koichi
Du, Wenlin
Yamada, Taketo
Hozumi, Masashi
Ichikawa, Daiju
Hattori, Yutaka
author_sort Matsushita, Maiko
title A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts
title_short A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts
title_full A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts
title_fullStr A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts
title_full_unstemmed A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts
title_sort novel phthalimide derivative, tc11, has preclinical effects on high-risk myeloma cells and osteoclasts
description Despite the recent advances in the treatment of multiple myeloma (MM), MM patients with high-risk cytogenetic changes such as t(4;14) translocation or deletion of chromosome 17 still have extremely poor prognoses. With the goal of helping these high-risk MM patients, we previously developed a novel phthalimide derivative, TC11. Here we report the further characterization of TC11 including anti-myeloma effects in vitro and in vivo, a pharmacokinetic study in mice, and anti-osteoclastogenic activity. Intraperitoneal injections of TC11 significantly delayed the growth of subcutaneous tumors in human myeloma-bearing SCID mice. Immunohistochemical analyses showed that TC11 induced apoptosis of MM cells in vivo. In the pharmacokinetic analyses, the Cmax was 2.1 μM at 1 h after the injection of TC11, with 1.2 h as the half-life. TC11 significantly inhibited the differentiation and function of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts in mouse osteoclast cultures using M-CSF and RANKL. We also revealed that TC11 induced the apoptosis of myeloma cells accompanied by α-tubulin fragmentation. In addition, TC11 and lenalidomide, another phthalimide derivative, directly bound to nucleophosmin 1 (NPM1), whose role in MM is unknown. Thus, through multiple molecular interactions, TC11 is a potentially effective drug for high-risk MM patients with bone lesions. The present results suggest the possibility of the further development of novel thalidomide derivatives by drug designing.
publisher Public Library of Science
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305313/
_version_ 1613180464204349440

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