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PLoS One. 2015 Jan 24;10(1):e0116135. doi: 10.1371/journal.pone.0116135. eCollection 2015.

A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts.

Author information

1
Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
2
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
3
Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan.
4
Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.

Abstract

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.

PMID:
25617756
PMCID:
PMC4305313
DOI:
10.1371/journal.pone.0116135
[Indexed for MEDLINE]
Free PMC Article

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