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A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts.
- Source :
-
PloS one [PLoS One] 2015 Jan 24; Vol. 10 (1), pp. e0116135. Date of Electronic Publication: 2015 Jan 24 (Print Publication: 2015). - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Apoptosis drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Drug Evaluation, Preclinical
Half-Life
Heterografts drug effects
Humans
Lenalidomide
Male
Mice, Inbred ICR
Mice, SCID
Multiple Myeloma genetics
Nuclear Proteins chemistry
Nucleophosmin
Osteoclasts drug effects
Phthalimides chemistry
Phthalimides pharmacokinetics
Thalidomide analogs & derivatives
Thalidomide chemistry
Thalidomide pharmacology
Multiple Myeloma pathology
Phthalimides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25617756
- Full Text :
- https://doi.org/10.1371/journal.pone.0116135