Linked Life Data

18204782

Source:http://linkedlifedata.com/resource/pubmed/id/18204782

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2008-1-21
pubmed:abstractText
To ascertain the exact anti-myeloma mechanism of thalidomide in vivo, we performed structural development studies of thalidomide, and obtained various analogues with specific molecular properties. Among these derivatives, we found that a new thalidomide analogue, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33) had the most potent anti-myeloma effect and tubulin-polymerization-inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cell lines (RPMI8226, U266, and IM9) in a dose-dependent manner with IC50 of 1-10 microM. In contrast, thalidomide itself did not inhibit cellular growth of RPMI8226 cells. Cultivation with 10 microM 5HPP-33 induced G2/M phase cell cycle arrest, followed by apoptosis of myeloma cells. Treatment with 5HPP-33 induced caspase-3 activity and PARP cleavage. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 showed potent tubulin-polymerization-inhibiting activity with IC50 of 8.1 microM, comparable to that of the known tubulin-polymerization inhibitor, rhizoxin. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Notably, the structural requirement for its activity was critical, as other analogues and derivatives of 5HPP-33 showed only slight tubulin-polymerization-inhibiting activity. Our data suggest that 5HPP-33 is a promising candidates for a therapeutic agent of multiple myeloma. In addition, these results suggest that the tubulin-polymerization inhibiting activity of thalidomide might be a possible mechanism for inducing the apoptosis of myeloma cells by thalidomide.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1107-3756
pubmed:author
pubmed:issnType
Print
pubmed:volume
21
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
163-8
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: possible anti-myeloma mechanism of thalidomide.
pubmed:affiliation
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
pubmed:publicationType
Journal Article