PMID- 18728964
OWN - NLM
STAT- MEDLINE
DCOM- 20081229
LR  - 20220318
IS  - 1029-2403 (Electronic)
IS  - 1042-8194 (Print)
IS  - 1026-8022 (Linking)
VI  - 49
IP  - 10
DP  - 2008 Oct
TI  - Growth control of multiple myeloma cells through inhibition of glycogen synthase 
      kinase-3.
PG  - 1945-53
LID - 10.1080/10428190802304966 [doi]
AB  - Anti-apoptotic pathways play a central role in the survival of multiple myeloma 
      cells. The contribution of PI3-kinase and Akt kinase in mediating myeloma cell 
      survival is well established although the role of glycogen synthase kinase-3 
      (GSK3) is less defined. In this study we determined the contribution of GSK3 in 
      growth regulation of myeloma cells. We treated six different multiple myeloma 
      cell lines with a Thiadiazolidinone (TDZD), a non-competitive inhibitor of GSK3 
      and determined its effects on proliferation and apoptosis. In addition we 
      determined the activation of forkhead transcription factors (FOXO) in response to 
      TDZD. TDZD inhibited proliferation and induced apoptosis of all myeloma cell 
      lines. TDZD was also effective in inducing apoptosis of primary myeloma cells 
      whereas CD34 positive normal hematopoietic cells were protected from apoptosis. 
      Furthermore, TDZD-mediated inhibition of GSK3 resulted in dephosphorylation and 
      activation of FOXO3a. In primary myeloma cells FOXO transcription factors were 
      highly phosphorylated where as the levels of GSK3 phosphorylation was quite low. 
      The levels of the pro-apoptotic proteins Fas ligand (FasL) and IkappaBalpha 
      increased after treatment with TDZD in myeloma cell lines. These studies provide 
      the basis for further testing of GSK3 inhibitors in the clinical setting.
FAU - Zhou, Ying
AU  - Zhou Y
AD  - Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
FAU - Uddin, Shahab
AU  - Uddin S
FAU - Zimmerman, Todd
AU  - Zimmerman T
FAU - Kang, Jeong-Ah
AU  - Kang JA
FAU - Ulaszek, Jodie
AU  - Ulaszek J
FAU - Wickrema, Amittha
AU  - Wickrema A
LA  - eng
GR  - R01 CA098550-04/CA/NCI NIH HHS/United States
GR  - R01 CA098550/CA/NCI NIH HHS/United States
GR  - CA98550/CA/NCI NIH HHS/United States
GR  - R01 CA098550-05/CA/NCI NIH HHS/United States
GR  - R01 CA098550-02/CA/NCI NIH HHS/United States
GR  - R01 CA098550-01A1/CA/NCI NIH HHS/United States
GR  - R01 CA098550-03/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Leuk Lymphoma
JT  - Leukemia & lymphoma
JID - 9007422
RN  - 0 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione)
RN  - 0 (FOXO3 protein, human)
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Thiadiazoles)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Fas Ligand Protein/analysis
MH  - Forkhead Box Protein O3
MH  - Forkhead Transcription Factors/metabolism
MH  - Glycogen Synthase Kinase 3/*antagonists & inhibitors
MH  - Humans
MH  - I-kappa B Proteins/analysis
MH  - Multiple Myeloma/drug therapy/*pathology
MH  - NF-KappaB Inhibitor alpha
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Thiadiazoles/pharmacology
PMC - PMC2574790
MID - NIHMS65653
EDAT- 2008/08/30 09:00
MHDA- 2008/12/30 09:00
PMCR- 2009/09/01
CRDT- 2008/08/30 09:00
PHST- 2008/08/30 09:00 [pubmed]
PHST- 2008/12/30 09:00 [medline]
PHST- 2008/08/30 09:00 [entrez]
PHST- 2009/09/01 00:00 [pmc-release]
AID - 901924027 [pii]
AID - 10.1080/10428190802304966 [doi]
PST - ppublish
SO  - Leuk Lymphoma. 2008 Oct;49(10):1945-53. doi: 10.1080/10428190802304966.