Document Detail

Differential sensitivity of breast cancer and melanoma cells to proteasome inhibitor Velcade.
MedLine Citation:
PMID:  19020781     Owner:  NLM     Status:  MEDLINE    
Velcade (also known as PS-341 or Bortezomib) is a highly selective and reversible inhibitor of the 26S proteasome and is approved for the treatment of patients with advanced multiple myeloma. Here we investigated the anti-proliferative effect of Velcade on 4T1 breast cancer and B16F10 melanoma cells and evaluated the mechanism of action. It was found that two cell lines are differentially sensitive to proteasome inhibitor Velcade. The IC50 concentrations for B16F10 and 4T1 were 2.5 nM and 71 nM, respectively, indicating that B16F10 cells are more sensitive to proteasomal inhibition. Velcade was equally potent in inhibiting the chymotrypsin-like activity of the proteasome in both cell lines. It was determined that B16F10 cells proliferate more rapidly than 4T1 cells; doubling time (Td) =14.2 h versus Td =22.9 h, suggesting that a rapid proliferation rate may be an important factor in cellular resistance towards proteasomal inhibition. We observed for the first time that p53 and p21 proteins were increased in B16F10 cells but not in 4T1 following Velcade-treatment, demonstrating that p53 and p21 may enhance Velcade sensitivity. Furthermore, it was observed that caspase-3 proenzyme was reduced by approximately 20% in B16F10 melanoma cells, but not in 4T1 cells in response to 26S proteasomal inhibition by Velcade. Altogether, we concluded that p53 protein plays a central role in higher sensitivity of B16F10 cells to Velcade by inducing the accumulation of p21, a cell cycle inhibitor, as well as by stimulating the mitochondrial pathway of apoptosis through caspase-3 activation.
Azmi Yerlikaya; Nuray Erin
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of molecular medicine     Volume:  22     ISSN:  1107-3756     ISO Abbreviation:  Int. J. Mol. Med.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-21     Completed Date:  2009-07-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9810955     Medline TA:  Int J Mol Med     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  817-23     Citation Subset:  IM    
Dumlupinar University, Art and Science Faculty, Department of Biology, Kütahya, Turkey.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Boronic Acids / pharmacology*
Breast Neoplasms / metabolism*,  pathology
Caspase 3 / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects*
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Inhibitory Concentration 50
Melanoma / metabolism*,  pathology
Protease Inhibitors / pharmacology
Proteasome Endopeptidase Complex / antagonists & inhibitors
Pyrazines / pharmacology*
Tumor Suppressor Protein p53 / metabolism
Reg. No./Substance:
0/Antineoplastic Agents; 0/Boronic Acids; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Protease Inhibitors; 0/Pyrazines; 0/Tumor Suppressor Protein p53; 0/bortezomib; EC 3.4.22.-/Caspase 3; EC Endopeptidase Complex; EC 3.4.99.-/ATP dependent 26S protease

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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