Document Detail

Gallium-induced cell death in lymphoma: role of transferrin receptor cycling, involvement of Bax and the mitochondria, and effects of proteasome inhibition.
MedLine Citation:
PMID:  17121930     Owner:  NLM     Status:  MEDLINE    
Gallium nitrate is a metallodrug with clinical efficacy in non-Hodgkin's lymphoma. Its mechanisms of antineoplastic action are not fully understood. In the present study, we investigated the roles of transferrin receptor (TfR) targeting and apoptotic pathways in gallium-induced cell death. Although DoHH2 lymphoma cells displayed a 3-fold lower number of TfRs than CCRF-CEM lymphoma cells, they were 3- to 4-fold more sensitive to gallium nitrate. Despite a lower TfR expression, DoHH2 cells had greater TfR cycling and iron and gallium uptake than CCRF-CEM cells. In other lymphoma cell lines, TfR levels per se did not correlate with gallium sensitivity. Cells incubated with gallium nitrate showed morphologic changes of apoptosis, which were decreased by the caspase inhibitor Z-VAD-FMK and by a Bax-inhibitory peptide. Cells exposed to gallium nitrate released cytochrome c from mitochondria and displayed a dose-dependent increase in caspase-3 activity. An increase in active Bax levels without accompanying changes in Bcl-2 or Bcl-X(L) was seen in cells incubated with gallium nitrate. The endogenous expression of antiapoptotic Bcl-2 was greater in DoHH2 cells than in CCRF-CEM cells, suggesting that endogenous Bcl-2 levels do not correlate with cell sensitivity to gallium nitrate. Gallium-induced apoptosis was enhanced by the proteasome inhibitor bortezomib. Our results suggest that TfR function rather than TfR number is important in gallium targeting to cells and that apoptosis is triggered by gallium through the mitochondrial pathway by activating proapoptotic Bax. Our studies also suggest that the antineoplastic activity of combination gallium nitrate and bortezomib warrants further investigation.
Christopher R Chitambar; Janine P Wereley; Shigemi Matsuyama
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  5     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-23     Completed Date:  2007-02-15     Revised Date:  2010-04-21    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2834-43     Citation Subset:  IM    
Division of Neoplastic Diseases, Department of Medicine, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226.
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MeSH Terms
Antineoplastic Agents / pharmacology,  toxicity*
Caspase 3 / antagonists & inhibitors,  metabolism
Cell Death
Cytochromes c / metabolism
Dose-Response Relationship, Drug
Gallium / pharmacology,  toxicity*
Iron / metabolism
Jurkat Cells
Lymphoma, Non-Hodgkin / enzymology,  metabolism*,  pathology
Mitochondria / metabolism*
Proteasome Endopeptidase Complex / pharmacology
Receptors, Transferrin / metabolism*
Signal Transduction / drug effects
Tumor Cells, Cultured
bcl-2-Associated X Protein / antagonists & inhibitors,  metabolism*
Grant Support
R01 CA109518/CA/NCI NIH HHS; R01 CA109518-01A1/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Receptors, Transferrin; 0/bcl-2-Associated X Protein; 13494-90-1/gallium nitrate; 7439-89-6/Iron; 7440-55-3/Gallium; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspase 3; EC Endopeptidase Complex

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