Document Detail

Doxorubicin and selenium cooperatively induce fas signaling in the absence of Fas/Fas ligand interaction.
MedLine Citation:
PMID:  17970047     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: The synergistic effect of doxorubicin and selenium in apoptosis induction in MCF-7 breast cancer cells has been previously reported. Mitochondrial activation of caspase-9 is in part responsible for the synergy. The present study aimed at examining the death receptor pathway in activating caspase-8 by the two-drug combination. MATERIALS AND METHODS: We determined the expression of TRAIL and FasL signaling molecules and monitored activated caspase-8 in response to neutralizing/blocking antibodies against ligands/receptors. RESULTS: Our data suggest that TRAIL signaling might not play a role. With respect to the Fas pathway, it was found that doxorubicin enhanced Fas oligomerization (i.e. activation) independent of FasL-Fas interaction. Selenium, on the other hand, increased the expression of FADD, a key adaptor molecule responsible for recruitment of caspase-8 to the Fas oligomer. The significance of the above changes was confirmed by the detection of considerably more caspase-8 in both the Fas or FADD immunoprecipitate obtained from cells treated with the doxorubicin/selenium combination. CONCLUSION: Doxorubicin and selenium cooperatively activate Fas signaling by targeting key regulatory steps.
Song Li; Yunfei Zhou; Yan Dong; Clement Ip
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Anticancer research     Volume:  27     ISSN:  0250-7005     ISO Abbreviation:  Anticancer Res.     Publication Date:    2007 Sep-Oct
Date Detail:
Created Date:  2007-10-31     Completed Date:  2007-11-27     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8102988     Medline TA:  Anticancer Res     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  3075-82     Citation Subset:  IM    
Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
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MeSH Terms
Antigens, CD95 / metabolism*
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / drug therapy,  metabolism,  pathology
Caspase 8 / metabolism
Cell Line, Tumor
Doxorubicin / administration & dosage,  pharmacology*
Drug Synergism
Enzyme Activation
Fas Ligand Protein / metabolism*
Fas-Associated Death Domain Protein / metabolism
Organoselenium Compounds / administration & dosage,  pharmacology*
Receptors, Death Domain / metabolism
Signal Transduction / drug effects
TNF-Related Apoptosis-Inducing Ligand / metabolism
Grant Support
Reg. No./Substance:
0/Antigens, CD95; 0/FADD protein, human; 0/Fas Ligand Protein; 0/Fas-Associated Death Domain Protein; 0/Organoselenium Compounds; 0/Receptors, Death Domain; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 23214-92-8/Doxorubicin; 28274-57-9/methylselenic acid; EC 3.4.22.-/Caspase 8

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