Document Detail

Combined treatment with Ad-hTRAIL and DTIC or SAHA is associated with increased mitochondrial-mediated apoptosis in human melanoma cell lines.
MedLine Citation:
PMID:  17410615     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Currently, dacarbazine (DTIC) is the only approved systemic treatment for metastatic malignant melanoma. However, the modest treatment effect encourages studies on novel therapeutic molecules, delivery systems and combination therapies. Full-length TRAIL, delivered from an adenoviral vector (Ad-hTRAIL), was studied in combination with DTIC or the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in human melanoma cell lines. METHODS: The cytotoxic potential of the combination treatments was assessed by cell viability measurements and CalcuSyn analysis. Involvement of apoptosis was analyzed by TUNEL staining, mitochondrial membrane potential measurements, and activation and expression levels of caspases and other mediators of apoptosis. RESULTS: Ad-hTRAIL in combination with DTIC or SAHA resulted in additive or synergistic growth inhibition compared to each treatment used as single agent. Both combinations augmented apoptosis, which was mediated through the death receptor (DR) pathway by enhanced activation of caspase-8, and through increased loss of mitochondrial integrity. Provoked cleavage of Bid, which bridges the extrinsic and intrinsic apoptosis pathways, and downregulation of the anti-apoptotic mediators Bcl-X(L), Mcl-1 and XIAP (but not Bcl-2) were critical contributing factors. Increased levels of DR4 and DR5 were not a common underlying mechanism as DTIC did not affect the levels of either of the receptors. However, SAHA-induced expression of DR4 may have reduced the TRAIL resistance in the SKMEL-28 cell line. CONCLUSION: Administration of Ad-hTRAIL in combination with DTIC or SAHA enhances apoptosis in human melanoma cell lines, and suggests that the therapeutic potential of such treatment strategies should be further evaluated for possible clinical use.
Trine Lillehammer; Birgit O Engesaeter; Lina Prasmickaite; Gunhild M Maelandsmo; Oystein Fodstad; Olav Engebraaten
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The journal of gene medicine     Volume:  9     ISSN:  1099-498X     ISO Abbreviation:  J Gene Med     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-06-04     Completed Date:  2007-09-27     Revised Date:  2008-07-09    
Medline Journal Info:
Nlm Unique ID:  9815764     Medline TA:  J Gene Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  440-51     Citation Subset:  IM    
Department of Tumor Biology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway.
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MeSH Terms
Adenoviridae / genetics*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*
BH3 Interacting Domain Death Agonist Protein / metabolism
Caspases / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Dacarbazine / pharmacology*
Down-Regulation / drug effects
Drug Synergism
Hydroxamic Acids / pharmacology*
Melanoma / pathology*
Membrane Potential, Mitochondrial / drug effects
Mitochondria / drug effects*
Neoplasm Proteins / metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism
TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Transduction, Genetic
X-Linked Inhibitor of Apoptosis Protein / genetics
bcl-X Protein / metabolism
Reg. No./Substance:
0/Antineoplastic Agents; 0/BCL2L1 protein, human; 0/BH3 Interacting Domain Death Agonist Protein; 0/Hydroxamic Acids; 0/Neoplasm Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/TNF-Related Apoptosis-Inducing Ligand; 0/X-Linked Inhibitor of Apoptosis Protein; 0/bcl-X Protein; 0/myeloid cell leukemia sequence 1 protein; 149647-78-9/vorinostat; 4342-03-4/Dacarbazine; EC 3.4.22.-/Caspases

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