Document Detail

Transfection of melanoma cells with antisense PAX3 oligonucleotides additively complements cisplatin-induced cytotoxicity.
MedLine Citation:
PMID:  15956257     Owner:  NLM     Status:  MEDLINE    
Advanced melanoma is difficult to treat, in part because of greater resistance to therapy compared with other cancer types. The mechanisms underlying this resistance are not well-understood. One factor that is reported to be involved in melanoma cell survival is PAX3, a transcription factor normally expressed during embryonic development, and which is critically required for development of neural crest-derivatives, including skin melanocytes. PAX3 expression is deregulated in primary melanomas and most melanoma cell lines. Here we have investigated whether targeting PAX3 expression in melanoma cell lines together with chemotherapeutic treatment increases susceptibility to therapeutic cell death. Using PAX3-specific antisense oligodeoxynucleotides (PAX3-AS) to treat melanoma cell lines in vitro, we showed dose-dependent reduction of proliferation of melanoma cells, and induction of apoptosis compared with control treatments. Induction of apoptosis was accompanied by the induction of active caspase-3 in UACC62 and M14 cells, and p53 protein in UACC62 cells. Treatment of melanoma cells with cisplatin induces DNA damage and cytotoxicity, which is thought to be via p53-dependent and -independent mechanisms. Treatment of either p53 mutant (M14) or wild-type (UACC62) melanoma cells with cisplatin, and varying doses of PAX3-AS, resulted in percentages of cells undergoing apoptosis equivalent to the sum of the individual treatments, irrespective of mutation status [e.g., UACC62, 43.8% (1 micromol/L PAX3-AS), 30.1% (20 micromol/L cisplatin), 69.6% (PAX3-AS + cisplatin); M14, 12.6% (1 micromol/L PAX3-AS), 41.5% (40 micromol/L cisplatin), 50.2% (PAX3-AS + cisplatin)]. These data suggest that treatment of melanoma cells with PAX3-AS complements cytotoxicity induced by cisplatin.
Shu-Jie He; Graham Stevens; Antony W Braithwaite; Michael R Eccles
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  4     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-06-15     Completed Date:  2005-09-26     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  996-1003     Citation Subset:  IM    
Department of Pathology, Dunedin School of Medicine, New Zealand.
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MeSH Terms
Caspase 3
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cisplatin / toxicity*
DNA-Binding Proteins / deficiency*,  genetics*,  metabolism
Melanoma / genetics,  metabolism*,  pathology*
Oligonucleotides, Antisense / genetics,  metabolism*
Paired Box Transcription Factors
RNA, Messenger / genetics,  metabolism
Transcription Factors / deficiency*,  genetics*,  metabolism
Tumor Suppressor Protein p53 / genetics,  metabolism
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Oligonucleotides, Antisense; 0/PAX3 protein, human; 0/Paired Box Transcription Factors; 0/RNA, Messenger; 0/Transcription Factors; 0/Tumor Suppressor Protein p53; 15663-27-1/Cisplatin; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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