Source:http://linkedlifedata.com/resource/pubmed/id/16103092
Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
16
|
| pubmed:dateCreated |
2005-8-16
|
| pubmed:abstractText |
Hepatocellular carcinomas (HCC) are drug-resistant tumors that frequently possess high telomerase activity. It was therefore the aim of our study to investigate the potential of telomerase-dependent virotherapy in multimodal treatment of HCC. In contrast to normal liver, HCC xenografts showed high telomerase activity, resulting in tumor-restricted expression of E1A by a telomerase-dependent replicating adenovirus (hTERT-Ad). Neither tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or chemotherapy alone nor the combined treatment with both agents resulted in significant destruction of HCC cells. Application of hTERT-Ad at low titers was also not capable to destroy HCC cells, but telomerase-dependent virotherapy overcame the resistance of HCC against TRAIL and chemotherapy. The synergistic effects are explained by a strong down-regulation of Mcl-1 expression through hTERT-Ad that sensitizes HCC for TRAIL- and chemotherapy-mediated apoptosis. To investigate whether down-regulation of Mcl-1 alone is sufficient to explain synergistic effects observed with virotherapy, Mcl-1 expression was inhibited by RNA interference. Treatment with Mcl-1-siRNA significantly enhanced caspase-3 activity after chemotherapy and TRAIL application, confirming that elimination of Mcl-1 is responsible for the drug sensitization by hTERT-Ad. Consistent with these results, heterologous overexpression of Mcl-1 significantly reduced the sensitization of hTERT-Ad transduced cells against apoptosis-inducing agents. Chemotherapy did not interfere with quantitative hTERT-Ad production in HCC cells. Whereas hTERT-Ad virotherapy alone was only capable to inhibit the growth of Hep3B xenografts, virochemotherapy resulted in vast destruction of the drug-resistant HCC. In conclusion our data indicate that telomerase-dependent virotherapy is an attractive strategy to overcome the natural resistance of HCC against anticancer drugs by elimination of Mcl-1.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenovirus E1A Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/TNF-Related Apoptosis-Inducing...,
http://linkedlifedata.com/resource/pubmed/chemical/TNFSF10 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Telomerase,
http://linkedlifedata.com/resource/pubmed/chemical/Tnfsf10 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/myeloid cell leukemia sequence 1...
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Aug
|
| pubmed:issn |
0008-5472
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
15
|
| pubmed:volume |
65
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
7393-402
|
| pubmed:dateRevised |
2008-7-9
|
| pubmed:meshHeading |
pubmed-meshheading:16103092-Adenoviridae,
pubmed-meshheading:16103092-Adenovirus E1A Proteins,
pubmed-meshheading:16103092-Animals,
pubmed-meshheading:16103092-Apoptosis Regulatory Proteins,
pubmed-meshheading:16103092-Carcinoma, Hepatocellular,
pubmed-meshheading:16103092-Cell Line, Tumor,
pubmed-meshheading:16103092-Combined Modality Therapy,
pubmed-meshheading:16103092-Down-Regulation,
pubmed-meshheading:16103092-Drug Resistance, Neoplasm,
pubmed-meshheading:16103092-Drug Synergism,
pubmed-meshheading:16103092-Humans,
pubmed-meshheading:16103092-Liver Neoplasms,
pubmed-meshheading:16103092-Male,
pubmed-meshheading:16103092-Membrane Glycoproteins,
pubmed-meshheading:16103092-Mice,
pubmed-meshheading:16103092-Mice, Nude,
pubmed-meshheading:16103092-Neoplasm Proteins,
pubmed-meshheading:16103092-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:16103092-TNF-Related Apoptosis-Inducing Ligand,
pubmed-meshheading:16103092-Telomerase,
pubmed-meshheading:16103092-Tumor Necrosis Factor-alpha,
pubmed-meshheading:16103092-Xenograft Model Antitumor Assays
|
| pubmed:year |
2005
|
| pubmed:articleTitle |
Telomerase-dependent virotherapy overcomes resistance of hepatocellular carcinomas against chemotherapy and tumor necrosis factor-related apoptosis-inducing ligand by elimination of Mcl-1.
|
| pubmed:affiliation |
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|