Telomerase-Dependent Virotherapy Overcomes Resistance of Hepatocellular Carcinomas against Chemotherapy and Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand by Elimination of Mcl-1
Abstract
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.
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Telomerase-dependent virotherapy overcomes tumor resistance against chemotherapy in hepatocellular carcinoma.
“Telomerase-dependent virotherapy has also been shown to overcome tumor resistance against chemotherapy in hepatocellular carcinoma.(112)”
From Understanding and exploiting <i>hTERT</i> promoter regulation for diagnosis and treatment of human cancers (2008) · cites this paper as [112]
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- Authors
- Wirth, T., Kühnel, F., Fleischmann-Mundt, B., Woller, N., Djojosubroto, M., Rudolph, K. L., Manns, M., Zender, L., & Kubicka, S.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany
- Venue
- Cancer Research
- Published
- 2005-08-15
- Volume
- 65
- Issue
- 16
- Pages
- 7393-7402
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2104500895
- Cited by
- 65
- References
- 42
- Citations by year
- 2024: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 6
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-10-15)
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- hepatocellular carcinoma, Mcl-1, TRAIL resistance, chemoresistance, apoptosis, caspase-3, drug sensitization, RNA interference
- MeSH terms
- Adenoviridae, Animals, Combined Modality Therapy, Drug Synergism, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Membrane Glycoproteins, Mice, Nude, Neoplasm Proteins, Tumor Necrosis Factor-alpha, Down-Regulation, Adenovirus E1A Proteins, Drug Resistance, Neoplasm, Telomerase, Proto-Oncogene Proteins c-bcl-2, Xenograft Model Antitumor Assays, Cell Line, Tumor, Apoptosis Regulatory Proteins, Mice, TNF-Related Apoptosis-Inducing Ligand, Myeloid Cell Leukemia Sequence 1 Protein
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