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Replication-competent adenoviruses with the type 35-derived fiber-knob region achieve reactive oxygen species-dependent cytotoxicity and produce greater toxicity than those with the type 5-derived region in pancreatic carcinoma
- Source :
- Apoptosis. 20:1587-1598
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- Pancreatic carcinoma is relatively resistant to chemotherapy and cell death induced by replication of adenoviruses (Ad) can be one of the therapeutic options. Transduction efficacy of conventional type 5 Ad (Ad5) is however low and the cytotoxic mechanism by replication-competent Ad was not well understood. We constructed replication-competent Ad5 of which the E1A promoter region was replaced with a transcriptional regulatory region of the midkine, the survivin or the cyclooxygenase-2 gene, all of which were expressed at a high level in human tumors. We also prepared replication-competent Ad5 that were activated with the same region but had the type 35 Ad-derived fiber-knob region (AdF35) to convert the major cellular receptor for Ad infection from the coxsackie adenovirus receptor to CD46 molecules. Replication-competent AdF35 that were activated with the exogenous region produced cytotoxic effects on human pancreatic carcinoma cells greater than the corresponding Ad5 bearing with the same regulatory region. Cells infected with the AdF35 showed cytopathic effects and increased sub-G1 fractions. Caspase-9, less significantly caspase-8 and poly (ADP-ribose) polymerase, but not caspase-3 was cleaved and expression of molecules involved in autophagy and caspase-independent cell death pathways remained unchanged. Nevertheless, H2A histone family member X molecules were phosphorylated, and N-acetyl-L-cystein, an inhibitor for reactive oxygen species, suppressed the AdF35-mediated cytotoxicity. These data indicated a novel mechanism of Ad-mediated cell death and suggest a possible clinical application of the fiber-knob modified Ad.
- Subjects :
- Coxsackie and Adenovirus Receptor-Like Membrane Protein
Cancer Research
Programmed cell death
DNA damage
viruses
Poly ADP ribose polymerase
Clinical Biochemistry
Pharmaceutical Science
Biology
Virus Replication
medicine.disease_cause
Adenoviridae
Cell Line
Membrane Cofactor Protein
Transduction, Genetic
Cell Line, Tumor
Survivin
medicine
Humans
Cytotoxic T cell
Promoter Regions, Genetic
Pharmacology
Cell Death
Biochemistry (medical)
HEK 293 cells
Cell Biology
Molecular biology
Acetylcysteine
Pancreatic Neoplasms
HEK293 Cells
Cyclooxygenase 2
Cell culture
Caspases
Poly(ADP-ribose) Polymerases
Reactive Oxygen Species
Subjects
Details
- ISSN :
- 1573675X and 13608185
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Apoptosis
- Accession number :
- edsair.doi.dedup.....62663941c33e0482cbc16e4b764a46fa
- Full Text :
- https://doi.org/10.1007/s10495-015-1171-8