Oncolytic vaccinia virus combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis.
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Date
2016-12-06Author
Wilkinson, MJ
Smith, HG
McEntee, G
Kyula-Currie, J
Pencavel, TD
Mansfield, DC
Khan, AA
Roulstone, V
Hayes, AJ
Harrington, KJ
Type
Journal Article
Metadata
Show full item recordAbstract
Advanced extremity melanoma and sarcoma present a significant therapeutic challenge, requiring multimodality therapy to treat or even palliate disease. These aggressive tumours are relatively chemo-resistant, therefore new treatment approaches are urgently required. We have previously reported on the efficacy of oncolytic virotherapy (OV) delivered by isolated limb perfusion. In this report, we have improved therapeutic outcomes by combining OV with radiotherapy. In vitro, the combination of oncolytic vaccinia virus (GLV-1h68) and radiotherapy demonstrated synergistic cytotoxicity. This effect was not due to increased viral replication, but mediated through induction of intrinsic apoptosis. GLV-1h68 therapy downregulated the anti-apoptotic BCL-2 proteins (MCL-1 and BCL-XL) and the downstream inhibitors of apoptosis, resulting in cleavage of effector caspases 3 and 7. In an in vivo ILP model, the combination of OV and radiotherapy significantly delayed tumour growth and prolonged survival compared to single agent therapy. These data suggest that the virally-mediated down-regulation of anti-apoptotic proteins may increase the sensitivity of tumour cells to the cytotoxic effects of ionizing radiation. Oncolytic virotherapy represents an exciting candidate for clinical development when delivered by ILP. Its ability to overcome anti-apoptotic signals within tumour cells points the way to further development in combination with conventional anti-cancer therapies.
Collections
Subject
Cell Line, Tumor
Animals
Rats, Inbred BN
Humans
Vaccinia virus
Fibrosarcoma
Radiotherapy, Adjuvant
Dose-Response Relationship, Radiation
Signal Transduction
Apoptosis
Gene Expression Regulation, Neoplastic
Time Factors
Male
Oncolytic Virotherapy
Oncolytic Viruses
Apoptosis Regulatory Proteins
bcl-X Protein
Caspase 3
Caspase 7
Host-Pathogen Interactions
Myeloid Cell Leukemia Sequence 1 Protein
Research team
Sarcoma and Melanoma Surgery
Targeted Therapy
Language
eng
Date accepted
2016-10-11
License start date
2016-12
Citation
Oncotarget, 2016, 7 (49), pp. 81208 - 81222
Publisher
IMPACT JOURNALS LLC