Journal
GENE THERAPY
Volume 17, Issue 3, Pages 315-327Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2009.126
Keywords
ICP10PK; oncolytic viruses; calpain; caspases; autophagy; pyroptosis
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Funding
- NIAMS, NIH [AR053512]
- NIEHS, NIH [ES07263]
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Malignant melanoma is a highly aggressive and drug-resistant cancer. Virotherapy is a novel therapeutic strategy based on cancer cell lysis through selective virus replication. However, its clinical efficacy is modest, apparently related to poor virus replication within the tumors. We report that the growth compromised herpes simplex virus type 2 (HSV-2) mutant, Delta PK, has strong oncolytic activity for melanoma largely caused by a mechanism other than replication-induced cell lysis. The ratio of dead cells (determined by trypan blue or ethidium homodimer staining) to cells that stain with antibody to the major capsid protein VP5 (indicative of productive infection) was 1.8-4.1 for different melanoma cultures at 24-72 h post-infection. Cell death was due to activation of calpain as well as caspases-7 and-3 and it was abolished by the combination of calpain (PD150606) and pancaspase (benzyloxycarbonyl-Val-Ala-Asp-fluormethyl ketone, z-VAD-fmk) inhibitors. Upregulation of the autopahgy protein Beclin-1 and the pro-apoptotic protein H11/HspB8 accompanied Delta PK-induced melanoma oncolysis. Intratumoral Delta PK injection (10(6)-10(7) plaque-forming unit (pfu)) significantly reduced melanoma tumor burden associated with calpain and caspases-7 and-3 activation, Beclin-1 and H11/HspB8 upregulation and activation of caspase-1-related inflammation. Complete remission was seen for 87.5% of the LM melanoma xenografts at 5 months after treatment termination. The data indicate that Delta PK is a promising virotherapy for melanoma that functions through virus-induced programmed cell death pathways. Gene Therapy (2010) 17, 315-327; doi:10.1038/gt.2009.126; published online 1 October 2009
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