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The HSV-2 mutant DeltaPK induces melanoma oncolysis through nonredundant death programs and associated with autophagy and pyroptosis proteins.

Abstract
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, DeltaPK, 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 DeltaPK-induced melanoma oncolysis. Intratumoral DeltaPK 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 DeltaPK is a promising virotherapy for melanoma that functions through virus-induced programmed cell death pathways.
AuthorsA G Colunga, J M Laing, L Aurelian
JournalGene therapy (Gene Ther) Vol. 17 Issue 3 Pg. 315-27 (Mar 2010) ISSN: 1476-5462 [Electronic] England
PMID19798049 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Capsid Proteins
  • Caspase Inhibitors
  • ICP10 protein, herpes simplex virus type 2
  • Ribonucleotide Reductases
  • Protein-Serine-Threonine Kinases
  • Calpain
  • Caspase 3
  • Caspase 7
Topics
  • Animals
  • Apoptosis
  • Autophagy
  • Calpain (antagonists & inhibitors, metabolism)
  • Capsid Proteins (metabolism)
  • Caspase 3 (metabolism)
  • Caspase 7 (metabolism)
  • Caspase Inhibitors
  • Cell Line, Tumor
  • Gene Deletion
  • Herpesvirus 2, Human (genetics)
  • Humans
  • Melanoma (therapy)
  • Mice
  • Mice, Nude
  • Oncolytic Virotherapy (methods)
  • Oncolytic Viruses (genetics)
  • Protein-Serine-Threonine Kinases (genetics)
  • Ribonucleotide Reductases (genetics)
  • Skin Neoplasms (therapy)
  • Virus Replication
  • Xenograft Model Antitumor Assays

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