An HSV-2-based oncolytic virus deleted in the PK domain of the ICP10 gene is a potent inducer of apoptotic death in tumor cells.
The N-terminus of the ICP10 gene of type 2 herpes simplex virus (HSV-2) encodes a serine/threonine protein kinase (PK) domain that facilitates HSV-2 replication by activating the Ras/MEK/MAPK mitogenic pathway and suppressing apoptosis. We recently demonstrated that deletion of this oncogenic PK domain converts it to a potent oncolytic agent. This mutant, which we have designated FusOn-H2, preferentially replicates in and thus lyses tumor cells in which the Ras signaling pathway is constitutively activated. Here we show that FusOn-H2 exerts strong ability in inducing apoptosis in different lines of human tumor cells and in esophageal tumors growing in mice. The apoptotic effect produced by FusOn-H2 was not restricted to infected cells but extended to uninfected bystander cells, thereby increasing the lethality of the virus. These results add a novel killing mechanism to those previously assigned to FusOn-H2, rendering it an attractive candidate for clinical trials.
Fu
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Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Tao
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Zhang
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D000818:Animals; D017209:Apoptosis; D024201:Bystander Effect; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000473:pathology / Q000628:therapy; D005260:Female; D017353:Gene Deletion; D006801:Humans; D020287:In Situ Nick-End Labeling; D015552:Injections, Intralesional; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012264:Ribonucleotide Reductases / Q000235:genetics*; D014779:Virus Replication
C100671:ICP10 protein, herpes simplex virus type 2; D012264:Ribonucleotide Reductases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases