2-aminopurine enhances the oncolytic activity of an E1b-deleted adenovirus in hepatocellular carcinoma cells

• Published in: PloS one 2013-06, Vol.8 (6), p.e65222
• Main Authors: Sharon, David, Schümann, Michael, MacLeod, Sheena, McPherson, Robyn, Chaurasiya, Shyambabu, Shaw, Andrew, Hitt, Mary M
• Format: Article
• Language: English
• Subjects: 2-Aminopurine; 2-Aminopurine - pharmacology; Adenoviridae - drug effects; Adenoviridae - genetics; Adenoviridae - pathogenicity; Adenoviridae - physiology; Adenovirus E1B Proteins - chemistry; Adenovirus E1B Proteins - deficiency; Adenovirus E1B Proteins - genetics; Adenoviruses; Amino Acid Substitution; Apoptosis; Biology; Biotechnology; Cancer; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Carcinoma, Hepatocellular - virology; Cell death; Cell Death - drug effects; Cell Line; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; Drugs; Gene Deletion; Gene expression; Genes; Hepatocellular carcinoma; Herpes viruses; Humans; Infections; Interferon; Liver cancer; Liver Neoplasms - pathology; Liver Neoplasms - virology; Medicine; Mutation; Oncology; Oncolysis; Oncolytic Viruses - drug effects; Oncolytic Viruses - genetics; Oncolytic Viruses - pathogenicity; Oncolytic Viruses - physiology; Phosphorylation; Protein Structure, Tertiary; Protein synthesis; Proteins; Replication; Ribonucleic acid; RNA; RNA, Viral - genetics; Selectivity; Tumor cell lines; Viral proteins; Virus replication; Virus Replication - drug effects; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0065222

Adenoviruses with deletions of viral genes have been extensively studied as potential cancer therapeutics. Although a high degree of cancer selectivity has been demonstrated with these conditionally replicating adenoviruses, low levels of virus replication can be detected in normal cells. Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells. Recent studies have shown that co-administration of chemotherapeutic drugs may increase the activity of these viruses without affecting their specificity. We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines. Furthermore, we show that 2-aminopurine (2'AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2'AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co-administration of 2'AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdΔE1bΔVA without reducing its selectivity for HCC cells.