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

Sharon D, Schümann M, MacLeod S, McPherson R, Chaurasiya S, Shaw A, Hitt MM - PLoS ONE (2013)

Bottom Line: Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT
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.

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2′AP increased virus-mediated death of HepG2 and Hep3B HCC cells but not normal fibroblasts.HepG2 and Hep3B HCC cells as well as MRC5 and WI-38 normal cells were infected at the indicated MOIs and then incubated with or without 2.5 mM 2′AP. Six days post-infection, cell survival was measured by Alamar Blue fluorescence measurements and normalized to uninfected controls. Error bars correspond to +/−SD of quadruplicates.
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pone-0065222-g006: 2′AP increased virus-mediated death of HepG2 and Hep3B HCC cells but not normal fibroblasts.HepG2 and Hep3B HCC cells as well as MRC5 and WI-38 normal cells were infected at the indicated MOIs and then incubated with or without 2.5 mM 2′AP. Six days post-infection, cell survival was measured by Alamar Blue fluorescence measurements and normalized to uninfected controls. Error bars correspond to +/−SD of quadruplicates.

Mentions: The ability of 2′AP treatment to increase virus-mediated cell death was evaluated using the HCC cell lines, Hep3B and HepG2, and the normal cell lines, MRC5 and WI-38 (Figure 6). In the absence of 2′AP, HepG2 and Hep3B cells were found to be sensitive to Ad-dl309- and Ad-dl309ΔVA-mediated cell killing at MOI of 10 VP/cell. Furthermore, unlike HepG2 cells, Hep3B cells were also found to be sensitive to killing by the E1b-deleted viruses, although at a higher MOI. 2′AP treatment increased killing of both HepG2 and Hep3B cells by all of the viruses except Ad-dl1520. Interestingly, even in the presence of 2′AP, the normal cell lines were resistant to killing by all the replicating viruses, suggesting that the 2′AP increase in virus-mediated HCC cell death could be dependent on pathways specifically deregulated in HCC cells.


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

Sharon D, Schümann M, MacLeod S, McPherson R, Chaurasiya S, Shaw A, Hitt MM - PLoS ONE (2013)

2′AP increased virus-mediated death of HepG2 and Hep3B HCC cells but not normal fibroblasts.HepG2 and Hep3B HCC cells as well as MRC5 and WI-38 normal cells were infected at the indicated MOIs and then incubated with or without 2.5 mM 2′AP. Six days post-infection, cell survival was measured by Alamar Blue fluorescence measurements and normalized to uninfected controls. Error bars correspond to +/−SD of quadruplicates.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672087&req=5

pone-0065222-g006: 2′AP increased virus-mediated death of HepG2 and Hep3B HCC cells but not normal fibroblasts.HepG2 and Hep3B HCC cells as well as MRC5 and WI-38 normal cells were infected at the indicated MOIs and then incubated with or without 2.5 mM 2′AP. Six days post-infection, cell survival was measured by Alamar Blue fluorescence measurements and normalized to uninfected controls. Error bars correspond to +/−SD of quadruplicates.
Mentions: The ability of 2′AP treatment to increase virus-mediated cell death was evaluated using the HCC cell lines, Hep3B and HepG2, and the normal cell lines, MRC5 and WI-38 (Figure 6). In the absence of 2′AP, HepG2 and Hep3B cells were found to be sensitive to Ad-dl309- and Ad-dl309ΔVA-mediated cell killing at MOI of 10 VP/cell. Furthermore, unlike HepG2 cells, Hep3B cells were also found to be sensitive to killing by the E1b-deleted viruses, although at a higher MOI. 2′AP treatment increased killing of both HepG2 and Hep3B cells by all of the viruses except Ad-dl1520. Interestingly, even in the presence of 2′AP, the normal cell lines were resistant to killing by all the replicating viruses, suggesting that the 2′AP increase in virus-mediated HCC cell death could be dependent on pathways specifically deregulated in HCC cells.

Bottom Line: Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus