p21 promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker

Flak, Magdalena B.; Connell, Claire M.; Chelala, Claude; Archibald, Kyra M; Salako, Michael A.; Pirlo, Katrina; Lockley, Michelle; Wheatley, Sally P.; Balkwill, Frances R.; McNeish, Iain A.

doi:10.1186/1476-4598-9-175

Cited by 19 publications

(22 citation statements)

References 52 publications

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“…These data indicated that p21 expression was associated with adenoviral E1A mediated antitumor activity. Although there were publications showed that p21 expression reduced oncolytic adenovirus activity in tumor cells [29], our data was identical with the reports that p21 overexpression appeared an important factor in elevating anti-tumor activity mediated by adenoviral E1A [30]. …”

Section: Discussionsupporting

confidence: 91%

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

et al. 2016

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The conserved regions (CR) of adenoviral E1A had been shown to be necessary for disruption of pRb-E2F transcription factor complexes and induction of the S phase. Here we constructed a mutant adenoviral E1A with Rb-binding ability absent (E1A 30-60aa and 120-127aa deletion, mE1A) and investigated its antitumor capacities in vitro and in vivo. The mE1A suppressed the viability of tumor cells as efficiently as the wild type E1A, and there was no cytotoxic effect on normal cells. Although the mE1A arrested tumor cell cycle with the same manner as E1A, the former played a different role on cell cycle regulation compared with E1A in normal cells, which might contribute to its selective antitumor activity. E1A and mE1A had accumulated inactive p53, decreased the expression of mdm2, Cdkn1a (also named p21), increased p21's nuclear distribution and induced tumor cell apoptosis in a p53-indenpent manner. Further, E1A or mE1A significantly suppressed tumor growth in subcutaneous hepatocellular carcinoma xenograft models. Especially, tumor-bearing mice treated with mE1A had higher survival rate than those treated with E1A. Our data demonstrated that mutant adenoviral E1A significantly induced tumor cell apoptosis in a p53-indenpednt manner and had selective tumor suppressing ability. The observations of adenoviral E1A mutant had provided a novel mechanism for E1A's complex activities during infection.

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Section: Discussionsupporting

confidence: 91%

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

et al. 2016

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“…The sensitivity of cancer cell lines to the oncolytic adenovirus dl922-947 varies considerably, even in cells with similar infectivity (8). TOV21G, IGROV1, and A2780CP are 3 ovarian cancer cell lines that cover a range of sensitivities, with IC 50 values varying over 3 log scales ( Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…We have recently demonstrated that expression of p21 in ovarian cancer is a marker for a host cell environment conducive to the expression of E1A (8). E1A is the first viral gene to be expressed after infection, and its expression correlates with cellular sensitivity.…”

Section: Figurementioning

confidence: 99%

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Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

Connell¹,

Shibata²,

Tookman³

et al. 2011

J. Clin. Invest.

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Oncolytic adenoviruses replicate selectively within and lyse malignant cells. As such, they are being developed as anticancer therapeutics. However, the sensitivity of ovarian cancers to adenovirus cytotoxicity varies greatly, even in cells of similar infectivity. Using both the adenovirus E1A-CR2 deletion mutant dl922-947 and WT adenovirus serotype 5 in a panel of human ovarian cancer cell lines that cover a 3-log range of sensitivity, we observed profound overreplication of genomic DNA only in highly sensitive cell lines. This was associated with the presence of extensive genomic DNA damage. Inhibition of ataxia telangiectasia and Rad3-related checkpoint kinase 1 (ATR-Chk1), but not ataxia telangiectasia mutated (ATM), promoted genomic DNA damage and overreplication in resistant and partially sensitive cells. This was accompanied by increased adenovirus cytotoxicity both in vitro and in vivo in tumor-bearing mice. We also demonstrated that Cdc25A was upregulated in highly sensitive ovarian cancer cell lines after adenovirus infection and was stabilized after loss of Chk1 activity. Knockdown of Cdc25A inhibited virus-induced DNA damage in highly sensitive cells and blocked the effects of Chk1 inhibition in resistant cells. Finally, inhibition of Chk1 decreased homologous recombination repair of virus-induced genomic DNA double-strand breaks. Thus, virus-induced host cell DNA damage signaling and repair are key determinants of oncolytic adenoviral activity, and promoting unscheduled DNA synthesis and/or impeding homologous recombination repair could potentiate the effects of oncolytic adenoviruses in the treatment of ovarian cancer.

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“…Another oncolytic virus (vesicular stomatitis virus) as well as HDAC inhibitors showed synergistic interaction by dampening the innate immunity towards the oncolytic virus (13,19). In another report, transfection of p21 promoted oncolytic adenoviral activity in ovarian cancer by increasing E1A expression (20).…”

Section: Introductionmentioning

confidence: 96%

Combination therapy of conditionally replicating adenovirus and histone deacetylase inhibitors

Lee¹

2011

Int J Mol Med

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Abstract. Combination therapy of adenoviral gene therapy and a histone deacetylase (HDAC) inhibitor is important due to the enhancing effect of HDAC inhibitors on adenoviral transduction and transcription. However, contradictory results have been reported on the effect of combination of CRAd (conditionally replicating adenovirus) and HDAC inhibitors. This study was designed to investigate the interaction of CRAd and HDAC inhibitors and determine the ideal way to combine the two agents. Combination of HDAC inhibitors (SK7041, SBHA and vorinostat) at pre-and post-transductional periods with CRAd enhanced the transduction of CRAd and expression of luciferase expression from Δ24-luc in vitro. However, suppression of luciferase expression from Δ24-luc injected tumor mass was observed by in vivo tumor bioluminescence imaging and drug interaction analysis also showed an antagonistic interaction that was probably related with the inhibitory effect of the HDAC inhibitor on adenoviral replication. Suppression of p21 induction by p21 siRNA reversed the suppressive effect of vorinostat on the replication of CRAd, but still failed to reverse the antagonistic interaction. Addition of vorinostat at the pre-transductional period revealed an improvement in the transduction efficiency of CRAd and also induced a synergistic interaction between CRAd and vorinostat, which was possibly related with prevention of the suppressive effect of vorinostat on adenoviral replication. In conclusion, the addition of HDAC inhibitor before CRAd injection showed synergistic antitumor effects, which warrants further investigation on the sequence of HDAC inhibitor and CRAd treatment in an animal tumor model.

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p21 promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker

Cited by 19 publications

References 52 publications

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

Combination therapy of conditionally replicating adenovirus and histone deacetylase inhibitors

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