Oncolytic adenoviral mutants induce a novel mode of programmed cell death in ovarian cancer

Baird, Sarah K.; Aerts, Joeri L.; Eddaoudi, Ayad; Lockley, Michelle; Lemoine, Nick R.; McNeish, Iain A.

doi:10.1038/sj.onc.1210977

Cited by 65 publications

(53 citation statements)

References 37 publications

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“…Our recent work argues against well-characterized modes of cell death, including apoptosis, autophagy, and necrosis (16). Based on the association of nuclear survivin with p53 and Bax expression (17), it was conceivable that nuclear survivin could predispose to apoptotic induction following infection.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent work argues that cytotoxicity induced by oncolytic adenoviruses does not involve the classic pathways of apoptosis, autophagy, and necrosis (16). Nuclear survivin is associated with p53 and Bax induction (17), and so, to assess whether nuclear survivin promotes apoptosis following viral infection, cells were infected with dl922-947 and caspase-3 activity measured in a fluorogenic tetrapeptide cleavage assay.…”

Section: Cancer Researchmentioning

confidence: 99%

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Nuclear Survivin Abrogates Multiple Cell Cycle Checkpoints and Enhances Viral Oncolysis

Connell

Wheatley

McNeish³

2008

Cancer Research

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Survivin (BIRC5) promotes cell division and survival with roles as chromosomal passenger protein and inhibitor of apoptosis protein (IAP). It is overexpressed in many cancers and is associated with resistance to chemotherapy and radiation. Previously, we showed that expression of survivin within the nucleus of HeLa cells accelerates its degradation and blocks apoptosis inhibition without affecting localization during mitosis. Here, we have investigated the effects of survivin on cell cycle control and potential therapeutic consequences using HeLa and IGROV1 cells expressing wildtype and nuclear-targeted survivin. We show that overexpression of survivin, especially within the nucleus, increases control over G 1 -S checkpoint via increased nuclear accumulation of cyclin D and cyclin-dependent kinase 4 and subsequent pRb phosphorylation. We investigated the influence of survivin on the activity of the E1A CR2-deleted oncolytic adenovirus dl922-947, which depends critically on an aberrant G 1 -S checkpoint. Nuclear expression of survivin augments virus-induced S-phase induction and increases viral protein expression and overall viral replication. There is a consequent increase in antitumor activity both in vitro and in vivo. The increased dl922-947 activity is restricted to malignant cells and is not associated with induction of apoptosis, nor does it rely on the role of survivin as an IAP. In addition, we observe the appearance of a large z4N population coincident with multiple mitotic defects in dl922-947-infected cells, both of which are significantly increased by nuclear survivin. This indicates that adenoviral activity is facilitated by abrogation of multiple cell cycle checkpoints and can be enhanced by expression of survivin within the nucleus.

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Section: Discussionmentioning

confidence: 99%

Section: Cancer Researchmentioning

confidence: 99%

Nuclear Survivin Abrogates Multiple Cell Cycle Checkpoints and Enhances Viral Oncolysis

Connell

Wheatley

McNeish³

2008

Cancer Research

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“…Multiple different Rb pathway abnormalities have been described in ovarian cancer (5,6), and, even in ovarian cancer cells that are readily infected with adenovirus serotype 5 (Ad5) vectors, there is huge variability in sensitivity to dl922-947-mediated cell death. In addition, the mechanisms by which oncolytic adenoviruses induce cell death in cancer cells remain unclear (7).…”

Section: Introductionmentioning

confidence: 99%

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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“…Several approaches to selectivity have been explored; for example, specifically retargeting viruses to cancer cells (2); linking virus replication to cancer-specific transcription factors such as telomerase (3) or prostate-specific antigen (4); and deleting viral genes for advancing cell cycle and/or preventing apoptosis, typically unnecessary for infecting cancer cells (1). An infected tumor cell is eventually killed by the oncolytic virus through several routes such as lysis, apoptosis, immune-modulated cell killing, or other forms of programmed cell death (5).…”

Section: Introductionmentioning

confidence: 99%

A Multiscale Mathematical Model for Oncolytic Virotherapy

et al. 2009

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One of the most promising strategies to treat cancer is attacking it with viruses. Oncolytic viruses can kill tumor cells specifically or induce anticancer immune response. A multiscale model for virotherapy of cancer is investigated through simulations. It was found that, for intratumoral virus administration, a solid tumor can be completely eradicated or keep growing after a transient remission. Furthermore, the model reveals undamped oscillatory dynamics of tumor cells and virus populations, which demands new in vivo and in vitro quantitative experiments aiming to detect this oscillatory response. The conditions for which each one of the different tumor responses dominates, as well as the occurrence probabilities for the other nondominant therapeutic outcomes, were determined. From a clinical point of view, our findings indicate that a successful, single agent virotherapy requires a strong inhibition of the host immune response and the use of potent virus species with a high intratumoral mobility. Moreover, due to the discrete and stochastic nature of cells and their responses, an optimal range for viral cytotoxicity is predicted because the virotherapy fails if the oncolytic virus demands either a too short or a very large time to kill the tumor cell. This result suggests that the search for viruses able to destroy tumor cells very fast does not necessarily lead to a more effective control of tumor growth.

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Oncolytic adenoviral mutants induce a novel mode of programmed cell death in ovarian cancer

Cited by 65 publications

References 37 publications

Nuclear Survivin Abrogates Multiple Cell Cycle Checkpoints and Enhances Viral Oncolysis

Nuclear Survivin Abrogates Multiple Cell Cycle Checkpoints and Enhances Viral Oncolysis

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

A Multiscale Mathematical Model for Oncolytic Virotherapy

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