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Temozolomide renders murine cancer cells susceptible to oncolytic adenovirus replication and oncolysis.

ABSTRACT: The preclinical evaluation of oncolytic adenoviruses (OAds) has been limited to cancer xenograft mouse models because OAds replicate poorly in murine cancer cells. The alkylating agent temozolomide (TMZ) has been shown to enhance oncolytic virotherapy in human cancer cells; therefore, we investigated whether TMZ could increase OAd replication and oncolysis in murine cancer cells. To test our hypothesis, three murine cancer cells were infected with OAd (E1b-deleted) alone or in combination with TMZ. TMZ increased OAd-mediated oncolysis in all three murine cancer cells tested. This increased oncolysis was, at least in part, due to productive virus replication, apoptosis, and autophagy induction. Most importantly, murine lung non-cancerous cells were not affected by OAd+TMZ. Moreover, TMZ increased Ad transduction efficiency. However, TMZ did not increase coxsackievirus and adenovirus receptor; therefore, other mechanism could be implicated on the transduction efficiency. These results showed, for the first time, that TMZ could render murine tumor cells more susceptible to oncolytic virotherapy. The proposed combination of OAds with TMZ presents an attractive approach towards the evaluation of OAd potency and safety in syngeneic mouse models using these murine cancer cell-lines in vivo.

SUBMITTER: Garza-Morales R

PROVIDER: S-EPMC5836815 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Temozolomide renders murine cancer cells susceptible to oncolytic adenovirus replication and oncolysis.

Garza-Morales Rodolfo R Yaddanapudi Kavitha K Perez-Hernandez Rigoberto R Riedinger Eric E McMasters Kelly M KM Shirwan Haval H Yolcu Esma E Montes de Oca-Luna Roberto R Gomez-Gutierrez Jorge G JG

Cancer biology & therapy 20180122 3

The preclinical evaluation of oncolytic adenoviruses (OAds) has been limited to cancer xenograft mouse models because OAds replicate poorly in murine cancer cells. The alkylating agent temozolomide (TMZ) has been shown to enhance oncolytic virotherapy in human cancer cells; therefore, we investigated whether TMZ could increase OAd replication and oncolysis in murine cancer cells. To test our hypothesis, three murine cancer cells were infected with OAd (E1b-deleted) alone or in combination with T ...[more]

PMID: 29252087

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Project description:BackgroundOncolytic viruses are currently experiencing accelerated development in several laboratories worldwide, with some forty-seven clinical trials currently recruiting. Many oncolytic viruses combine targeted cytotoxicity to cancer cells with a proinflammatory cell lysis. Due to their additional potential to express immunomodulatory transgenes, they are also often known as oncolytic viral vaccines. However, several types of oncolytic viruses are human-specific and the lack of suitable immune-competent animal models complicates biologically relevant evaluation of their vaccine potential. This is a particular challenge for group B adenoviruses, which fail to infect even those immunocompetent animal model systems identified as semi-permissive for type 5 adenovirus. Here, we aim to develop a murine cell line capable of supporting replication of a group B oncolytic adenovirus, enadenotucirev (EnAd), for incorporation into a syngeneic immunocompetent animal model to explore the oncolytic vaccine potential of group B oncolytic viruses.MethodsTransgenic murine cell lines were infected with EnAd expressing GFP transgene under replication-independent or -dependent promoters. Virus mRNA expression, genome replication, and late protein expression were determined by qRT-PCR, qPCR, and immunoblotting, respectively. We also use Balb/c immune-competent mice to determine the tumourogenicity and infectivity of transgenic murine cell lines.ResultsOur results show that a broad range of human carcinoma cells will support EnAd replication, but not murine carcinoma cells. Murine cells can be readily modified to express surface human CD46, one of the receptors for group B adenoviruses, allowing receptor-mediated uptake of EnAd particles into the murine cells and expression of CMV promoter-driven transgenes. Although the early E1A mRNA was expressed in murine cells at levels similar to human cells, adenovirus E2B and Fibre mRNA expression levels were hampered and few virus genomes were produced. Unlike previous reports on group C adenoviruses, trans-complementation of group B adenoviruses by co-infection with mouse adenovirus 1 did not rescue replication. A panel of group B adenoviruses expressing individual mouse adenovirus 1 genes were also unable to rescue EnAd replication.ConclusionTogether, these results indicate that there may be major differences in the early stages of replication of group C and B adenoviruses in murine cells, and that the block to the life cycle of B adenoviruses in murine cells occurs in the early stage of virus replication, perhaps reflecting poor activity of Ad11p E1A in murine cells.

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Temozolomide renders murine cancer cells susceptible to oncolytic adenovirus replication and oncolysis.

Publications

Temozolomide renders murine cancer cells susceptible to oncolytic adenovirus replication and oncolysis.

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