Differential sensitivity of normal and transformed human cells to reovirus infection

Duncan, Michael R.; Stanish, Sandra M.; Çox, Donald C.

doi:10.1128/jvi.28.2.444-449.1978

Cited by 130 publications

(59 citation statements)

References 18 publications

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“…Reovirus has an inherent preference to replicate in tumor cells, making it ideally suited for use in oncolytic therapy (15, 16). Reovirus can be delivered to patients via intratumoral and intravenous administration and can be effective in combination therapy (14).…”

Section: Discussionmentioning

confidence: 99%

“…Reovirus can be delivered to patients via intratumoral and intravenous administration and can be effective in combination therapy (14). Reovirus has an inherent preference to replicate in tumor cells, making it ideally suited for use in oncolytic virotherapies (15, 16). However, the cellular and viral factors that promote preferential reovirus infection of cancer cells are not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Stewart

Berry

Berger

et al. 2019

Preprint

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20Breast cancer is the second-leading cause of cancer-related deaths in women in the 21 United States. Triple-negative breast cancer constitutes a subset of breast cancer that is 22 Importance 38Patients afflicted by triple-negative breast cancer have decreased survival and limited 39 therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is 40 unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, 41 we generated two novel reoviruses that more efficiently infect and kill triple-negative breast 42 cancer cells. We show that infection in the presence of DNA-damaging agents enhances 43 infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a 44 combination of a genetically engineered oncolytic reovirus and topoisomerase inhibitors may 45 provide a potent therapeutic option for patients afflicted with triple-negative breast cancer. 46 47Breast cancer is the leading cause of cancer and second leading cause of deaths by cancer 48 in women in the United States (1). Triple-negative breast cancer (TNBC) constitutes 49 approximately 15% of breast cancers, has a higher rate of relapse, and shorter overall survival 50 after metastasis than other subtypes of breast cancer (2). TNBC more frequently affects the 51 young, is more prevalent in African American women, and tumors are larger in size and 52 biologically more aggressive (3). TNBC is characterized by the lack of expression of estrogen 53 receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 54 (HER2/neu) and can be classified into seven subtypes based on their genetic signature (3). 55

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Stewart

Berry

Berger

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Reoviruses are double-stranded RNA viruses that replicate preferentially in transformed cell lines but not in normal cells. (52)(53)(54) In theory, oncolytic properties of reovirus depend on activated Ras signaling. (55,56) Reolysin is the T3D strain of reovirus, which has been most extensively studied among several serotypes as an anticancer agent, and is currently the only therapeutic wild-type reovirus in clinical development.…”

Section: Naturally Occurring Oncolytic Virusesmentioning

confidence: 99%

Oncolytic virus therapy: A new era of cancer treatment at dawn

2016

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Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T‐Vec (talimogene laherparepvec), a second‐generation oncolytic herpes simplex virus type 1 (HSV‐1) armed with GM‐CSF, was recently approved as the first oncolytic virus drug in the USA and Europe. The phase III trial proved that local intralesional injections with T‐Vec in advanced malignant melanoma patients can not only suppress the growth of injected tumors but also act systemically and prolong overall survival. Other oncolytic viruses that are closing in on drug approval in North America and Europe include vaccinia virus JX‐594 (pexastimogene devacirepvec) for hepatocellular carcinoma, GM‐CSF‐expressing adenovirus CG0070 for bladder cancer, and Reolysin (pelareorep), a wild‐type variant of reovirus, for head and neck cancer. In Japan, a phase II clinical trial of G47∆, a third‐generation oncolytic HSV‐1, is ongoing in glioblastoma patients. G47∆ was recently designated as a “Sakigake” breakthrough therapy drug in Japan. This new system by the Japanese government should provide G47∆ with priority reviews and a fast‐track drug approval by the regulatory authorities. Whereas numerous oncolytic viruses have been subjected to clinical trials, the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor‐specific viral replication. It appears that it will not be long before oncolytic virus therapy becomes a standard therapeutic option for all cancer patients.

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“…Reoviruses infect most mammalian species, and although most humans are exposed to reovirus during childhood, infection seldom results in disease (1,2). Reovirus infects primary and transformed cells in culture, although infection of transformed cells is more efficient (3)(4)(5). Infection of host cells by reovirus results in cell death via caspasedependent and caspase-independent pathways (6)(7)(8).…”

Section: -Nt) Impairs Reovirus Infection By Altering Viral Transportmentioning

confidence: 99%

Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry

Mainou

Smith

Dorset

et al. 2015

J Virol

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Mammalian orthoreoviruses (reoviruses) are nonenveloped double-stranded RNA viruses that infect most mammalian species, including humans. Reovirus binds to cell surface glycans, junctional adhesion molecule A (JAM-A), and the Nogo-1 receptor (depending on the cell type) and enters cells by receptor-mediated endocytosis. Within the endocytic compartment, reovirus undergoes stepwise disassembly, which is followed by release of the transcriptionally active viral core into the cytoplasm. In a small-molecule screen to identify host mediators of reovirus infection, we found that treatment of cells with 5-nonyloxytryptamine (5-NT), a prototype serotonin receptor agonist, diminished reovirus cytotoxicity. 5-NT also blocked reovirus infection. In contrast, treatment of cells with methiothepin mesylate, a serotonin antagonist, enhanced infection by reovirus. 5-NT did not alter cell surface expression of JAM-A or attachment of reovirus to cells. However, 5-NT altered the distribution of early endosomes with a concomitant impairment of reovirus transit to late endosomes and a delay in reovirus disassembly. Consistent with an inhibition of viral disassembly, 5-NT treatment did not alter infection by in vitro-generated infectious subvirion particles, which bind to JAM-A but bypass a requirement for proteolytic uncoating in endosomes to infect cells. We also found that treatment of cells with 5-NT decreased the infectivity of alphavirus chikungunya virus and coronavirus mouse hepatitis virus. These data suggest that serotonin receptor signaling influences cellular activities that regulate entry of diverse virus families and provides a new, potentially broad-spectrum target for antiviral drug development. IMPORTANCEIdentification of well-characterized small molecules that modulate viral infection can accelerate development of antiviral therapeutics while also providing new tools to increase our understanding of the cellular processes that underlie virus-mediated cell injury. We conducted a small-molecule screen to identify compounds capable of inhibiting cytotoxicity caused by reovirus, a prototype double-stranded RNA virus. We found that 5-nonyloxytryptamine (5-NT) impairs reovirus infection by altering viral transport during cell entry. Remarkably, 5-NT also inhibits infection by an alphavirus and a coronavirus. The antiviral properties of 5-NT suggest that serotonin receptor signaling is an important regulator of infection by diverse virus families and illuminate a potential new drug target. A s obligate intracellular pathogens, viruses exploit broadly conserved cellular processes to internalize, replicate, assemble, and release to infect adjacent cells and tissues. To counteract viral infection, hosts have evolved a variety of innate and adaptive immune mechanisms that antagonize these viral replication steps. Understanding host components that regulate the outcome of viral infection can uncover previously overlooked cellular pathways that might serve as new targets for antiviral therapeutics and enhance design of v...

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Differential sensitivity of normal and transformed human cells to reovirus infection

Cited by 130 publications

References 18 publications

Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Oncolytic virus therapy: A new era of cancer treatment at dawn

Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry

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