Antiviral effects of pan-caspase inhibitors on the replication of coxsackievirus B3

Martin, Ulrike; Jarasch, Nadine; Nestler, Matthias; Rassmann, Alexander; Münder, Thomas; Seitz, Simone; Zell, Roland; Wutzler, Peter; Henke, Andreas

doi:10.1007/s10495-006-0015-y

Cited by 31 publications

(26 citation statements)

References 42 publications

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“…The first evidence that the pan-caspase inhibitor zVAD(OMe).fmk is also an inhibitor of proteolytic activity of 2A pro of rhinovirus 2 and coxsackievirus B4 was reported by Deszcz et al (27). In the case of coxsackievirus B3, both 2A and 3C proteases appeared to be suppressed by the drug (57). As far as cardioviruses are concerned, we reported preliminary data on the inhibition of EMCV protease 3C…”

Section: Discussionsupporting

confidence: 50%

Interactions between Viral and Prokaryotic Pathogens in a Mixed Infection with Cardiovirus and Mycoplasma

Lidsky

Romanova

Kolesnikova

et al. 2009

J Virol

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In the natural environment, animal and plant viruses often share ecological niches with microorganisms, but the interactions between these pathogens, although potentially having important implications, are poorly investigated. The present report demonstrates, in a model system, profound mutual effects of mycoplasma and cardioviruses in animal cell cultures. In contrast to mycoplasma-free cells, cultures contaminated with Mycoplasma hyorhinis responded to infection with encephalomyocarditis virus (EMCV), a picornavirus, but not with poliovirus (also a picornavirus), with a strong activation of a DNase(s), as evidenced by the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) immunofluorescence assay and electrophoretic analysis of host DNA. This degradation was reminiscent of that observed upon apoptosis but was caspase independent, judging by the failure of the specific pan-caspase inhibitor Q-VD-OPh to prevent it. The electrophoretic mobility of the enzyme responsible for DNA degradation and dependence of its activity on ionic conditions strongly suggested that it was represented by a DNase(s) of mycoplasma origin. In cells not infected with EMCV, the relevant DNase was dormant. The possibility is discussed that activation of the mycoplasma DNase might be linked to a relatively early increase in permeability of plasma membrane of the infected cells caused by EMCV. This type of unanticipated virus-mycoplasma "cooperation" may exemplify the complexity of pathogen-host interactions under conditions when viruses and microorganisms are infecting the same host. In the course of the present study, it was also demonstrated that pan-caspase inhibitor zVAD(OMe).fmk strongly suppressed cardiovirus polyprotein processing, illustrating an additional pitfall in investigations of viral effects on the apoptotic system of host cells.

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Section: Discussionsupporting

confidence: 50%

Interactions between Viral and Prokaryotic Pathogens in a Mixed Infection with Cardiovirus and Mycoplasma

Lidsky

Romanova

Kolesnikova

et al. 2009

J Virol

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“…Generally, a wide range of cancers are known to be resistant to apoptosis following chemotherapy (33). Thus, the ability of CVB3 to induce apoptosis is an attractive property for the treatments of refractory NSCLC (34,35). A role of PI3K/Akt signaling in accelerating CVB3 replication in NSCLC cells was also shown by use of cotreatment with a PTEN inhibitor and CVB3 infection (Fig.…”

Section: Discussionmentioning

confidence: 95%

Coxsackievirus B3 Is an Oncolytic Virus with Immunostimulatory Properties That Is Active against Lung Adenocarcinoma

et al. 2012

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Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacy is hampered by low tumor selectivity. To identify a potent and selective oncolytic virotherapy, we carried out large-scale two-step screening of 28 enteroviral strains and found that coxsackievirus B3 (CVB3) possessed specific oncolytic activity against nine human non-small cell lung cancer (NSCLC) cell lines. CVB3-mediated cytotoxicity was positively correlated with the expression of the viral receptors, coxsackievirus and adenovirus receptor, and decayaccelerating factor, on NSCLC cells. In vitro assays revealed that the CVB3 induced apoptosis and phosphoinositide 3-kinase/Akt and mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of preestablished NSCLC tumors in vivo. Furthermore, administrations of CVB3 into xenografts on the right flank resulted in significantly durable regression of uninjected xenografts on the left flank, where replication-competent CVB3 was detected. All treatments with CVB3 were well tolerated without treatment-related deaths. In addition, after CVB3 infection, NSCLC cells expressed abundant cell surface calreticulin and secreted ATP as well as translocated extranuclear high-mobility group box 1, which are required for immunogenic cell death. Moreover, intratumoral CVB3 administration markedly recruited natural killer cells and granulocytes, both of which contributed to the antitumor effects as shown by depletion assays, macrophages, and mature dendritic cells into tumor tissues. Together, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC. Cancer Res; 72(10); 2609-21. Ó2012 AACR.

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“…the trade-off between viral apoptosis-inducing and apoptosispreventing activities are not expected to be uniform either. In certain picornavirus/cell systems, the inhibition of apoptosis may adversely affect viral reproduction and/or externalization (32,65). In contrast, the yield of infectious L-deficient MV in HeLa cells was essentially unaffected by QVD, a caspase inhibitor.…”

Section: Apoptosis-triggering and Apoptosis-preventing Functions Of Cmentioning

confidence: 99%

Antiapoptotic Activity of the Cardiovirus Leader Protein, a Viral “Security” Protein

Romanova

Lidsky

Kolesnikova

et al. 2009

J Virol

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Apoptosis is a common antiviral defensive mechanism that potentially limits viral reproduction and spread. Many viruses possess apoptosis-suppressing tools. Here, we show that the productive infection of HeLa cells with encephalomyocarditis virus (a cardiovirus) was not accompanied by full-fledged apoptosis (although the activation of caspases was detected late in infection) but rather elicited a strong antiapoptotic state, as evidenced by the resistance of infected cells to viral and nonviral apoptosis inducers. The development of the antiapoptotic state appeared to depend on a function(s) of the viral leader (L) protein, since its mutational inactivation resulted in the efflux of cytochrome c from mitochondria, the early activation of caspases, and the appearance of morphological and biochemical signs of apoptosis in a significant proportion of infected cells. Infection with both wild-type and L-deficient viruses induced the fragmentation of mitochondria, which in the former case was not accompanied with cytochrome c efflux. Although the exact nature of the antiapoptotic function(s) of cardioviruses remains obscure, our results suggested that it includes previously undescribed mechanisms operating upstream and possibly downstream of the mitochondrial level, and that L is involved in the control of these mechanisms. We propose that cardiovirus L belongs to a class of viral proteins, dubbed here security proteins, whose roles consist solely, or largely, in counteracting host antidefenses. Unrelated L proteins of other picornaviruses as well as their highly variable 2A proteins also may be security proteins. These proteins appear to be independent acquisitions in the evolution of picornaviruses, implying multiple cases of functional (though not structural) convergence.

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Antiviral effects of pan-caspase inhibitors on the replication of coxsackievirus B3

Cited by 31 publications

References 42 publications

Interactions between Viral and Prokaryotic Pathogens in a Mixed Infection with Cardiovirus and Mycoplasma

Interactions between Viral and Prokaryotic Pathogens in a Mixed Infection with Cardiovirus and Mycoplasma

Coxsackievirus B3 Is an Oncolytic Virus with Immunostimulatory Properties That Is Active against Lung Adenocarcinoma

Antiapoptotic Activity of the Cardiovirus Leader Protein, a Viral “Security” Protein

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