Antiviral activity and RNA polymerase degradation following Hsp90 inhibition in a range of negative strand viruses

Connor, John H.; McKenzie, Margie O.; Parks, Griffith D.; Lyles, Douglas S.

doi:10.1016/j.virol.2006.12.026

Cited by 134 publications

(144 citation statements)

References 39 publications

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“…There was significant decrease in colony formation in MV-CEA/GA group as compared to either single-agent MV-CEA alone at comparable MOIs, or single-agent GA (30 nM) in both cell lines, indicating that combination treatment significantly increases the antitumor effect of MV-CEA virotherapy. The IC 50 for MD-MB231 cells and SK0V3.IP cells treated with MV-CEA/GA were MOIs of 0.20 and 0.34, respectively, whereas MV-CEA alone did not achieve an IC 50 in either cell line up to the MOIs tested.…”

Section: Mv-cea/ga Combination Treatment Increased Antitumor Effect Imentioning

confidence: 87%

“…The latter has been associated with suppression of replication of RNA viruses such as HCV 49 and paramyxoviruses. 50 Heat shock protein inhibitor/measles virus combination treatment could have additional advantages, since HSP70 induction in the tumor environment by GA or other heat shock protein inhibitors has the potential to result in augmentation of antitumoral immune response. HSP70 induction has been shown to increase lysability of tumor cells by cytotoxic T lymphocytes, without interfering with MHC class I expression and antigen presentation.…”

Section: Combining Measles Virus With Heat Shock Protein Inhibitors Cmentioning

confidence: 99%

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Heat shock protein inhibitors increase the efficacy of measles virotherapy

Liu

Erlichman

et al. 2008

Gene Ther

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Oncolytic measles virus strains have activity against multiple tumor types and are currently in phase I clinical testing. Induction of the heat shock protein 70 (HSP70) constitutes one of the earliest changes in cellular gene expression following infection with RNA viruses including measles virus, and HSP70 upregulation induced by heat shock has been shown to result in increased measles virus cytotoxicity. HSP90 inhibitors such as geldanamycin (GA) or 17-allylaminogeldanamycin result in pharmacologic upregulation of HSP70 and they are currently in clinical testing as cancer therapeutics. We therefore investigated the hypothesis that heat shock protein inhibitors could augment the measles virus-induced cytopathic effect. We tested the combination of a measles virus derivative expressing soluble human carcinoembryonic antigen (MV-CEA) and GA in MDA-MB-231 (breast), SKOV3.IP (ovarian) and TE671 (rhabdomyosarcoma) cancer cell lines. Optimal synergy was accomplished when GA treatment was initiated 6-24 h following MV infection. Western immunoblotting confirmed HSP70 upregulation in combination-treated cells. Combination treatment resulted in statistically significant increase in syncytia formation as compared to MV-CEA infection alone. Clonogenic assays demonstrated significant decrease in tumor colony formation in MV-CEA/GA combination-treated cells. In addition there was increase in apoptosis by 4,6-diamidino-2-phenylindole staining. Western immunoblotting for caspase-9, caspase-8, caspase-3 and poly(ADP-ribose) polymerase (PARP) demonstrated increase in cleaved caspase-8 and PARP. The pan-caspase inhibitor Z-VAD-FMK and caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9 inhibitor Z-IEHD-FMK, protected tumor cells from MV-CEA/GA-induced PARP activation, indicating that apoptosis in combinationtreated cells occurs mainly via the extrinsic caspase pathway. Treatment of normal cells, such as normal human fibroblasts, however, with the MV-CEA/GA combination, did not result in cytopathic effect, indicating that GA did not alter the MV-CEA specificity for tumor cells. One-step viral growth curves, western immunoblotting for MV-N protein expression, QRT-PCR quantitation of MV-genome copy number and CEA levels showed comparable proliferation of MV-CEA in GAtreated vs -untreated tumor cells. Rho activation assays and western blot for total RhoA, a GTPase associated with the actin cytoskeleton, demonstrated decrease in RhoA activation in combination-treated cells, a change previously shown to be associated with increase in paramyxovirus-induced cell-cell fusion. The enhanced cytopathic effect resulting from measles virus/GA combination supports the translational potential of this approach in the treatment of cancer.

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Section: Mv-cea/ga Combination Treatment Increased Antitumor Effect Imentioning

confidence: 87%

Section: Combining Measles Virus With Heat Shock Protein Inhibitors Cmentioning

confidence: 99%

Heat shock protein inhibitors increase the efficacy of measles virotherapy

Liu

Erlichman

et al. 2008

Gene Ther

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“…Hsp90 has been believed to facilitate viral protein folding and activity of non-structural proteins such as polymerase, protease and helicase as well as the structural proteins [3]. The polymerase of several viruses require Hsp90 for genome replication which include influenza virus A [12], herpes simplex virus [26], flock house virus [27] and vesicular stomatitis virus and treatment with Hsp90 inhibitors such as geldanamycin and 17-AAG lead to degradation of polymerase complexes [28,22].…”

Section: Discussionmentioning

confidence: 99%

Antiviral evaluation of an Hsp90 inhibitor, gedunin, against dengue virus

Amraiz¹,

Zaidi²,

Fatima³

2017

Trop. J. Pharm Res

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“…Knockdown and treatment with an Hsp90 inhibitor have revealed that Hsp90 activity is important for the rapid growth of negative-strand RNA viruses (9). Furthermore, Hsp90 has been shown to be required for the activity of hepatitis B virus reverse transcriptase (21,22).…”

Section: Discussionmentioning

confidence: 99%

Human Butyrate-Induced Transcript 1 Interacts with Hepatitis C Virus NS5A and Regulates Viral Replication

Taguwa

Okamoto

Abe

et al. 2008

J Virol

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Hepatitis C virus (HCV) infects approximately 170 million people worldwide and induces serious chronic hepatitis that results in steatosis, cirrhosis, and ultimately hepatocellular carcinoma (7, 64). More than two-thirds of the HCV-positive population in Western countries and Japan face chronic infection by genotypes 1a and 1b. The current combination therapy using pegylated alpha interferon (IFN) plus ribavirin has achieved a sustained virological response in 50% of individuals infected with HCV genotypes 1a and 1b (37,53).HCV belongs to the genus Hepacivirus of the family Flaviviridae and has a single-stranded, positive-sense RNA genome of approximately 9.6 kb, encoding a large polyprotein composed of approximately 3,000 amino acid residues. The polyprotein is cleaved by host and viral proteases, resulting in viral structural proteins (core, E1, and E2), a putative ion channel-forming protein (p7), and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (40, 55). Highly structured untranslated regions are flanked at both the 5Ј and 3Ј ends of the open reading frame. The initiation of translation of the viral RNA is dependent on an internal ribosome entry site (IRES) localized in the 5Ј untranslated region (28, 58).The HCV RNA is suggested to replicate in a replication complex composed of the viral nonstructural proteins and several host proteins. An HCV replicon system established as a representative functional system was composed of an antibiotic gene for selection and HCV genomic RNA for autonomous replication in the intracellular compartments of human hepatoma cell line Huh7 without production of infectious particles (34). Recently, cell culture systems for production of an infectious HCV have been established based on HCV genotype 2a (32,62,74). Furthermore, a mouse model consisting of an immunodeficient mouse xenotransplanted with human liver fragments has been established for the study of in vivo replication of HCV (38). These in vitro and in vivo systems have enabled us to investigate the life cycle of HCV and to develop antiviral drugs for chronic hepatitis C.NS5A is a phosphoprotein that possesses multiple functions in viral replication, IFN resistance, and pathogenesis (35). Adaptive mutations to increase RNA replication are frequently mapped to the coding region of NS5A, indicating that NS5A is critical for HCV replication (1, 71). NS5A has been shown to be associated with a range of cellular proteins involved in cellular signaling pathways, such as IFN-induced kinase PKR (14), growth factor receptor-binding protein 2 (Grb2) (56), p53 (36,48), and the phosphoinositide-3-kinase p85 subunit (18), and with proteins involved in protein trafficking and membrane morphology, such as karyopherin b3 (8), apolipoprotein A1 (52), amphiphysin II (73), F-box and leucine-rich repeat protein 2 (FBL2) (26,63,70), and vesicleassociated membrane protein-associated protein subtype A (VAP-A) (59). We have previously reported that the host proteins VAP-B and FKBP8, a member of the FK506-binding protein (FKBP) ...

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Antiviral activity and RNA polymerase degradation following Hsp90 inhibition in a range of negative strand viruses

Cited by 134 publications

References 39 publications

Heat shock protein inhibitors increase the efficacy of measles virotherapy

Heat shock protein inhibitors increase the efficacy of measles virotherapy

Antiviral evaluation of an Hsp90 inhibitor, gedunin, against dengue virus

Human Butyrate-Induced Transcript 1 Interacts with Hepatitis C Virus NS5A and Regulates Viral Replication

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