title: The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-beta-mediated antiviral activity in vitro and in vivo.
abstract: The 2009 outbreak of pandemic H1N1 influenza, increased drug resistance, and the significant delay in obtaining adequate numbers of vaccine doses have heightened awareness of the need to develop new antiviral drugs that can be used prophylactically or therapeutically. Previously, we showed that the experimental anti-tumor drug DMXAA potently induced IFN-β but relatively low TNF-α expression in vitro. This study confirms these findings in vivo and demonstrates further that DMXAA induces potent antiviral activity in vitro and in vivo. In vitro, DMXAA protected RAW 264.7 macrophage-like cells from VSV-induced cytotoxicity and moreover, inhibited replication of influenza, including the Tamiflu®-resistant H1N1 influenza A/Br strain, in MDCK cells. In vivo, DMXAA protected WT C57BL/6J but not IFN-β(-/-) mice from lethality induced by the mouse-adapted H1N1 PR8 influenza strain when administered before or after infection. Protection was accompanied by mitigation of weight loss, increased IFN-β mRNA and protein levels in the lung, and significant inhibition of viral replication in vivo early after DMXAA treatment. Collectively, this study provides data to support the use of DMXAA as a novel antiviral agent.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.forename: Quan M
authors.initials: QM
authors.lastname: Nhu
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Yim
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Roberts
authors.forename: John R
authors.initials: JR
authors.lastname: Teijaro
authors.forename: Donna L
authors.initials: DL
authors.lastname: Farber
authors.forename: Jorge C
authors.initials: JC
authors.lastname: Blanco
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000502:physiology; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D053139:Oseltamivir / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D018116:Vesiculovirus / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D044004:Xanthones / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D008070:Lipopolysaccharides; D020011:Protective Agents; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C066668:vadimezan; D053139:Oseltamivir; D016899:Interferon-beta