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The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulates an antiviral state and protects mice against herpes simplex virus-induced neurological disease.

ABSTRACT: Herpes simplex virus (HSV)-?1 is the most common cause of sporadic viral encephalitis and accounts for 5-10% of cases worldwide. A key factor in host control of viral infection is the initiation of the interferon (IFN) response, mediated in part by the stimulator of interferon genes (STING) pathway. In these studies, we examined the ability of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a STING agonist, to protect against HSV-1 infection. DMXAA reduced viral replication through increased production of type I IFN in vitro. Furthermore, administration of DMXAA to HSV-1 infected mice resulted in a reduction of viral burden in the peripheral and central nervous systems. This reduced viral burden also correlated with increased survival of DMXAA-treated infected mice. These results therefore demonstrate the potential of STING agonists for immunotherapy against HSV-1.

SUBMITTER: Ceron S

PROVIDER: S-EPMC6382592 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulates an antiviral state and protects mice against herpes simplex virus-induced neurological disease.

Cerón Stacey S North Brian J BJ Taylor Sean A SA Leib David A DA

Virology 20190106

Herpes simplex virus (HSV)- 1 is the most common cause of sporadic viral encephalitis and accounts for 5-10% of cases worldwide. A key factor in host control of viral infection is the initiation of the interferon (IFN) response, mediated in part by the stimulator of interferon genes (STING) pathway. In these studies, we examined the ability of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a STING agonist, to protect against HSV-1 infection. DMXAA reduced viral replication through increased produ ...[more]

PMID: 30648635

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Project description:5,6-Dimethylxanthenone 4-acetic acid (DMXAA), also known as ASA404 and vadimezan, is a potent tumor blood vessel-disrupting agent and cytokine inducer used alone or in combination with other cytotoxic agents for the treatment of non-small cell lung cancer (NSCLC) and other cancers. However, the latest Phase III clinical trial has shown frustrating outcomes in the treatment of NSCLC, since the therapeutic targets and underlying mechanism for the anticancer effect of DMXAA are not yet fully understood. This study aimed to examine the proteomic response to DMXAA and unveil the global molecular targets and possible mechanisms for the anticancer effect of DMXAA in NSCLC A549 cells using a stable-isotope labeling by amino acids in cell culture (SILAC) approach. The proteomic data showed that treatment with DMXAA modulated the expression of 588 protein molecules in A549 cells, with 281 protein molecules being up regulated and 306 protein molecules being downregulated. Ingenuity pathway analysis (IPA) identified 256 signaling pathways and 184 cellular functional proteins that were regulated by DMXAA in A549 cells. These targeted molecules and signaling pathways were mostly involved in cell proliferation and survival, redox homeostasis, sugar, amino acid and nucleic acid metabolism, cell migration, and invasion and programed cell death. Subsequently, the effects of DMXAA on cell cycle distribution, apoptosis, autophagy, and reactive oxygen species (ROS) generation were experimentally verified. Flow cytometric analysis showed that DMXAA significantly induced G1 phase arrest in A549 cells. Western blotting assays demonstrated that DMXAA induced apoptosis via a mitochondria-dependent pathway and promoted autophagy, as indicated by the increased level of cytosolic cytochrome c, activation of caspase 3, and enhanced expression of beclin 1 and microtubule-associated protein 1A/1B-light chain 3 (LC3-II) in A549 cells. Moreover, DMXAA significantly promoted intracellular ROS generation in A549 cells. Collectively, this SILAC study quantitatively evaluates the proteomic response to treatment with DMXAA that helps to globally identify the potential molecular targets and elucidate the underlying mechanism of DMXAA in the treatment of NSCLC.

Dataset Information

The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulates an antiviral state and protects mice against herpes simplex virus-induced neurological disease.

Publications

The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulates an antiviral state and protects mice against herpes simplex virus-induced neurological disease.

Similar Datasets

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