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Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment.

ABSTRACT: Glioblastoma (GBM) is the most aggressive among the neurological tumors. At present, no chemotherapy or radiotherapy regimen is associated with a positive long-term outcome. In the majority of cases, the tumor recurs within 32-36 weeks of initial treatment. The recent discovery that Zika virus (ZIKV) has an oncolytic action against GBM has brought hope for the development of new therapeutic approaches. ZIKV is an arbovirus of the Flaviviridae family, and its infection during development has been associated with central nervous system (CNS) malformations, including microcephaly, through the targeting of neural stem/progenitor cells (NSCs/NPCs). This finding has led various groups to evaluate ZIKV's effects against glioblastoma stem cells (GSCs), supposedly responsible for GBM onset, progression, and therapy resistance. While preliminary data support ZIKV tropism toward GSCs, a more accurate study of ZIKV mechanisms of action is fundamental in order to launch ZIKV-based clinical trials for GBM patients.

SUBMITTER: Francipane MG

PROVIDER: S-EPMC8537796 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment.

Francipane Maria Giovanna MG Douradinha Bruno B Chinnici Cinzia Maria CM Russelli Giovanna G Conaldi Pier Giulio PG Iannolo Gioacchin G

International journal of molecular sciences 20211012 20

Glioblastoma (GBM) is the most aggressive among the neurological tumors. At present, no chemotherapy or radiotherapy regimen is associated with a positive long-term outcome. In the majority of cases, the tumor recurs within 32-36 weeks of initial treatment. The recent discovery that Zika virus (ZIKV) has an oncolytic action against GBM has brought hope for the development of new therapeutic approaches. ZIKV is an arbovirus of the <i>Flaviviridae</i> family, and its infection during development h ...[more]

PMID: 34681654

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Project description:Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute to tumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we investigated the safety and efficacy of a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a GSC-derived orthotopic model. Intracerebral injection of ZIKV-LAV into mice caused no neurological symptoms or behavioral abnormalities. The neurovirulence of ZIKV-LAV was more attenuated than that of the licensed Japanese encephalitis virus LAV 14-14-2, underlining the superior safety of ZIKV-LAV for potential GBM treatment. Importantly, ZIKV-LAV significantly reduced intracerebral tumor growth and prolonged animal survival by selectively killing GSCs within the tumor. Mechanistically, ZIKV infection elicited antiviral immunity, inflammation, and GSC apoptosis. Together, these results further support the clinical development of ZIKV-LAV for GBM therapy.IMPORTANCE Glioblastoma (GBM), the deadliest type of brain tumor, is currently incurable because of its high recurrence rate after traditional treatments, including surgery to remove the main part of the tumor and radiation and chemotherapy to target residual tumor cells. These treatments fail mainly due to the presence of a cell subpopulation called glioma stem cells (GSCs), which are resistant to radiation and chemotherapy and capable of self-renewal and tumorigenicity. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we tested a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a human GSC-derived orthotopic model. Our results showed that ZIKV-LAV retained good efficacy against glioblastoma by selectively killing GSCs within the tumor. In addition, ZIKV-LAV exhibited an excellent safety profile upon intracerebral injection into the treated animals. The good balance between the safety of ZIKV-LAV and its efficacy against human GSCs suggests that it is a potential candidate for combination with the current treatment regimen for GBM therapy.

Project description:BackgroundZika virus (ZIKV) infection is a global health problem, and its complications, including congenital Zika syndrome and Guillain-Barré syndrome, constitute a continued threat to humans. Unfortunately, effective therapeutics against ZIKV infection are not available thus far.MethodsWe screened the compounds collection consisting of 1789 FDA-approved drugs by a computational docking method to obtain anti-ZIKV candidate compounds targeting ZIKV RNA-dependent RNA polymerase (RdRp). SPR (BIAcore) assay was employed to demonstrate the candidate compounds' direct binding to ZIKV RdRp, and polymerase activity assay was used to determine the inhibitory effect on ZIKV RdRp-catalyzed RNA synthesis. The antiviral effects on ZIKV in vitro and in vivo were detected in infected cultured cells and in Ifnar1-/- mice infected by ZIKV virus using plaque assay, western blotting, tissue immunofluorescence, and immunohistochemistry.ResultsHere, we report that a first-in-class macrocyclic antibiotic, which has been clinically used to treat Clostridium difficile infection, fidaxomicin, potently inhibits ZIKV replication in vitro and in vivo. Our data showed that fidaxomicin was effective against African and Asian lineage ZIKV in a wide variety of cell lines of various tissue origins, and prominently suppressed ZIKV infection and significantly improved survival of infected mice. In addition, fidaxomicin treatment reduced the virus load in the brains and testes, and alleviated ZIKV-associated pathological damages, such as paralysis, hunching, and neuronal necrosis in the cerebra. Furthermore, our mechanistic study showed that fidaxomicin directly bound ZIKV NS5 protein and inhibited the RNA synthesis-catalyzing activity of ZIKV RdRp.ConclusionsOur data suggest that fidaxomicin may represent an effective anti-ZIKV agent. In the light that fidaxomicin is already a clinically used drug, there might be a promising prospect in the development of fidaxomicin to be an antiviral therapeutic.

Project description:The spread of Zika virus (ZIKV) infection across the USA and various countries in the last three years will not only have a direct impact on the U.S. health care system but has caused international concerns as well. The ultimate impact of ZIKV infection remains to be understood. Currently, there are no therapeutic or vaccine options available to protect those infected by ZIKV. The drug ivermectin (IVM) was found to be a viable agent for the prevention of transmission of ZIKV. Ivermectin is unstable in the presence of water and does not remain in adequate concentration in the human bloodstream to be effective in treatment for ZIKV. Biodegradable nanoparticles would aid in the delivery of ivermectin by providing a high enough concentration of drug and ensuring the drug is gradually released to maintain an appropriate level in the body. The overall goal of this study was to develop and optimize an orally administrable nanoformulation of IVM which can circulate in the blood for a long period for efficient delivery. To achieve the goal, we synthesized and optimized a synthetic nanoformulation of IVM for oral use which can cross the intestinal epithelial barrier to enter the bloodstream. Our studies documented that when delivered with the synthetic nanoparticle (NP), IVM can be accumulated in the blood at a higher concentration and preliminary studies highlighted that NP delivered IVM has the ability to target nonstructural 1 protein of ZIKV. For potential clinical relevance, long-term storable formulation of IVM-nanoparticle in dry powder state for inclusion in a capsule form and cryoprotectant containing frozen forms revealed promising findings. Further, our preliminary in vitro studies documented that ivermectin crosses the placental barrier, thus making it unsafe for the pregnant ZIKV population, whereas the ivermectin-loaded nanoparticle did not show any significant placental barrier crossing, thus indicating its potential suitability for such population. We envision that this work will fill a great unmet need by developing safer and more effective therapies for the treatment of viral infections, including ZIKV.

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Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment.

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Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment.

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