Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model

Abstract Molecules from animal venoms are promising candidates for the development of new drugs. Previous in vitro studies have shown that the venom of the spider Phoneutria nigriventer (PnV) is a potential source of antineoplastic components with activity in glioblastoma (GB) cell lines. In the pre...

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Autores principales:	Amanda Pires Bonfanti, Natália Barreto, Jaqueline Munhoz, Marcus Caballero, Gabriel Cordeiro, Thomaz Rocha-e-Silva, Rafael Sutti, Fernanda Moura, Sérgio Brunetto, Celso Dario Ramos, Rodolfo Thomé, Liana Verinaud, Catarina Rapôso
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8f66ea68d0594f4aa29e67469b65a9d0
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id	oai:doaj.org-article:8f66ea68d0594f4aa29e67469b65a9d0
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amanda Pires Bonfanti Natália Barreto Jaqueline Munhoz Marcus Caballero Gabriel Cordeiro Thomaz Rocha-e-Silva Rafael Sutti Fernanda Moura Sérgio Brunetto Celso Dario Ramos Rodolfo Thomé Liana Verinaud Catarina Rapôso Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model
description	Abstract Molecules from animal venoms are promising candidates for the development of new drugs. Previous in vitro studies have shown that the venom of the spider Phoneutria nigriventer (PnV) is a potential source of antineoplastic components with activity in glioblastoma (GB) cell lines. In the present work, the effects of PnV on tumor development were established in vivo using a xenogeneic model. Human GB (NG97, the most responsive line in the previous study) cells were inoculated (s.c.) on the back of RAG−/− mice. PnV (100 µg/Kg) was administrated every 48 h (i.p.) for 14 days and several endpoints were evaluated: tumor growth and metabolism (by microPET/CT, using 18F-FDG), tumor weight and volume, histopathology, blood analysis, percentage and profile of macrophages, neutrophils and NK cells isolated from the spleen (by flow cytometry) and the presence of macrophages (Iba-1 positive) within/surrounding the tumor. The effect of venom was also evaluated on macrophages in vitro. Tumors from PnV-treated animals were smaller and did not uptake detectable amounts of 18F-FDG, compared to control (untreated). PnV-tumor was necrotic, lacking the histopathological characteristics typical of GB. Since in classic chemotherapies it is observed a decrease in immune response, methotrexate (MTX) was used only to compare the PnV effects on innate immune cells with a highly immunosuppressive antineoplastic drug. The venom increased monocytes, neutrophils and NK cells, and this effect was the opposite of that observed in the animals treated with MTX. PnV increased the number of macrophages in the tumor, while did not increase in the spleen, suggesting that PnV-activated macrophages were led preferentially to the tumor. Macrophages were activated in vitro by the venom, becoming more phagocytic; these results confirm that this cell is a target of PnV components. Spleen and in vitro PnV-activated macrophages were different of M1, since they did not produce pro- and anti-inflammatory cytokines. Studies in progress are selecting the venom molecules with antitumor and immunomodulatory effects and trying to better understand their mechanisms. The identification, optimization and synthesis of antineoplastic drugs from PnV molecules may lead to a new multitarget chemotherapy. Glioblastoma is associated with high morbidity and mortality; therefore, research to develop new treatments has great social relevance. Natural products and their derivatives represent over one-third of all new molecular entities approved by FDA. However, arthropod venoms are underexploited, although they are a rich source of new molecules. A recent in vitro screening of the Phoneutria nigriventer spider venom (PnV) antitumor effects by our group has shown that the venom significantly affected glioblastoma cell lines. Therefore, it would be relevant to establish the effects of PnV on tumor development in vivo, considering the complex neoplastic microenvironment. The venom was effective at impairing tumor development in murine xenogeneic model, activating the innate immune response and increasing tumor infiltrating macrophages. In addition, PnV activated macrophages in vitro for a different profile of M1. These activated PnV-macrophages have potential to fight the tumor without promoting tumorigenesis. Studies in progress are selecting the venom molecules with antitumor and immunomodulatory effects and trying to better understand their mechanisms. We aim to synthesize and carry out a formulation with these antineoplastic molecules for clinical trials. Spider venom biomolecules induced smaller and necrotic xenogeneic GB; spider venom activated the innate immune system; venom increased blood monocytes and the migration of macrophages to the tumor; activated PnV-macrophages have a profile different of M1 and have a potential to fight the tumor without promote tumorigenesis.
format	article
author	Amanda Pires Bonfanti Natália Barreto Jaqueline Munhoz Marcus Caballero Gabriel Cordeiro Thomaz Rocha-e-Silva Rafael Sutti Fernanda Moura Sérgio Brunetto Celso Dario Ramos Rodolfo Thomé Liana Verinaud Catarina Rapôso
author_facet	Amanda Pires Bonfanti Natália Barreto Jaqueline Munhoz Marcus Caballero Gabriel Cordeiro Thomaz Rocha-e-Silva Rafael Sutti Fernanda Moura Sérgio Brunetto Celso Dario Ramos Rodolfo Thomé Liana Verinaud Catarina Rapôso
author_sort	Amanda Pires Bonfanti
title	Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model
title_short	Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model
title_full	Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model
title_fullStr	Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model
title_full_unstemmed	Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model
title_sort	spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/8f66ea68d0594f4aa29e67469b65a9d0
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spelling	oai:doaj.org-article:8f66ea68d0594f4aa29e67469b65a9d02021-12-02T18:17:42ZSpider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model10.1038/s41598-020-62620-92045-2322https://doaj.org/article/8f66ea68d0594f4aa29e67469b65a9d02020-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-62620-9https://doaj.org/toc/2045-2322Abstract Molecules from animal venoms are promising candidates for the development of new drugs. Previous in vitro studies have shown that the venom of the spider Phoneutria nigriventer (PnV) is a potential source of antineoplastic components with activity in glioblastoma (GB) cell lines. In the present work, the effects of PnV on tumor development were established in vivo using a xenogeneic model. Human GB (NG97, the most responsive line in the previous study) cells were inoculated (s.c.) on the back of RAG−/− mice. PnV (100 µg/Kg) was administrated every 48 h (i.p.) for 14 days and several endpoints were evaluated: tumor growth and metabolism (by microPET/CT, using 18F-FDG), tumor weight and volume, histopathology, blood analysis, percentage and profile of macrophages, neutrophils and NK cells isolated from the spleen (by flow cytometry) and the presence of macrophages (Iba-1 positive) within/surrounding the tumor. The effect of venom was also evaluated on macrophages in vitro. Tumors from PnV-treated animals were smaller and did not uptake detectable amounts of 18F-FDG, compared to control (untreated). PnV-tumor was necrotic, lacking the histopathological characteristics typical of GB. Since in classic chemotherapies it is observed a decrease in immune response, methotrexate (MTX) was used only to compare the PnV effects on innate immune cells with a highly immunosuppressive antineoplastic drug. The venom increased monocytes, neutrophils and NK cells, and this effect was the opposite of that observed in the animals treated with MTX. PnV increased the number of macrophages in the tumor, while did not increase in the spleen, suggesting that PnV-activated macrophages were led preferentially to the tumor. Macrophages were activated in vitro by the venom, becoming more phagocytic; these results confirm that this cell is a target of PnV components. Spleen and in vitro PnV-activated macrophages were different of M1, since they did not produce pro- and anti-inflammatory cytokines. Studies in progress are selecting the venom molecules with antitumor and immunomodulatory effects and trying to better understand their mechanisms. The identification, optimization and synthesis of antineoplastic drugs from PnV molecules may lead to a new multitarget chemotherapy. Glioblastoma is associated with high morbidity and mortality; therefore, research to develop new treatments has great social relevance. Natural products and their derivatives represent over one-third of all new molecular entities approved by FDA. However, arthropod venoms are underexploited, although they are a rich source of new molecules. A recent in vitro screening of the Phoneutria nigriventer spider venom (PnV) antitumor effects by our group has shown that the venom significantly affected glioblastoma cell lines. Therefore, it would be relevant to establish the effects of PnV on tumor development in vivo, considering the complex neoplastic microenvironment. The venom was effective at impairing tumor development in murine xenogeneic model, activating the innate immune response and increasing tumor infiltrating macrophages. In addition, PnV activated macrophages in vitro for a different profile of M1. These activated PnV-macrophages have potential to fight the tumor without promoting tumorigenesis. Studies in progress are selecting the venom molecules with antitumor and immunomodulatory effects and trying to better understand their mechanisms. We aim to synthesize and carry out a formulation with these antineoplastic molecules for clinical trials. Spider venom biomolecules induced smaller and necrotic xenogeneic GB; spider venom activated the innate immune system; venom increased blood monocytes and the migration of macrophages to the tumor; activated PnV-macrophages have a profile different of M1 and have a potential to fight the tumor without promote tumorigenesis.Amanda Pires BonfantiNatália BarretoJaqueline MunhozMarcus CaballeroGabriel CordeiroThomaz Rocha-e-SilvaRafael SuttiFernanda MouraSérgio BrunettoCelso Dario RamosRodolfo ThoméLiana VerinaudCatarina RapôsoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)

Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model

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