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 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 18 F-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 18 F-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 antiinflammatory 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

Spider venom components decrease glioblastoma cell migration and invasion through RhoA-ROCK and Na+/K+-ATPase β2: potential molecular entities to treat invasive brain cancer

“…for 14 days induced a reduction or eradication of xenogeneic implanted tumor in mice. The study also showed that the systemic treatment with the venom improved the general condition of the animals, increasing body weight and survival, while did not decrease blood cells, but increased monocytes, indicating the low toxicity of the treatment [28].…”

“…Ca 2+ is widely regarded as an important coordinator of these events [39][40][41]. Cell adhesion is another important phenotypic feature during GB progression and is also influenced by Ca 2+ channel activity [28]. The detachment of cells from the primary glioma tumor mass comprises several events involving the destabilization and disorganization of cell-cell adhesion, as well as the loss of expression of neural cell adhesion molecules [42].…”

Bioactive peptides from venoms against glioma progression

“…As mentioned above, components of the wandering spider ( Phoneutria nigriventer ) venom (PnV), such as PnTx3-6 and PnTx3-3 peptides, have recently been shown to have anti-GB effects ( 49 ). Structurally and functionally uncharacterized peptides isolated from the PnV venom, namely fractions F1, F2, F3 and subfractions SF1–SF11, affected GB cells in vitro ( 56 – 58 ) and impaired GB progression in a xenogeneic mouse model in vivo ( 130 ). However, in this study, PnV venom also affected the TME and especially the local tumor immunosuppressive microenvironment to reactivate anti-tumor immunity, in particular tumor-associated macrophages (TAMs).…”

Isolated Components From Spider Venom Targeting Human Glioblastoma Cells and Its Potential Combined Therapy With Rapamycin

“…It has been shown that biomolecules from scorpion and spider venoms have a chemotherapeutic effect on glioma, neuroblastoma, leukemia, lymphoma, breast cancer, lung cancer, hepatoma, and pancreatic and prostate cancer, among others ( Rapôso, 2017 ). Our group demonstrated that Phoneutria nigriventer spider venom (PnV) decreased cell viability and proliferation, impaired cell cycle and induced apoptosis of human GB lineages ( Barreto dos Santos et al, 2019 ), and reduced or eradicated the development of GB in a preclinical trial developed in mice ( Bonfanti et al, 2020 ), and PnV-isolated components impaired cell migration and adhesion through RhoA-ROCK and Na + /K + -ATPase ( Barreto et al, 2020 ).…”