Analysis of the effect and mechanism of action of P. nigriventer venom and its isolated toxins on the development of brain tumor implanted in mice

Abstract

Animal venoms are a mixture of biologically active molecules with specific targets in cells and tissues. These molecules may be useful for investigating pathophysiological mechanisms, and serve as a prototype for the development of new drugs. Our group recently demonstrated that astrocytes are directly targeted by molecules present in the Phoneutria nigriventer spider venom (PNV) (Ctenidae, Araneomorpha). In the astrocytic primary culture, PNV evoked transient Ca2+ waves, impaired the actin cytoskeleton (stress fibers), the balance between F- and G-actin, modified cellular morphology and increased Na+/K+ATPase. In addition, recent results show that PNV increases PTEN expression and reduces PI3K and Akt in neural tissue, suggesting that the venom inhibits this pathway. These PNV targets are involved in tumorigenesis, migration, invasion, growth and survival of gliomas, indicating that PNV may be useful to treat tumors. Malignant brain tumors are one of the most devastating forms of human cancer. The ability to invade healthy nervous tissue is a characteristic of gliomas that make it difficult to treat. The present project, therefore, aims to identify and characterize the PNV isolated toxin(s) with antitumor effects in glioma implanted in mice brain, by MRI analysis. Furthermore, since PNV alters a range of proteins from different signaling pathways, unraveling its mechanism of action through analysis of single proteins and pathways has been challenging. Proteomics is a powerful tool in the identification of multiple proteins that are altered after a neuropharmacological intervention in diseases of the CNS and has been applied in several areas of neuroscience, including brain tumors studies. Proteomic provades a range of qualitative and quantitative information on multiple proteins. This tool will be used in this project to capture the dynamics of altered biological systems, evaluating a large spectrum of proteins during the PNV mechanism in healthy and tumor tissue. (AU)