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Identification of new molecules with chemotherapeutic effect in human glioma and characterization of the mechanism


Malignant brain tumors are among the most devastating types of human cancer. The ability to invade healthy neural tissue is a characteristic of gliomas that makes the treatment difficult. The PI3K/Akt/mTOR (and the PTEN phosphatasis, which innactivates that pathway) and RhoA/ROCK pathways and the Na+/K+-ATPase pump are involved in the tumorigenesis, migration, invasion, growth and survival of gliomas. To use these pathways as a therapeutic target is a strategy which can contribute for tumor treatment. Venoms from animals are a mix of biologically active molecules, with specific target in cells and tissues. In spite of it high toxicity, these molecules can be tools to investigate pathophysiological mechanisms and serve as prototype for development of new drugs. Phoneutria nigriventer (Ctenidae, Araneomorpha) spider venom (PNV) has potent peptides, some neurotoxic, that interfere in the physiology of ion channels and in the release and uptake of neurotransmitters. It was recently demonstrated by our research group that the astrocytes are direct target of PNV. In astrocytes primary culture, PNV evoked Ca2+ transients in a dose-dependent way, changed actin cytoskeleton (stress fibers), the balance between F- and G-actin, modified cell morphology and increased Na+/K+-ATPase expression. In addition, recent results showed that PNV increases the expression of phosphatase PTEN and decreases PI3K and Akt expression in neural tissue, suggesting that the venom inhibits this pathway. Therefore, to identify and characterize toxins present in the PNV which have astrocytes as a target can be useful for the treatment of brain tumors such as glioma, which are originated from glia. PI3K/Akt/mTOR (and PTEN, which inactivate this therefore, the present work aims to investigate the anti-tumor role of PNV, in vitro, in glioma NG97ht and glioblastoma U87MG cells and describe the venom effects and mechanism in the cytoskeleton, migration and morphology of tumor cells, evaluating the PI3K/Akt/mTOR and RhoA/ROCK pathways and Na+/K+-ATPase. The present study also aims to characterize isolated toxins from venom with antitumor effects, in vivo, in glioma and glioblastoma inoculated in mice brain. In addition, since PNV and it purified toxins present multiple signaling pathways and proteins as target, it has been complex to delineate their mechanism. The present work will use proteomic analyses to evaluate a wide range of possible venom and toxins targets in healthy and tumor tissue. Using this method can capture the dynamic of changed biologic systems, investigating a broad spectrum of proteins. Preliminary results M showed in this project demonstrate that the venom has significant chemotherapeutic action in glioma cells and it is relevant to investigate the mechanisms of this effect. The study will use in vivo and in vitro models and will be developed through morphologic, molecular, biochemical, analytic and image methods and will contribute for the developing of new potential treatments for brain tumor. In addition, the study will advance in the knowledge about pathophysiology of P. nigriventer envenoming. (AU)

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BARRETO, NATALIA; CABALLERO, MARCUS; BONFANTI, AMANDA PIRES; PINHEIRO DE MATO, FELIPE CEZAR; MUNHOZ, JAQUELINE; DA ROCHA-E-SILVA, THOMAZ A. A.; SUTTI, RAFAEL; VITORINO-ARAUJO, JOAO LUIZ; VERINAUD, LIANA; RAPOSO, CATARINA. Spider venom components decrease glioblastoma cell migration and invasion through RhoA-ROCK and Na+/K+-ATPase beta 2: potential molecular entities to treat invasive brain cancer. CANCER CELL INTERNATIONAL, v. 20, n. 1, . (15/04194-0, 15/06134-4, 17/05402-0, 17/16196-2, 17/24331-7, 19/10003-3, 18/23559-7)
DOS SANTOS, NATALIA BARRETO; BONFANTI, AMANDA PIRES; ALVES DA ROCHA-E-SILVA, THOMAZ AUGUSTO; DA SILVA, JR., PEDRO ISMAEL; DA CRUZ-HOFLING, MARIA ALICE; VERINAUD, LIANA; RAPOSO, CATARINA. Venom of the Phoneutria nigriventer spider alters the cell cycle, viability, and migration of cancer cells. Journal of Cellular Physiology, v. 234, n. 2, p. 1398-1415, . (15/04194-0, 17/05402-0, 17/16196-2, 16/15827-6)
DA SILVA, CAROLINA NUNES; LOMEO, ROSANGELA SILVA; TORRES, FERNANDO SILVA; BORGES, MARCIA HELENA; NASCIMENTO, MARTA CORDEIRO; RODRIGUES MESQUITA-BRITTO, MARIA HELENA; RAPOSO, CATARINA; DE CASTRO PIMENTA, ADRIANO MONTEIRO; DA CRUZ-HOFLING, MARIA ALICE; GOMES, DAWIDSON ASSIS; et al. PnTx2-6 (or delta-CNTX-Pn2a), a toxin from Phoneutria nigriventer spider venom, releases L-glutamate from rat brain synaptosomes involving Na+ and Ca2+ channels and changes protein expression at the blood-brain barrier. Toxicon, v. 150, p. 280-288, . (15/04194-0)
BONFANTI, AMANDA PIRES; BARRETO, NATALIA; MUNHOZ, JAQUELINE; CABALLERO, MARCUS; CORDEIRO, GABRIEL; ROCHA-E-SILVA, THOMAZ; SUTTI, RAFAEL; MOURA, FERNANDA; BRUNETTO, SERGIO; RAMOS, CELSO DARIO; et al. Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model. SCIENTIFIC REPORTS, v. 10, n. 1, . (18/03051-9, 16/15827-6, 17/05402-0, 15/06134-4, 17/16196-2, 15/04194-0, 18/23559-7)
MUNHOZ, JAQUELINE; PERON, GABRIELA; BONFANTI, AMANDA PIRES; OLIVEIRA, JANINE; DA ROCHA-E-SILVA, THOMAZ A. A.; SUTTI, RAFAEL; THOME, RODOLFO; BOMBEIRO, ANDRE LUIS; BARRETO, NATALIA; CHALBATANI, GHANBAR MAHMOODI; et al. Components from spider venom activate macrophages against glioblastoma cells: new potential adjuvants for anticancer immunotherapy. JOURNAL OF BIOCHEMISTRY, v. 170, n. 1, p. 51-68, . (15/04194-0, 15/06134-4, 18/23559-7, 18/03051-9, 19/10003-3)

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