14, 15-epoxygeranylgeraniol and extracts isolated from Pterodon emarginatus Vog. fruits: antitumor activity on glioblastoma cells.

Plant-derived substances have traditionally played important roles in the treatment of human diseases, including of great significance to cancer therapy. Plants of the genus Pterodon (Fabaceae, Leguminosae), commonly known as ‘sucupira’, are disseminated throughout the central region of Brazil and have been used frequently in popular medicine. In recent years, interest in these plants has increased considerably. The biological effects of their extracts and pure metabolites have been investigated in several experimental models in vivo and in vitro. Until the present day, the antitumor effect of Pterodon plants on brain tumors is unknown. Therefore, the aim of this work was to investigate the action of P. emarginatus Vogel extracts and its fractions on glioblastoma cells. The hexane (HE), dichloromethane (DE) and ethanol (EE) extracts were obtained from seeds powder in each solvent. The diterpene 14,15-epoxygeranylgeraniol was obtained from HE fractionation. For tumorigenic assays, the extracts and fractions were added to U87MG, a human glioblastoma cells line. The cell viability assay showed that the proliferation of U87MG was inhibited by both extracts and the 14,15- epoxygeranylgeraniol. Further trials in vivo will help to confirm these results, and may contribute to generate natural compounds for the treatment of this type of cancer.

Aberrant signaling pathways in medulloblastomas: a stem cell connection / Vias de sinalização aberrantes no meduloblastoma: uma conexão com célula-tronco

Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFβ, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers.

Meduloblastoma é um tumor maligno do sistema nervoso central (SNC). Na infância, representa o tumor sólido mais frequente e a principal causa de morte relacionada ao câncer. Tratamentos atuais incluem cirurgia, quimioterapia e radioterapia, que podem trazer prejuízos cognitivos e desenvolvimento de tumores secundários. Novas perspectivas terapêuticas surgem com a identificação de células-tronco em gliomas, as quais apresentam alto potencial tumorigênico e maior resistência à radioterapia e quimioterapia. A hipótese das células-tronco tumorais sugere que a transformação de células-tronco e/ou progenitores neurais do cerebelo está envolvida no desenvolvimento do meduloblastoma. Portanto, analisar alterações genéticas e moleculares envolvidas nesse processo é de grande importância na pesquisa básica e aplicada ao câncer. Nesse sentido, discutimos o possível envolvimento de vias de sinalização bioquímica críticas a ambos os processos de neurogênese normal ou tumorigênese, com base em evidências atuais na área de genética e biologia molecular dos meduloblastomas. Do ponto de vista clínico, a modulação de vias de sinalização como a do TGFβ, regulando proliferação de célula-tronco neural e desenvolvimento tumoral, pode ser uma estratégia alternativa para o desenvolvimento de novos medicamentos objetivando-se terapias mais eficientes e melhora do prognóstico dos pacientes pediátricos com câncer de SNC.

What's the importance of peptidases in cancer?: [review] / Qual é a importância das peptidases em câncer?: [revisão]

A synonym for a successful tumor spread is a productive invasive cell migration, a process by which the extracellular matrix plays the role of substrate for cells to move and reach a secondary site. Peptidases participate actively in this process to degrade the extracellular matrix. The activity of these enzymes is regulated by inhibitors, activators and receptors. However, cancer occurs in a breach of the balance of proteolytic-antiproteolytic activity. The peptidases, enzymes that hydrolyze peptide bonds of proteins, can act directly by degrading the components of the extracellular matrix or indirectly by activating other peptidases, in a process that may also generate bioactive fragments, interact with cell surface receptors, and be involved in the angiogenic process. The modification and remodeling of the extracellular matrix caused by peptidases modify the anchoring mediated by integrins, focal adhesion and architecture of the cytoskeleton, and direct signaling molecules that can affect gene expression and influence some behavioral aspects, such as proliferation, survival, differentiation and mobility. Recently, some studies showed an inverse correlation between the low expression of peptidases and increased potential for tumor development. Thus, despite offering an excellent alternative of a more effective and targeted cancer treatment, protease inhibitors should be specific, administered at the correct time with the aid of biomarkers and act locally, and finally, their activity should not be prolonged to the point of interfering with the activity of peptidases when they are, for example, being used in a process of remodeling.

Um sinônimo para o sucesso da disseminação do tumor é uma produtiva migração celular invasiva, um processo pelo qual a matriz extracelular possui papel de substrato para as células se moverem e atingirem um sítio secundário. Para degradar a matriz extracelular, as peptidases participam ativamente deste processo. A atividade destas enzimas é regulada por inibidores, ativadores e receptores. Entretanto, no câncer ocorre uma quebra do balanço da atividade proteolítica-antiproteolítica. As peptidases, enzimas que clivam ligações peptídicas, podem atuar de forma direta ao degradar componentes da matriz extracelular ou de forma indireta, ao ativar outras peptidases a gerar fragmentos bioativos, interagir com receptores da superfície celular, e participar no processo angiogênico. A modificação e o remodelamento da matriz extracelular causadas por peptidases modificam a ancoragem mediada por integrinas, a adesão focal e a arquitetura do citoesqueleto direcionam moléculas de sinalização que podem afetar a expressão gênica e influenciar no comportamento como proliferação, sobrevivência, diferenciação, e mobilidade. Recentemente, alguns trabalhos demonstraram uma correlação inversa entre a baixa expressão de peptidases e o aumento do potencial do desenvolvimento do tumor. Desta forma, apesar de oferecerem uma excelente alternativa mais efetiva e direcionada para o tratamento do câncer, os inibidores de peptidases devem ser específicos, administrados no tempo correto com o auxílio de biomarcadores e atuar localizadamente.