A Bifunctional Molecule with Lectin and Protease Inhibitor Activities Isolated from Crataeva tapia Bark Significantly Affects Cocultures of Mesenchymal Stem Cells and Glioblastoma Cells

Author(s)

Bonturi, Camila Ramalho ^[1] ; Cabral Silva, Mariana Cristina ^[1] ; Motaln, Helena ^[2] ; Salu, Bruno Ramos ^[1] ; Ferreira, Rodrigo da Silva ^[1] ; Batista, Fabricio Pereira ^[1] ; dos Santos Correia, Maria Tereza ^[3] ; Guedes Paiva, Patricia Maria ^[3] ; Turnsek, Tamara Lah ^[4] ; Vilela Oliva, Maria Luiza ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Biochem, BR-04044020 Sao Paulo, SP - Brazil

^[2] Jozef Stefan Inst, Dept Biotechnol, Ljubljana 1000 - Slovenia

^[3] Univ Fed Pernambuco, Dept Biochem, BR-50670910 Recife, PE - Brazil

^[4] Natl Inst Biol, Dept Genet Toxicol & Canc Biol, Ljubljana 1000 - Slovenia

• Document type: Journal article
• Source: Molecules; v. 24, n. 11 JUN 1 2019.
• Web of Science Citations: 0

Abstract

Currently available drugs for treatment of glioblastoma, the most aggressive brain tumor, remain inefficient, thus a plethora of natural compounds have already been shown to have antimalignant effects. However, these have not been tested for their impact on tumor cells in their microenvironment-simulated cell models, e.g., mesenchymal stem cells in coculture with glioblastoma cell U87 (GB). Mesenchymal stem cells (MSC) chemotactically infiltrate the glioblastoma microenvironment. Our previous studies have shown that bone-marrow derived MSCs impair U87 growth and invasion via paracrine and cell-cell contact-mediated cross-talk. Here, we report on a plant-derived protein, obtained from Crataeva tapia tree Bark Lectin (CrataBL), having protease inhibitory/lectin activities, and demonstrate its effects on glioblastoma cells U87 alone and their cocultures with MSCs. CrataBL inhibited U87 cell invasion and adhesion. Using a simplified model of the stromal microenvironment, i.e., GB/MSC direct cocultures, we demonstrated that CrataBL, when added in increased concentrations, caused cell cycle arrest and decreased cocultured cells' viability and proliferation, but not invasion. The cocultured cells' phenotypes were affected by CrataBL via a variety of secreted immunomodulatory cytokines, i.e., G-CSF, GM-CSF, IL-6, IL-8, and VEGF. We hypothesize that CrataBL plays a role by boosting the modulatory effects of MSCs on these glioblastoma cell lines and thus the effects of this and other natural lectins and/or inhibitors would certainly be different in the tumor microenvironment compared to tumor cells alone. We have provided clear evidence that it makes much more sense testing these potential therapeutic adjuvants in cocultures, mimicking heterogeneous tumor-stroma interactions with cancer cells in vivo. As such, CrataBL is suggested as a new candidate to approach adjuvant treatment of this deadly tumor. (AU)

• FAPESP's process: 17/07972-9 - Development of lead agents for prophylaxis and treatment of cardiovascular diseases
• Grantee: Maria Luiza Vilela Oliva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/06630-7 - Fragments derived from the structure of protease inhibitors with selectivity for inhibition of mammalian and microorganism enzymes and its role as an anti-inflammatory, antimicrobial, antithrombotic and anti- tumor agent: mechanism of action
• Grantee: Maria Luiza Vilela Oliva
• Support Opportunities: Research Projects - Thematic Grants