Gliomas, ranging from low-grade pilocytic astrocytomas to highly malignant glioblastomas, are primary brain tumors that originate from neural or glial stem cells. Classified by the WHO into grades 1 to 4, these tumors exhibit varying prognoses, with oligodendrogliomas and astrocytomas having better and intermediate outcomes, respectively, while glioblastomas are associated with a poor prognosis. Despite advancements in molecular and genetic research that have improved diagnosis and the development of targeted therapies, treating high-grade gliomas remains a significant challenge due to their diffuse nature. In this context, lectins, carbohydrate-binding proteins, have shown promise as diagnostic and therapeutic agents for cancer, including gliomas. Plant lectins, particularly those from legumes, exhibit significant antiproliferative effects on glioma cells. These effects include decreased cell viability and migration, alongside the induction of autophagy and apoptosis, suggesting their potential as therapeutic agents. Although the mechanisms underlying these effects are not yet fully understood, molecular targets and pathways involved in the antiglioma activity of lectins have been identified. Key targets include matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), CD98 (xc^- system), AMPA receptor, and CD73. This review focuses on the antiglioma potential of legume lectins, their applications, and the main molecular targets based on their functions, structures, and associated molecular mechanisms.

Studies have revealed the dependence of glioma cells on iron, making them sensitive to ferroptosis. Ferroptosis can be triggered by inhibition of the xc- system, resulting in redox imbalance and membrane lipid peroxidation. The xc- system is composed of two coupled proteins, xCT and CD98hc. The control of transporters, such as xCT, by the CD98hc glycoprotein suggests that molecules targeting glycans may have an impact on the treatment of glioma. This study evaluated the effect of the Canavalia brasiliensis (ConBr) lectin on C6 glioma cells and compared it with erastin, an xc- system inhibitor. Both induced dose-dependent cell death, accompanied by an increase in the production of reactive oxygen species and a decrease in reduced glutathione. However, co-treatment did not show an additive effect. The analysis was updated by molecular dynamics assessments of the xc- system interacting with ConBr or erastin. The interaction of erastin with the xc- system affects its interaction with ConBr, reducing the antagonistic effect when both are in the protein complex. The data show that ConBr is effective in inducing cell death in glioma cells and regulates the xc system through interaction with CD98hc glycans, showing that lectins have the potential to promote ferroptosis in glioma cells.

The genus Centrolobium comprises species of Neotropical trees with seeds that possess medicinal and bioactive applications. Lectins from this genus exhibit anti-inflammatory and immunomodulatory effects, influencing the activation of the immune system. This study focuses on characterizing the structure and carbohydrate-binding properties of the lectin from Centrolobium microchaete (CML) and evaluating its potential against gliomas. The structure of the lectin in complex with methyl-mannose-α1,3-mannose (MDM) was resolved using X-ray crystallography at 1.3 Å resolution, with its interactions further analyzed through molecular dynamics simulations. Structurally, CML adopts a β-sandwich motif and assembles into canonical dimers. In vitro assays revealed that CML reduced the viability of C6 glioma cells, although only at high concentrations, without impacting cell migration or morphology. CML activated autophagic processes, albeit with lower efficacy compared with other mannose-specific lectins. The limited antiglioma activity of CML may be linked to its inability to form tetramers and unusual specificity toward asymmetric glycans, both crucial features for interactions with cellular glycans and the activation of signaling pathways. This study represents the first investigation of the antiglioma potential of a mannose-specific lectin from the Dalbergieae tribe, highlighting both its structural characteristics and functional limitations.

Background/Objective: New therapeutic targets are urgently needed for glioblastoma, the most aggressive primary brain tumor in adults. Monepantel (MPL), a repurposed anthelmintic, is thought to act in cancer cells through ATF4-mediated endoplasmic reticulum (ER) stress that inhibits mTORC1, but this axis had not been examined in glioma. The present study aimed to evaluate the effects of monepantel (MPL) in rat C6 glioma and human U87-MG glioblastoma cells, focusing on the ER stress/mTOR/autophagy signaling network. Methods: Cells were treated with MPL, and cell viability was measured by MTT assay. The signaling pathways were analyzed by Western blotting, and autophagy by acridine orange staining and LC3-II detection. Cell migration was assessed using a scratch wound-healing assay and tumorspheres. Results: MPL increased the ER chaperone BiP/GRP78 and induced autophagy, as shown by concentration-dependent accumulation of acidic vesicular organelles and LC3-II. In parallel, MPL reduced phosphorylation of the mTORC1 substrate p70S6K, without affecting Akt, localizing its action at or below mTORC1, suggesting an ER-stress-to-autophagy route. MPL additionally produced a decrease in ERK2 phosphorylation, while p38^MAPK was unchanged. These molecular changes were accompanied by reduction in C6 viability and by impaired C6 migration and reduced U87-MG tumorsphere migratory area. Conclusions: Together, these data suggest that MPL engages an ER-stress/mTORC1 axis associated with autophagy and ERK2 inhibition in glioma. These findings indicate the potential of MPL as an antiglioma agent. However, further studies using additional cell lines, together with preclinical testing, are needed to better characterize its effects and determine its potential for future clinical application.