Soloxolone -methylanilide effectively suppresses aggressive phenotype of glioblastoma cells including TGF-β1-induced glial-mesenchymal transition and inhibits growth of U87 glioblastoma xenografts in mice.

Soloxolone amides are semisynthetic triterpenoids that can cross the blood-brain barrier and inhibit glioblastoma growth both and . Here we investigate the impact of these compounds on processes associated with glioblastoma invasiveness and therapy resistance. Screening of soloxolone amides against glioblastoma cells revealed the ability of compound (soloxolone -methylanilide) to inhibit transforming growth factor-beta 1 (TGF-β1)-induced glial-mesenchymal transition Compound inhibited morphological changes, wound healing, transwell migration, and expression of mesenchymal markers (N-cadherin, fibronectin, Slug) in TGF-β1-induced U87 and U118 glioblastoma cells, while restoring their adhesiveness. Confocal microscopy and molecular docking showed that reduced SMAD2/3 nuclear translocation probably by direct interaction with the TGF-β type I and type II receptors (TβRI/II). In addition, suppressed stemness of glioblastoma cells as evidenced by inhibition of colony forming ability, spheroid growth, and aldehyde dehydrogenase (ALDH) activity. Furthermore, exhibited a synergistic effect with temozolomide (TMZ) on glioblastoma cell viability. Using N-acetyl-L-cysteine (NAC) and flow cytometry analysis of Annexin V-FITC-, propidium iodide-, and DCFDA-stained cells, was found to synergize the cytotoxicity of TMZ by inducing ROS-dependent apoptosis. Further studies showed that , alone or in combination with TMZ, effectively suppressed the growth of U87 xenograft tumors in mice. Thus, demonstrated promising potential as a component of combination therapy for glioblastoma, reducing its invasiveness and increasing its sensitivity to chemotherapy.