Evaluation of the antitumor potential of soloxolone tryptamide against glioblastoma multiforme using in silico, in vitro and in vivo approaches

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive neoplasia characterized by uncontrollable diffusive growth, development of resistance to chemo- and radiotherapy and a high rate of recurrence that leads to low survival of patients with GBM. Given the number of signaling pathways regulating GBM pathogenesis, the development of novel anti-glioblastoma compounds based on multitarget natural metabolites is a promising direction for the study. In the current work, the antitumor potential of semisynthetic triterpenoid soloxolone tryptamide (STA) against human glioblastoma U87 cells was explored. It was found that STA effectively blocked the growth of U87 cells in 2D and 3D culture systems, enhanced the adhesiveness of tumor cells and displayed synergistic cytotoxicity with temozolomide. Performed in silico analysis revealed that the pronounced anti-glioblastoma activity of STA can be explained by its direct interaction with EGFR, ERBB2 and AKT1, which play an important role in the regulation of GBM malignancy. Along with observed direct modulatory action of STA on U87 cells, explored compound had a normalizing effect on the tumor microenvironment in murine heterotopic U87 xenograft model, suppressing the development of immature blood vessels and the production of elastin in tumor tissue. Taken together, obtained results clearly demonstrate that STA can be considered a novel promising antitumor candidate for GMB treatment.