Evaluation of the Antitumor Potential of Soloxolone Tryptamide against Glioblastoma Multiforme Using in silico, in vitro, and in vivo Approaches

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Andrey V. Markov^1,a*, Kirill V. Odarenko¹, Aleksandra V. Sen’kova¹, Anna A. Ilyina¹, and Marina A. Zenkova¹

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia

^* To whom correspondence should be addressed.

Received February 2, 2023; Revised March 13, 2023; Accepted April 3, 2023

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Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by uncontrollable diffusive growth, resistance to chemo- and radiotherapy, and a high recurrence rate leading to a low survival rate of patients with GBM. Due to a large number of signaling pathways regulating GBM pathogenesis, one of the promising directions is development of novel anti-glioblastoma compounds based on natural metabolites capable of affecting multiple targets. Here, we investigated the antitumor potential of the semisynthetic triterpenoid soloxolone tryptamide (STA) against human glioblastoma U87 cells. STA efficiently blocked the growth of U87 cells in 2D and 3D cultures, enhanced adhesiveness of tumor cells, and displayed synergistic cytotoxicity with temozolomide. In silico analysis suggested that the 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 direct effect on U87 cells, STA normalized tumor microenvironment in murine heterotopic U87 xenograft model by suppressing the development of immature blood vessels and elastin production in the tumor tissue. Taken together, our results clearly demonstrate that STA can be a novel promising antitumor candidate for GMB treatment.

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KEY WORDS: glioblastoma multiforme, cyanoenone pharmacophore, pentacyclic triterpenoids, spheroids, angiogenesis, synergistic effect, molecular docking, gene network, tumor microenvironment

DOI: 10.1134/S000629792307012X

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