Flubendazole exhibits anti-glioblastoma effect by inhibiting STAT3 and promoting cell cycle arrest

Abstract

Glioblastoma multiforme (GBM) belongs to most aggressive and invasive primary brain tumor in adults whose prognosis and survival remains poor. Potential new treatment modalities include targeting the cytoskeleton. In our study, we demonstrated that repurposed drug flubendazole (FLU) significantly inhibits proliferation and survival of GBM cells. FLU exerted its effect by affecting microtubule structure and our results also suggest that FLU influences tubulins expression to a certain degree. Moreover, FLU effects decreased activation of STAT3 and also partially inhibited its expression, leading to upregulation of p53 signaling pathway and subsequent cell cycle arrest at G2/M phase as well as caspase-dependent cell death in GBM cells. These results suggest FLU as a promising agent to be used in GBM treatment and prompting further testing of its effects on GBM.

Expression of STAT3 and hypoxia markers in long-term surviving malignant glioma patients

“…Still, a significantly increased expressions of STAT3 and pSTAT3 were found almost universally in repeated resections of most analyzed patients, thereby suggesting a possibly pronounced role of this molecule in recurrent glioblastoma. Accordingly, it is nowadays known that STAT3 is increasingly expressed in glioblastoma as shown by us and other groups [ 24 , 25 ], and this expression has likely significant influence on several key biological characteristics of this tumor such as immunosuppressive microenvironment, hypoxia-induced angiogenesis and tumor cells migration [ 26 , 27 ]. In addition, STAT3 was shown to be a positive regulator of HIF1α, VEGF, MMP-2 and TWIST in hypoxic glioblastoma [ 28 ] and its suppression induced proliferation arrest and apoptosis in glioblastoma cells [ 29 ].…”

Overcoming challenges in glioblastoma treatment: targeting infiltrating cancer cells and harnessing the tumor microenvironment

“…Among these candidates, FDA-approved drugs that are currently used for treating other conditions have shown promise (Jones et al, 2023;Moretti et al, 2023;Murali and Karuppasamy, 2023;Vítovcová et al, 2023). Recent preclinical examples include Flubendazole, an inhibitor of microtubule growth that activates autophagy and STAT3-dependent apoptosis, and auranofin (AF), an inhibitor of TrxR1, used alone or in combination with the prooxidant menadione (Szeliga and Rola, 2022).…”