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.

Department of Medical Biochemistry Faculty of Medicine in Hradec Králové Charles University Šimkova 870 500 03 Hradec Králové Czech Republic

Department of Medical Biology and Genetics Faculty of Medicine in Hradec Králové Charles University Šimkova 870 500 03 Hradec Králové Czech Republic

The Fingerland Department of Pathology Faculty of Medicine and University Hospital in Hradec Králové Charles University Sokolská 581 500 05 Hradec Králové Czech Republic

Sci Rep. 2023 Jun 23;13(1):10232. doi: 10.1038/s41598-023-37369-6. PubMed

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Ramos AD, Magge RS, Ramakrishna R. Molecular pathogenesis and emerging treatment for glioblastoma. World Neurosurg. 2018;116:495–504. doi: 10.1016/j.wneu.2018.04.021. PubMed DOI

de Gooijer MC, et al. An experimenter's guide to glioblastoma invasion pathways. Trends Mol. Med. 2018;24(9):763–780. doi: 10.1016/j.molmed.2018.07.003. PubMed DOI

Strobel H, et al. Temozolomide and other alkylating agents in glioblastoma therapy. Biomedicines. 2019;7(3):1. doi: 10.3390/biomedicines7030069. PubMed DOI PMC

Miranda, A., et al. Breaching barriers in glioblastoma. Part I: Molecular pathways and novel treatment approaches. Int. J. Pharm.531(1), 372–388 (2017). PubMed

Schreck, K.C., & Grossman, S.A. Role of temozolomide in the treatment of cancers involving the central nervous system. Oncology (Williston Park)32(11), 555–60, 569 (2018). PubMed

Balca-Silva J, et al. Cellular and molecular mechanisms of glioblastoma malignancy: Implications in resistance and therapeutic strategies. Semin. Cancer Biol. 2019;58:130–141. doi: 10.1016/j.semcancer.2018.09.007. PubMed DOI

Szopa W, et al. Diagnostic and therapeutic biomarkers in glioblastoma: Current status and future perspectives. Biomed. Res. Int. 2017;2017:8013575. doi: 10.1155/2017/8013575. PubMed DOI PMC

Katsetos CD, et al. Emerging microtubule targets in glioma therapy. Semin. Pediatr. Neurol. 2015;22(1):49–72. doi: 10.1016/j.spen.2015.03.009. PubMed DOI

Skalli O, et al. Astrocytoma grade IV (glioblastoma multiforme) displays 3 subtypes with unique expression profiles of intermediate filament proteins. Hum. Pathol. 2013;44(10):2081–2088. doi: 10.1016/j.humpath.2013.03.013. PubMed DOI

Zottel A, et al. Cytoskeletal proteins as glioblastoma biomarkers and targets for therapy: A systematic review. Crit. Rev. Oncol. Hematol. 2021;160:103283. doi: 10.1016/j.critrevonc.2021.103283. PubMed DOI

Katsetos CD, Draber P, Kavallaris M. Targeting betaIII-tubulin in glioblastoma multiforme: From cell biology and histopathology to cancer therapeutics. Anticancer Agents Med. Chem. 2011;11(8):719–728. doi: 10.2174/187152011797378760. PubMed DOI

Katsetos CD, et al. Tubulin targets in the pathobiology and therapy of glioblastoma multiforme II. gamma-Tubulin. J. Cell Physiol. 2009;221(3):514–520. doi: 10.1002/jcp.21884. PubMed DOI

Katsetos CD, et al. Tubulin targets in the pathobiology and therapy of glioblastoma multiforme. I. Class III beta-tubulin. J. Cell Physiol. 2009;221(3):505–513. doi: 10.1002/jcp.21870. PubMed DOI

Hanusova V, et al. Potential anti-cancer drugs commonly used for other indications. Curr. Cancer Drug Targets. 2015;15(1):35–52. doi: 10.2174/1568009615666141229152812. PubMed DOI

Michaelis M, et al. Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen. Sci. Rep. 2015;5:8202. doi: 10.1038/srep08202. PubMed DOI PMC

Canova K, Rozkydalova L, Rudolf E. Anthelmintic Flubendazole and its potential use in anticancer therapy. Acta Med. (Hradec Kralove) 2017;60(1):5–11. doi: 10.14712/18059694.2017.44. PubMed DOI

Zhou X, et al. Flubendazole inhibits glioma proliferation by G2/M cell cycle arrest and pro-apoptosis. Cell Death Discov. 2018;4:18. doi: 10.1038/s41420-017-0017-2. PubMed DOI PMC

Ren LW, et al. Benzimidazoles induce concurrent apoptosis and pyroptosis of human glioblastoma cells via arresting cell cycle. Acta Pharmacol. Sin. 2022;43(1):194–208. doi: 10.1038/s41401-021-00752-y. PubMed DOI PMC

Chen C, et al. Flubendazole plays an important anti-tumor role in different types of cancers. Int. J. Mol. Sci. 2022;23(1):1. doi: 10.3390/ijms23010519. PubMed DOI PMC

Lin S, et al. Flubendazole demonstrates valid antitumor effects by inhibiting STAT3 and activating autophagy. J. Exp. Clin. Cancer Res. 2019;38(1):293. doi: 10.1186/s13046-019-1303-z. PubMed DOI PMC

Oh E, et al. Flubendazole elicits anti-metastatic effects in triple-negative breast cancer via STAT3 inhibition. Int. J. Cancer. 2018;143(8):1978–1993. doi: 10.1002/ijc.31585. PubMed DOI

Hong S, Song MR. STAT3 but not STAT1 is required for astrocyte differentiation. PLoS ONE. 2014;9(1):e86851. doi: 10.1371/journal.pone.0086851. PubMed DOI PMC

Gray GK, et al. NF-κB and STAT3 in glioblastoma: Therapeutic targets coming of age. Expert Rev. Neurother. 2014;14(11):1293–1306. doi: 10.1586/14737175.2014.964211. PubMed DOI PMC

Luwor RB, Stylli SS, Kaye AH. The role of Stat3 in glioblastoma multiforme. J. Clin. Neurosci. 2013;20(7):907–911. doi: 10.1016/j.jocn.2013.03.006. PubMed DOI

Niu G, et al. Role of Stat3 in regulating p53 expression and function. Mol. Cell Biol. 2005;25(17):7432–7440. doi: 10.1128/MCB.25.17.7432-7440.2005. PubMed DOI PMC

Skarkova V, et al. The Evaluation of Glioblastoma Cell Dissociation and Its Influence on Its Behavior. Int. J. Mol. Sci. 2019;20(18):1. doi: 10.3390/ijms20184630. PubMed DOI PMC

Bai RY, et al. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro Oncol. 2011;13(9):974–982. doi: 10.1093/neuonc/nor077. PubMed DOI PMC

Khachigian LM. Emerging insights on functions of the anthelmintic flubendazole as a repurposed anticancer agent. Cancer Lett. 2021;522:57–62. doi: 10.1016/j.canlet.2021.09.013. PubMed DOI

Abbassi RH, et al. Lower tubulin expression in glioblastoma stem cells attenuates efficacy of microtubule-targeting agents. ACS Pharmacol. Transl. Sci. 2019;2(6):402–413. doi: 10.1021/acsptsci.9b00045. PubMed DOI PMC

Spagnuolo PA, et al. The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. Blood. 2010;115(23):4824–4833. doi: 10.1182/blood-2009-09-243055. PubMed DOI

Mc Gee MM. Targeting the mitotic catastrophe signaling pathway in cancer. Mediat. Inflamm. 2015;2015:146282. doi: 10.1155/2015/146282. PubMed DOI PMC

Carro MS, et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature. 2010;463(7279):318–325. doi: 10.1038/nature08712. PubMed DOI PMC

Ndubuisi MI, et al. Cellular physiology of STAT3: Where's the cytoplasmic monomer? J. Biol. Chem. 1999;274(36):25499–25509. doi: 10.1074/jbc.274.36.25499. PubMed DOI

Yan B, et al. STAT3 association with microtubules and its activation are independent of HDAC6 activity. DNA Cell Biol. 2015;34(4):290–295. doi: 10.1089/dna.2014.2713. PubMed DOI PMC

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