Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma

Li, Qian; Demir, Salih; Rio-Alvarez, Alvaro del; Maxwell, Rebecca; Wagner, Alexandra; Carrillo-Reixach, Juan; Armengol, Carolina; Vokuhl, Christian; Haeberle, Beate; Schweinitz, Dietrich von; Schmid, Irene; Cairo, Stefano und Kappler, Roland (2022): Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma. In: Cancers, Bd. 14, Nr. 17, 4196

Abstract

Simple Summary Hepatoblastoma patients with tumors that do not respond to preoperative chemotherapy often experience incomplete surgical resection and thus poor outcomes. By analyzing the gene expression data of chemoresistant and responsive tumors using sophisticated drug prediction software we identified mebendazole, a medication usually used to treat parasitic worm infestations, as a putative drug to circumvent chemoresistance. We evaluated the efficacy of this drug in cell culture models of hepatoblastoma and found that both short- and long-term tumor cell growth were significantly inhibited upon treatment. Moreover, we identified the cellular and molecular consequences of mebendazole treatment to be the arrest of cell division and the induction of programmed cell death by the deregulation of genes involved in the unwindosome. Most importantly, mebendazole also proved effective when tested in a mouse model carrying a patient-derived tumor. Our results demonstrate the successful repurposing of mebendazole as a new treatment option for chemoresistant hepatoblastoma. Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch