Repurposing the Antihelmintic Mebendazole as a Hedgehog Inhibitor

Abstract

The hedgehog (Hh) signaling pathway is activated in many types of cancer and therefore presents an attractive target for new anticancer agents. Here we show that mebendazole (MBZ), a benzamidazole with a long history of safe use against nematode infestations and hydatid disease, potently inhibited Hh signaling and slowed the growth of Hh-driven human medulloblastoma cells at clinically attainable concentrations. As an antiparasitic, MBZ avidly binds nematode tubulin and causes inhibition of intestinal microtubule synthesis. In human cells, MBZ suppressed the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for Hh pathway activation. The inhibition of Hh signaling by MBZ was unaffected by mutants in the gene that encodes the Hh pathway signaling protein SMO, which are selectively propagated in cell clones that survive treatment with the Hh inhibitor vismodegib. Combination of vismodegib and MBZ resulted in additive Hh signaling inhibition. Because MBZ can be safely administered to adults and children at high doses over extended time periods, we propose that MBZ could be rapidly repurposed and clinically tested as a prospective therapeutic agent for many tumors that are dependent on Hh signaling.

Repurposing of Anthelminthics as Anticancer Drugs

“…Mebendazole potently inhibited hedgehog (Hh) signaling and slowed the growth of Hh-driven human medulloblastoma cells at clinically attainable concentrations [27]. In human cells, mebendazole suppressed the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for Hh pathway activation.…”

“…Mebendazole at the standard antihelmintic dose of 100 mg twice daily for six weeks stabilized disease in one patient with metastatic colon cancer [27,31]. Clinical trials employing mebendazole for the treatment of high-grade glioma patients which receive temozolomide and for recurrent/progressive pediatric brain tumors are in the recruiting phase.…”

“…Cytotoxicity was enhanced by alterations of the regulators of apoptosis, such as Bcl2/XIAP, in melanoma, lung cancer and adrenocortical carcinoma [9,19,21,67]. In human cells, mebendazole suppressed the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for Hh pathway activation [27]. Correspondingly, the in vivo growth of hedgehog-dependent medulloblastoma was inhibited by orally administered mebendazole.…”

“…The substituted quinoline pyrvinium pamoate (PPAM) is a cyanine dye which has been used to treat pinworm (Enterobius vermicularis) infections as well as strongyloidiasis in humans [5,27]. Pyrvinium exhibits a dark-red fluorescent color which yields a higher signal upon interaction with DNA [82,83].…”

Molecular Bases for Combinatorial Treatment Strategies in Patients with KRAS Mutant Lung Adenocarcinoma and Squamous Cell Lung Carcinoma

“…Finally, mebendazole, a drug approved for treatment of nematode infections, has been found to suppress the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for Hh pathway activation [106]. …”