Mebendazole inhibits tumor growth and prevents lung metastasis in models of advanced thyroid cancer

Abstract

The most common thyroid malignancy is papillary thyroid cancer. While a majority respond to therapy and have a favorable prognosis, some papillary thyroid cancers persist. This subset may dedifferentiate to anaplastic thyroid cancer, an aggressive, highly invasive and rapidly fatal cancer. Thyroid cancer patients at risk for disease progression and metastasis need earlier, safer and more effective therapies. The purpose of this translational study was to determine if mebendazole could be repurposed to effectively treat thyroid cancer, in particular before metastasis. In vitro, mebendazole potently inhibited the growth of a panel of human papillary and anaplastic thyroid cancer cells. In papillary (B-CPAP) and anaplastic (8505c) cell lines, mebendazole increased the percentage of cells in G2/M cell cycle arrest and induced late stage apoptosis by activation of the caspase-3 pathway. In aggressive 8505c cells, mebendazole significantly repressed migratory and invasive potential in a wound healing and transwell invasion assay and inhibited expression of phosphorylated Akt and Stat3 and reduced Gli1. In vivo, mebendazole treatment resulted in significant orthotopic thyroid tumor regression (B-CPAP) and growth arrest (8505c), with treated tumors displaying reduced expression of the proliferation maker KI67 and less vascular epithelium as indicated by CD31+ immunohistochemistry. Most importantly, daily oral mebendazole prevented established thyroid tumors from metastasizing to the lung. Given the low toxicity and published anticancer mechanisms of mebendazole, this novel preclinical study of mebendazole in thyroid cancer has promising therapeutic implications for patients with treatment refractory papillary or anaplastic thyroid cancer.

Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways

“…We demonstrated that MBZ exerted more potent anti-proliferation activity than cisplatin in human HNSCC cells, and effectively inhibited cell proliferation, cell cycle progression and cell migration, and induced apoptosis in HNSCC cells [ 18 ]. Other studies indicate that MBZ and its derivatives exerted potent anticancer effect in non-small cell lung cancer [ 19 , 20 ], adrenocortical carcinoma [ 22 ], medulloblastoma [ 28 ], melanoma [ 21 ], leukemia and myeloma [ 24 ], glioblastoma multiform [ 23 , 34 ], colon cancer [ 26 ], cholangiocarcinoma [ 27 ], breast cancer [ 25 , 29 ], gastric cancer [ 30 ], mouse hepatoma [ 31 ], and thyroid cancer [ 32 ]. In this study, our results are the first to demonstrate that MBZ can overcome cisplatin resistance and synergize with cisplatin in inhibiting cell proliferation and inducing apoptosis in cisplatin-resistant ovarian cancer cells.…”

Overcoming cancer therapeutic bottleneck by drug repurposing

“…[385][386][387] In further agreement, a recent study reported that mebendazole reduced GLI1 expression in advanced thyroid cancer. 388 Mebendazole was also shown to have anticancer activity and enhanced cisplatin-induced DNA damage, by inhibition of DNA doublestrand break repair, in head and neck squamous cell carcinoma. 389 Interestingly, benzimidazole derivatives were reported as potential dual inhibitors for PARP-1 and DHODH, two key proteins involved in DNA replication and repair mechanisms, respectively.…”

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

“…Supplementary Table 1 ( 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 ) summarizes the antitumorigenicity of benzimidazole anthelmintics on cancer cell lines. Benzimidazole anthelmintics inhibit the progression of cancer through a variety of mechanisms.…”

“…We summarized the antitumorigenicity of benzimidazole anthelmintics in animal tumor models ( Supplementary Table 2 ) ( 4 8 11 12 13 14 15 16 17 20 27 28 29 30 34 35 36 37 39 45 47 51 52 54 55 56 57 61 63 64 65 66 69 70 71 74 75 76 78 79 80 92 93 94 ). Benzimidazole anthelmintics have been shown to inhibit the tumor growth in animals, which have been well-tolerated without significant side effects during the experimental period.…”