Mebendazole and a non-steroidal anti-inflammatory combine to reduce tumor initiation in a colon cancer preclinical model

Abstract

Inheritance of a gene mutation leads to the initiation of 5 to 10% of most cancers, including colon cancer cases. We developed a chemoprevention strategy using a novel combination of the non-steroidal anti-inflammatory (NSAID) sulindac plus the anthelminthic benzimidazole, mebendazole. This oral drug combination was effective in the ApcMin/+ mouse model of Familial Adenomatous Polyposis (FAP). Treatment with 35 mg/kg daily mebendazole reduced the number of intestinal adenomas by 56% (P = 0.0002), 160 ppm sulindac by 74% (P < 0.0001), and the combination by 90% (P < 0.0001). The combination significantly reduced microadenomas, polyp number and size in both the small intestines and colon when compared to untreated controls or sulindac alone. Mebendazole as a single agent decreased COX2 expression, blood vessel formation, VEGFR2 phosphorylation, and worked synergistically with sulindac to reduce overexpression of MYC, BCL2, and various pro-inflammatory cytokines. Given the low toxicity of mebendazole, these preclinical findings support the consideration of clinical trials for high risk cancer patients using mebendazole either alone or in combination. The findings have implications for populations with moderate and above risk for developing cancer.

Emergence of TNIK inhibitors in cancer therapeutics

“…An FDA‐approved anthelmintic drug, mebendazole, was recently identified as a selective inhibitor of TNIK . Mebendazole showed anti‐tumor effects in a broad range of pre‐clinical studies across a number of different cancer types, including colorectal cancer, and the combination of mebendazole with a non‐steroidal anti‐inflammatory drug reportedly reduced tumor initiation in Apc Min/+ mice . Remarkable tumor regression by the administration of mebendazole was observed in a patient with drug‐refractory metastatic colorectal cancer .…”

“…(62) Mebendazole showed anti-tumor effects in a broad range of pre-clinical studies across a number of different cancer types, including colorectal cancer, (68) and the combination of mebendazole with a non-steroidal anti-inflammatory drug reportedly reduced tumor initiation in Apc Min/+ mice. (69,70) Remarkable tumor regression by the administration of mebendazole was observed in a patient with drug-refractory metastatic colorectal cancer. (71) Based on promising preclinical efficacy data, (72) mebendazole is currently under clinical evaluation in adult and pediatric brain tumors (ClinicalTrials.gov Identifier: NCT01729260 and NCT01837862).…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Mebendazole can be administered with the non-steroidal anti-inflammatory drug sulindac for prevention of tumor initiation in a colon cancer model [33]. Colon Cancer [52] Breast Cancer Triple [29] Breast Cancer [53] Adrenocortical Cancer [19] Adrenocortical Cancer [39] Leukemia/Myeloma [25] Leukemia/Myeloma [34] Leukemia/Myeloma [59,64] NSCLC [20] NSCLC [36] Lung Cancer CSC [57] Cell Lines [9] Cancer stem cells [46] Cancer [61] Gastric Cancer [22] Osteosarcoma [37] Medulloblastoma [23] Prostate Cancer [36] Melanoma [21,29] Ovarian Cancer/ TICs [41 -44] Ovarian cancer [62] Breast CSC-like Cells [26] Breast CSC-like Cells [40] Breast CSC-like Cells [56] Glioblastoma [24,32] Glioblastoma [33] Glioblastoma CD133 + [60] This table lists reports on investigations employing mebendazole, niclosamide and pyrvinium (pamoate) as anticancer agents against cell lines or in experimental animal models.…”

In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

“…Here, we applied a multi-pronged approach to unveil and validate new molecular targets for a well-known repurposed drug called mebendazole (MBZ). This anti-helminthic agent, which belongs to the benzimidazole class, has been shown to display potent anti-cancer properties in various models of human cancers [7][8][9][10][11][12] and thus appears as promising candidate for drug repurposing in oncology. Although the discovery of its therapeutic potential in brain tumors was fortuitous [11], it already resulted in 3 ongoing clinical trials in high-grade gliomas in both adult and pediatric patients (NCT01729260, NCT02644291 and NCT01837862).…”

“…Several mechanisms of action have been proposed to explain the anticancer properties of MBZ. These include tumor angiogenesis inhibition [12,13], targeting of critical pathways involved in cancer such as Hedgehog signaling [14] and stimulation of anticancer immune response [15,16]. Most of these effects have been linked to the ability of MBZ to induce microtubule depolymerization in cancer cells [8,11,17,18].…”