The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma

Abstract

On-patent and off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication given their prior toxicity testing. To identify such compounds, we con-

Targeting the Microtubular Network as a New Antimyeloma Strategy

“…Benzimidazoles, including albendazole, fenbendazole, mebendazole, and nocodazole, have been used as anthelmintics and fungicides on the basis of their antimicrotubule activity (10) and have been reported to elicit promising antitumor effect (11)(12)(13). Although nocodazole has been recently categorized as an antineoplastic agent, the antimyeloma effects and its underlying mechanism of action have not been examined yet.…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Similar antitumor activity of mebendazole was found in gastric cancer, medulloblastoma, glioblastoma, leukemia and myeloma as well as in breast cancer stem cell-like cells [22][23][24][25][26]. Mebendazole potently inhibited hedgehog (Hh) signaling and slowed the growth of Hh-driven human medulloblastoma cells at clinically attainable concentrations [27].…”

“…For the anticancer activity of mebendazole impairment of the organization of tubulin was identified as main intracellular effect in lung cancer, gastric cancer, leukemia and brain tumors [9,20,22,25,32]. 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].…”

“…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.…”

“…Correspondingly, the in vivo growth of hedgehog-dependent medulloblastoma was inhibited by orally administered mebendazole. Targets Tubulin NSCLC [20], lung cancer [9], gastric carcinoma [22], leukemia [25], brain tumor [32] Apoptosis Adrenocortical CA [19], BCL2/XIAP melanoma [21,62], BCL-2 lung cancer [9].…”