Abstract
Mebendazole (Mbz), a well‑known anthelminthic drug, has demonstrated anticancer properties in tumor models and patients, and is thus under consideration for repositioning into an anticancer drug. Mbz is directly cytotoxic in cell lines by various mechanisms and acts indirectly via immunomodulation. In the present study, the anticancer effects of Mbz, alone and in combination with cytotoxic drugs, were further characterized using primary cultures of patient tumor cells ex vivo and the murine colon cancer cell line, CT26, in vitro and in vivo. Patient‑derived tumor cells from acute myeloid leukemia (AML) and ovarian, colorectal and renal cancer were exposed to Mbz alone and, for solid tumors and the CT26 cell line, in combination with irinotecan, cisplatin or gemcitabine (patient cells only). Cytotoxicity was assessed using the fluorometric microculture cytotoxicity assay. In vivo, the antitumor effects of Mbz and irinotecan, alone and in combination, were evaluated in the BALB/c CT26 colon cancer mouse model by tumor growth measurements and flow cytometric analysis of tumor immune cell infiltration. In the patient cell samples, Mbz showed modest single‑agent cytotoxicity, with the AML samples being the most sensitive, and displayed enhanced effects when combined with cytotoxic drugs, particularly irinotecan. CT26 cells showed modest dose‑independent sensitivity to Mbz, which enhanced the effect of both cisplatin and irinotecan. In vivo, Mbz and irinotecan both inhibited tumor growth, but the combination did not significantly outperform Mbz alone. Flow cytometry of the resected mouse tumors indicated that Mbz promoted macrophage polarization from the M2 to M1 phenotype, suggesting that immune modulation may contribute to its anticancer effect. Mbz has features making it a candidate for repositioning into an anticancer drug and part of its effect may be mediated by macrophage modulation.