Fenben is an antifungal drug with pleiotropic effects on cancer cells that lead to effective elimination of these tumors. It interferes with the formation of microtubules and inhibits glycolysis by interfering with expression of GLUT transporters and hexokinase, thereby preventing glycolysis-dependent cell growth. It also causes mitochondrial translocation of p53, leading to effective cell death via multiple pathways. These effects are expected to result in a greater therapeutic efficacy than single-target agents that only target one pathway, because resistance can develop through the selection of resistant cell populations.
The effect of fenbendazole (FZ) on radiation-induced local tumor growth was determined in EMT6 mouse tumor xenografts. Tumors were stratified by volume at the time of irradiation, and mice were treated with either FZ or a vehicle three times daily, starting immediately after tumor irradiation. After tumors reached a volume of 1000 mm3, they were euthanized and necropsied. Neither local tumor invasion nor lung metastases developed in either unirradiated or irradiated fenbendazole-treated mice.
Molecular studies showed that FZ alters the organization of the microtubule network by depolymerizing the -tubulin polymer into soluble and polymerized subunits. Its effects on tubulin were enhanced by colchicine treatment, which also disturbs the normal architecture of the microtubule system. The FZ-mediated alterations in tubulin structure were also detected by immunofluorescence using anti-a-tubulin antibodies and were confirmed by spectrophotometric measurement of polymerization, which was decreased by FZ and increased by colchicine.
To test whether fenbendazole interacts with P-gp, cultures were incubated for 2 or 24 h with varying concentrations of the compound and assayed for viability by a colony formation assay. Severe hypoxia significantly increased the toxicity of a 2-h treatment of cultures with FZ, but this cytotoxicity was abolished when the drug concentration was reduced to below the limit of solubility. fenben cancer treatment