Fenbendazole for Humans Cancer

The anthelmintic fenbendazole is an established anticancer drug with mechanisms of action that overlap with those of the hypoxia-selective nitroheterocyclic cytotoxins and radiosensitizers. To investigate the potential of fenbendazole as an anticancer agent, we tested its effects on EMT6 mammary tumor cells in vitro and on tumor-bearing mice. Intensive treatments of fenbendazole were toxic to EMT6 cells, with toxicity increasing over time and in the presence of severe hypoxia. Treatment with fenbendazole did not significantly alter radiation dose-response curves for aerobic or hypoxic cells, nor did it increase the sensitivity of EMT6 cells to docetaxel in combination regimens.

In a series of experiments, BALB/cRw mice were randomized at 100 mm3 to serve as untreated controls, or to receive three daily i.p. injections of fenbendazole, 10 Gy of x-rays or both. Tumor growth was rigorously monitored by comparing the time required for each tumor to grow from its initial volume to four times its size (Table I). No differences were observed in the growth of untreated tumors or irradiated tumors treated with fenbendazole alone, but a significant inhibition of tumor growth occurred when the tumors received a combined treatment of fenbendazole and x-rays.

To further evaluate the effect of fenbendazole on EMT6 cell viability and the ability of the drug to enhance antineoplastic therapy, we measured the protein expression of c-Myc and p53 in untreated and irradiated EMT6 cells. Both proteins were markedly decreased in irradiated cells, but the loss of c-Myc was more pronounced when fenbendazole was added to the treatment. Moreover, p53 was not significantly affected by fenbendazole in 5-fluorouracil-resistant SNU-C5 cells, whereas it was repressed in wild-type cells and inhibited by the drug in p53 mutants.

To determine whether fenbendazole and its active metabolite, oxifendazole, could enhance the antitumor effects of docetaxel in combination regimens, we examined the effects of 2-h and 24-h treatments of oxyfendazole on the viability of EMT6 cells in the presence and absence of radiation. Severe hypoxia augmented the cytotoxicity of oxyfendazole, but only at concentrations above its limit of solubility. Treatments of aerobic and hypoxic EMT6 cells with fenbendazole produced no change in cell numbers, although the numbers were slightly lower than those in cultures treated with oxifendazole alone. When the surviving fractions were normalized to account for the toxicity of fenbendazole, the oxifendazole-fenbendazole survival curves superimposed on each other and showed additive toxicity. Additivity was further confirmed by isobologram analysis. fenbendazole for humans cancer

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