Fenbendazole (Panacur)

Anti-cancer Mechanisms and Targets of Fenbendazole

 

fenbendazole for cancer, Studies attribute the anti-cancer mechanisms of fenbendazole to increasing p53 activation, inhibiting the GLUT1 transporter and hexokinase, and reducing glucose uptake in cancer cells .

Enhanced glycolysis is a crucial signal of tumor progression. Under anaerobic conditions, glycolysis produces lactate, which increases acidification in the tumor microenvironment and leads to drug resistance.

Metabolic disturbances, such as glutamine overuse, further enhance glycolysis, creating a feedback loop for tumor growth. Fenbendazole has been found to inhibit glucose uptake, resulting in reduced lactate levels (4). Thus, fenbendazole can serve as a viable treatment for drug-resistant cancer cells.

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Fenbendazole exhibits several other mechanisms contributing to its anti-cancer effects, primarily by disrupting energy metabolism. It functions as a microtubule destabilizing agent, impairs proteasomal function, and inhibits glucose metabolism.

Glucose, a primary energy source for tumor cells, is metabolized through aerobic glycolysis and delivered across the cell membrane via the GLUT1 transporter. Unlike normal cells, cancer cells perform glycolysis to metabolize glucose to lactate even under aerobic conditions.

Although aerobic glycolysis is not an efficient method of supplying energy and appears to produce less ATP than oxidative phosphorylation, it provides essential materials for tumor cell growth, such as nucleotides, amino acids, and lipids. Additionally, the ATP/ADP and NADH/NAD+ ratios in tumor cells remain high, indicating sufficient ATP supply through glycolytic tumor metabolism.

The GLUT1 transporter has been highly expressed in 99% of patients with squamous cell carcinoma and 50% of patients with adenocarcinoma, leading to being proposed as a promising therapeutic target in cancer therapy.

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Fenbendazole induces mitochondrial translocation of p53, indicating activation of the p53-p21 pathway, which inhibits GLUT transporter expression and prevents glucose uptake in cancer cells. Through p53 activation, fenbendazole is believed to impede hexokinase II (HKII), the first glycolytic pathway enzyme critical for cancer cell growth.

However, another study did not observe inhibition of HKII activity at 1 and 10 μM fenbendazole. As a primary enzyme in glucose metabolism, the inhibition of HKII would prevent tumor development. Therefore, fenbendazole’s actions on HKII warrant further exploration. Thus, through targeting GLUT1, HKII, and glycolysis, fenbendazole can lead to cancer cell starvation and reverse drug resistance, aiding cancer treatment.

In addition to glycolysis inhibition, fenbendazol induces apoptosis in cancer cells. In colorectal cancer (CRC) cells, fenbendazol triggers apoptosis through mitochondrial injury and the caspase 3-PARP pathway. In wild-type CRC, fenbendazole activates p53-mediated apoptosis by increasing p53 expression.

Additionally, it induces necrosis, autophagy, and ferroptosis. In 5-FU-resistant CRC, fenbendazole triggers apoptosis without affecting p53 expression, likely enhancing p53-independent ferroptosis-augmented apoptosis.

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Fenbendazole also acts as a microtubule destabilizing agent. Microtubule-targeting agents are promising cancer treatments due to the microtubules’ roles in mitosis, cell structure maintenance, and other cellular events.

Some cancer therapy drugs inhibit microtubule polymerization (vincristine, vinblastine), while others stabilize microtubules (paclitaxel, docetaxel), leading to apoptosis and metaphase arrest. Fenbendazol shows microtubule depolymerizing activity in human cancer cell lines and demonstrates anticancer effects in vitro and in vivo.

Fenbendazol induces cell cycle arrest in the G₂/M phase  and demonstrates tubulin destabilization activity at concentrations of 1 and 10 μM, with more cell cycle arrest demonstrated at higher concentrations.

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When administered orally at micromolar concentrations, fenbendazol induces cytotoxicity and effectively blocks cancer cell growth. Fenbendazol also causes oxidative stress and activates the MEK3/6-p38MAPK pathway, inhibiting cancer cell proliferation and enhancing apoptosis.

Fenbendazol reduces toxicity to normal cells while maintaining its anti-cancer effects of impairing energy metabolism and restraining cancer cell migration and invasion. Beyond oncology, fenbendazol shows potential in treating pulmonary fibrosis by inhibiting the progression of bleomycin-induced lung fibrosis.