The Fenbendazole Phenomenon: Remarkable Repurposing of Dog Dewormer

Fenbendazole, part of the benzimidazole carbamate drug family, is commonly used to treat parasitic infections in animals and humans. Its mechanism of action involves the inhibition of microtubule polymerization, disrupting parasites' energy management by blocking glucose uptake. This depletes glycogen stores and reduces ATP production, leading to parasite death.

Fenbendazole has garnered attention within the cancer community, particularly in South Korea, due to anecdotal reports of cancer patients using it as an alternative treatment. Most notably, a case involving a businessman, Joe Tippens, whose lung cancer was reportedly cured after self-administering fenbendazole alongside supplements, has sparked widespread interest. It's worth noting that Joe omitted the fact that he was participating in a clinical trial for pembrolizumab when he claimed to be cured by fenbendazole.

Drug Repurposing

Drug repurposing, or reprofiling, is an appealing strategy in oncology as it accelerates drug development by utilizing existing drugs with known safety profiles. This approach can expedite the availability of new treatments by bypassing some of the costly and time-consuming steps of traditional drug development. Several antiparasitic drugs, including mebendazole (MBZ) and albendazole (ABZ), have been investigated for their anticancer potential. Fenbendazole is another promising candidate due to its affordability, wide availability, and established safety in humans and animals.

Mechanism of Action

Fenbendazole's anticancer mechanism is related to its ability to disrupt microtubule dynamics, much like other anticancer drugs that target tubulin, such as vinblastine and paclitaxel. By binding to beta-tubulin, fenbendazole inhibits microtubule polymerization, leading to apoptosis in cancer cells. This activity is particularly effective in actively dividing cells.

In cancer cells, fenbendazole also affects glucose metabolism by downregulating key glycolytic enzymes and GLUT transporters, thus limiting glucose uptake, which is crucial for cancer cell survival. Furthermore, fenbendazole induces oxidative stress and mitochondrial dysfunction, leading to cancer cell death.

Preclinical Studies and Anticancer Activity

Several preclinical studies have demonstrated fenbendazole's anticancer activity across various cancer types, including non-small cell lung cancer (NSCLC), lymphoma, and hepatocellular carcinoma. These studies show that fenbendazole can induce apoptosis and disrupt multiple signaling pathways involved in cell survival, such as PI3K/AKT, JAK/STAT, and MAPK. Additionally, fenbendazole has been shown to enhance the effects of other anticancer drugs, such as paclitaxel.

However, despite its potential, fenbendazole’s poor pharmacokinetic properties, such as its low bioavailability, limit its systemic effectiveness. This has led to the need for further investigation into ways to enhance its bioavailability in humans.

Self-Administration and Controversy

The rise in popularity of fenbendazole as an alternative cancer treatment has been driven largely by anecdotal reports shared through social media. Joe Tippens’ case, where he reported a complete recovery from lung cancer after using fenbendazole, has been particularly influential, prompting cancer patients in South Korea and elsewhere to self-administer the drug without medical supervision.

This self-administration trend has sparked controversy, with medical professionals warning against the unregulated use of fenbendazole due to the lack of clinical trials in humans. Reports of adverse effects, such as liver injury in patients using fenbendazole, have further fueled concerns. Despite these warnings, many cancer patients continue to use the drug, hoping for similar outcomes to those reported in anecdotal cases.

Liver Injury Case

A case report highlighted the potential risks of self-administering fenbendazole. An 80-year-old NSCLC patient experienced severe liver injury after taking fenbendazole for one month based on social media recommendations. The patient was also undergoing treatment with pembrolizumab, and the liver injury improved after discontinuing fenbendazole.

The Korean Phenomenon

The popularity of fenbendazole in South Korea has been notable. Since September 2019, when Tippens' story was shared on a South Korean YouTube channel, interest in the drug has surged. Despite warnings from medical associations, many terminally ill patients have turned to fenbendazole, and vet pharmacies have reported shortages of the drug due to high demand from cancer patients.

The controversy escalated when public figures, including a South Korean comedian, Kim Chul-Min, endorsed fenbendazole after claiming that it helped alleviate his cancer symptoms. However, Kim later reported severe side effects and passed away, further complicating the debate around the drug’s use.

Immunotherapy

In a study on fenbendazole and its effects on EL-4 cells and a mouse T lymphoma model the researches found that fenbendazole treatment increased the expression of PD-L1 and CD86 in EL-4 cells, which are markers related to immune modulation, particularly involving T-cell immunity. This implies fenbendazole may influence immune activity in the tumor microenvironment. Hematoxylin and eosin (H&E) staining of the tumor tissues revealed a "starry sky" pattern, indicative of aggressive tumor proliferation. Moreover, immunohistochemical analysis showed a high presence of M2 macrophages,  associated with immunosuppression and tumor progression. This suggests that fenbendazole might contribute to an immunosuppressive tumor microenvironment, despite its direct anticancer effects seen in vitro. Fenbendazole-induced tumor growth and immunosuppressive responses within the tumor microenvironment underscore the importance of additional research to understand the detailed mechanisms by which fenbendazole influences cancer.

References

Gao, Ping & Dang, Chi & Watson, Julie. (2008). Unexpected Antitumorigenic Effect of Fenbendazole when Combined with Supplementary Vitamins. Journal of the American Association for Laboratory Animal Science : JAALAS. 47. 37-40. 

Jung, Haebeen & Kim, Si-Yeon & Joo, Hong-Gu. (2023). Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma. Current Issues in Molecular Biology. 45. 8925-8938. 10.3390/cimb45110560.

Sultana, Tania & Jan, Umair & Lee, Hyunsu & Lee, Hyejin & Lee, Jeong-Ik. (2022). Exceptional Repositioning of Dog Dewormer: Fenbendazole Fever. Current Issues in Molecular Biology. 44. 4977-4986. 10.3390/cimb44100338.