Fenbendazole

Overview of Fenbendazole

If you have a four legged friend it’s quite possible you will have heard of fenbendazole. It belongs to a family of drugs called benzimidazoles, which have been safely used around the world as anthelmintics (deworming medications) for animals for well over half a century [1].

Fenbendazole is commonly used in veterinary medicine for the treatment of gastrointestinal parasites like giardia, roundworms, hookworms, whipworms, and pinworms [2]. A sister product to fenbendazole, called mebendazole, is typically found in deworming medications for humans [1].

In recent decades, it has come to light that fenbendazole and other medications of the same family exhibit potent anticancer effects in laboratory (in vitro) and animal (in vivo) studies [2]. Benzimidazole anthelmintics (such as fenbendazole, albendazole, and mebendazole) have been shown to be toxic to cancer cells and minimally toxic to normal cells, induce apoptosis (programmed cell death) and autophagy (cellular repair and regeneration), impair glucose uptake of cancer cells, prevent angiogenesis (blood vessel formation of tumors), inhibit drug resistance, and exhibit other antitumor effects in preclinical studies with early clinical research ongoing to observe safety and efficacy in humans [3] [4] [5]. The drugs show promise as potential adjuvant therapies or novel anticancer drugs.

The development of multidrug resistance in patients with cancer receiving traditional chemotherapeutics causes 90% of deaths [6]. New therapeutic alternatives are therefore in great demand. Repurposing of already existing drugs is one approach used to find new therapeutic solutions, reduce drug development time and get to clinical trials more quickly. Fenbendazole is viewed as a potential candidate to be repositioned as an anticancer drug for multiple cancer types [3].

Despite its potential antitumor effects, there has been controversy surrounding the off-label use of fenbendazole in cancer treatment [6]. There have been anecdotal reports from cancer patients claiming its efficacy [2]. However, fenbendazole is not currently approved for use in humans and there are no clinical trials to date that confirm its safety and efficacy as an anticancer drug for humans. Mebendazole, however, is approved for use in humans and there is ongoing clinical research into its potential as an anticancer agent [7].

Historical Perspective of Fenbendazole

Merck & Co., an American multinational pharmaceutical company, began the use of anthelmintics in 1961. They were initially produced for animals, but soon after they were also prescribed for humans [1]. The first scientific studies on fenbendazole appeared in the literature around 1974 stating its efficacy as a novel deworming medication for animals [8]. Fenbendazole was created for both large and small animals including dogs, pigs, cats, cattle, horses, rabbits, and fish. It is extremely safe for animals when given as directed. Although fenbendazole has traditionally been considered an animal anthelmintic, when taken orally it is anecdotally reported to be well-tolerated in humans [1] [2].

The anticancer potential of fenbendazole was serendipitously discovered by research professor Gregory Riggins and neurosurgeon Gary Gallia in 2009 [9]. Riggins’ lab is renowned for discovering cancer causing genetic mutations and assessing novel cancer drugs prior to clinical trials. Under normal circumstances, the researchers would have no difficulty in triggering glioblastoma (brain cancer) cells to proliferate in mice. However, over a period of several months in 2009, they discovered a group of mice in which the tumors simply would not develop. These mice had been treated with fenbendazole.

The accidental discovery led the scientists to research more deeply into the anticancer effects of fenbendazole. Eventually, after screening many drugs in the same family of compounds they found that mebendazole, a related drug, was the most effective against glioblastoma cells. Research is ongoing and clinical trials are underway to help determine the efficacy of mebendazole in the treatment of glioblastoma [9].

A similar story also happened in 2008 when a group of researchers investigating human lymphoma in mice discovered that rodents pre-treated with fenbendazole did not develop tumors. The study later showed that fenbendazole in conjunction with certain vitamins in their diet significantly inhibited tumor growth in mice [10].

Over the last decade fenbendazole has gained popularity as an alternative cancer drug despite minimal data regarding its efficacy in humans. Anecdotal reports and viral success stories such as Joe Tippens, a businessman from Oklahoma, who was diagnosed with metastatic small cell lung cancer and given three months to live, have popularized the off-label use of the drug [2]. Three months later, after following a treatment protocol including (but not limited to) fenbendazole, Joe Tippens was completely cancer-free [2]. He shared his story online and many others in his network have also reported success stories [2]. However, this has sparked controversy and researchers have warned against self-administration due to a lack of clinical trials in humans, potential interference with standard of care treatment and some reports of liver injuries after extended use [2].

The patents for both fenbendazole and mebendazole have expired [1]. Fenbendazole has only been approved for veterinary use and is yet to be established as safe for human use [3]. This means the process of drug repurposing and approval for human use through clinical trials would be time consuming and costly. Without patent protection there is less of a financial incentive to develop the drug [1]. Given that mebendazole is already approved for human use the drug will be faster and cheaper to repurpose for cancer treatment [1]. Mebendazole currently has priority for clinical research over other benzimidazole anthelmintics such as fenbendazole [3]. Clinical trials will help to shed more light on the safety and efficacy of mebendazole [3]. Time will tell if benzimidazole anthelmintics will be approved for use in cancer treatment [3].

Research about Fenbendazole

There are no clinical studies on fenbendazole as an anticancer drug in humans. Therefore, the safety and efficacy for cancer treatment is currently unknown. The anticancer effects of fenbendazole against cancer cells in vitro (test-tube studies) have been known for a long time, but there is no definitive scientific evidence of anticancer effects in humans at this stage [11].

However, two other broad spectrum anthelmintics with similar mechanisms of action that are approved for human use, albendazole and mebendazole, have been repositioned as promising anticancer drugs [7]. They have been shown in test tube and animal studies to have potent anticancer effects against liver, lung, ovary, prostate, colorectal, breast, head and neck cancers, and melanoma [7].

Two case reports for mebendazole have revealed promising effects of these drugs in human patients with a range of cancer types [12] [13]. Mebendazole has a better toxicity profile than albendazole and a long track record of safety in humans, which makes it the favorite candidate for clinical trials. Clinical trials on these drugs are currently ongoing for various cancer types [7].

Despite limited data from clinical trials to confirm efficacy, some patients with metastatic late stage cancers have responded well to albendazole and mebendazole showing reduced tumor markers, metastasis (spread of cancer) and stabilized disease [3].

The poor bioavailability (ability to be absorbed and used) of anthelmintics is a hindrance that has been flagged as a potential limitation with this class of drugs [3]. Better formulation strategies to enhance bioavailability could be required to improve the antitumor effects and prolong overall survival in patients [3]. Anthelmintics approved for veterinary care have well-known safety for animals, however the safety has not yet been established for human use, which calls for further research into these drugs [3].

While mebendazole is the benzimidazole family member currently receiving greater attention for clinical trials, a 2018 study from a highly respected scientific journal has put renewed attention on fenbendazole and highlighted its promise as a potential therapeutic anticancer drug for humans [4]. Further research will give better insight to benzimidazole anthelmintics for primary and metastatic cancer treatments in the near future [3].

Proposed Applications of Fenbendazole

Conventional cancer treatment (including chemotherapy and radiation therapy) has toxic side effects such as destruction of healthy cells, neurotoxicity, cardiotoxicity, gastrointestinal toxicity, and immune suppression, which often results in a severely diminished quality of life in patients with cancer [14] [3].

Benzimidazole anthelmintics have been shown to exhibit synergistic and enhanced antitumor effects in combination with conventional chemotherapy and radiation [3]. They also have toxic effects on cancer cells that are resistant to standard of care treatments [3] [15]. As a result, benzimidazole anthelmintics, such as albendazole, fenbendazole and mebendazole, show potential as effective adjuvant therapies to enhance conventional treatment or for application in cases of chemoresistant cancers [3] [15]. Furthermore, this class of drugs have a strong safety and low toxicity profile [3]. Therefore, synergistic application may reduce the toxic effects of conventional therapy by lowering the dosages of chemotherapeutics and supplementing with higher doses of anthelmintics [3].

Fenbendazole is known to exert potent anticancer activities such as the disruption of microtubule polymerization (protein synthesis required for tumor growth), inducing apoptosis (programmed cell death), blocking glucose transport to cancer cells, preventing angiogenesis (blood vessel formation) that fuels new tumor growth, and reactivating the p53 gene that is responsible for suppressing tumors [3] [16]. Therefore, it shows promise as a powerful anticancer agent for humans [4]. However, further research and clinical trials are still needed to determine efficacy as an adjuvant or primary treatment for cancer [3].

If mebendazole is shown to be safe and effective as an anticancer drug in humans in clinical trials, it is possible that fenbendazole could also prove to be equally if not more effective due to its similar mechanism of action and related anticancer properties [3]. Fenbendazole has already proven to be more effective against certain other diseases than albendazole or mebendazole [17]. Nevertheless, clinical trials on fenbendazole are required to confirm its safety, efficacy and potential therapeutic applications for the treatment of cancer in humans.

Risks and Side Effects of Fenbendazole

Benzimidazole anthelmintics are used in both human and veterinary medicine. Decades of use since their introduction in the 1960s has shown them to be well-tolerated without severe side-effects in most species, which provides a basis for potential safety of fenbendazole in humans [3].

However, fenbendazole has not been approved for human consumption. There is no significant clinical data on its safety profile, recommended dosages, or toxicity thresholds for humans. Therefore, potential risks and side-effects are currently unknown.

The documented side-effects of benzimidazole anthelmintics as a class of drugs include [3]:

• Headaches
• Gastrointestinal issues
• Diarrhea
• Vomiting
• Liver toxicity
• Leukopenia
• Anorexia
• Anemia

Benzimidazole anthelmintics must be used with caution in patients with reduced liver function and with liver cirrhosis and liver cancer [3].

To date scientific studies have not reported significant adverse effects from human consumption of fenbendazole. However, there is scarce clinical data and observations in humans are limited [18].

Although fenbendazole may be considered a nontoxic drug in animals, benzimidazole anthelmintics that are approved for veterinary use do not have sufficient evidence of safety for human use [3]. Further studies are required.