From anti-worms to anti-cancer
Previously, we discussed on this website the anti-worm drug Mebendazole (Ref.), which based on a good amount of scientific and clinical evidence, shows relevant anti cancer potential. Indeed, there are case reports published in peer review papers showing that Mebendazole can induce anti-cancer response in some aggressive cancers.
In the same article (Ref.) we explored the mechanism behind the anticancer action of Mebendazole, and found out that Mebendazole acts in a similar way as a group of chemotherapies such as Taxol. Yet, in contrast to chemotherapies, due to the way Mebendazole works, its toxicity is incomparably lower. Because of its good safety profile, the drug is an over the counter drug in most of the countries.
I specifically like the anti-worms, anti-parasites, antibiotics, antiviral drugs, as a pattern start to emerge suggesting that the origin of cancer may be related to such a trigger (e.g. viruses, parasites, etc.) in much more cases than we currently are aware of. Multiple findings and observations, that I will discuss in a different post, indicate that such triggers may initiate cancer when they land in a “fertile ground”, represented by specific genetic weaknesses combined with a compromised immune system (due to e.g. stress, lifestyle, medication, etc.). This is why, I would seriously consider using anti-worms, anti-parasites, antibiotics, antiviral drugs as a part of more comprehensive treatment approaches that could also include conventional therapies. As long as the toxicity is low, it could make sense to cycle various drugs of this type.
The anti-worm drug Fenbendazole has anti-cancer potential
In the same group of drugs as Mebendazole, a group called benzimidazoles, there is another anti-worm drug called Fenbendazole. Fenbendazole, is a drug used typically not for humans like Mebendazole, but for animals (including fish, birds and mammals). It is labelled to kill worms such as roundworms, hookworms, whipworms, and some tapeworms. Fenbendazole is found under various brand names such as Panacur or Safe-Guard.
I did came across this drug some years ago during my research, but only recently I was motivated to look closely at it following several e-mails from friends who shared with me the blog of a man with Small Cell Lung Cancer, who successfully treated his cancer with Fenbendazole (Ref.). On his website, Joe Tippens, not only reports his experience but also anecdotally reports being in contact with more patients experiencing benefits while using Fenbendazole, including two cases of 4th stage Pancreatic Cancer, Prostrate Cancer, Colorectal Cancer, Non-Small Cell Lung Cancer, Melanoma, Colon Cancer. This anecdotal report would not be enough to trigger me writing this post, if I would not be convinced by the existing scientific evidence indicating the anti cancer potential connected with many of the benzimidazoles drugs. Therefore, I do believe that if Mebendazole could show relevant anti-cancer effects in humans, which it did, Fenbendazole could do it as well and hopefully even better.
In some diseases, it has been indeed shown that Fenbendazole can be more effective than Mebendazole. For example, when tested against Cryptococcus neoformans (an encapsulated fungal organism that can cause disease such as meningoencephalitis in immunocompromised hosts), it has been shown that Fenbendazole was more active than Mebendazole or other drugs against this opportunistic fungus (Ref.).
While there is more prior literature suggesting anti cancer effectiveness related to Fenbendazole, the paper I found most relevant to specifically cite here first is a paper that was just published during 2018 in one of the most prestigious scientific magazine, that is Nature, which adds a lot of weight to the communicated message. This paper, entitled “Fenbendazole acts as a moderate microtubule destabilizing agent and causes cancer cell death by modulating multiple cellular pathways“, concludes the following:
- “The results, in conjunction with our earlier data, suggest that Fenbendazole is a new microtubule interfering agent that displays anti-neoplastic activity and may be evaluated as a potential therapeutic agent because of its effect on multiple cellular pathways leading to effective elimination of cancer cells.”
In this paper, the authors cite potential anti cancer mechanisms associated with Fenbendazole, including disruption of microtubule function and proteasomal interference, but it was also associated with blocking the glucose uptake by cancer cells (through reducing the expression of Glut-4 transporter as well as hexokinase) and thus starving cancer cells. This means Fenbendazole could also work nicely in supporting chemotherapy and radiotherapy as well as metabolic therapies. Because of the way it works (interacting with a site on tubulin similar to colchicine but distinct from that of Vinca alkaloids), Fenbendazole will not compete with Vinca alkaloids (such as Taxol) but instead will add to the anti cancer effect of these conventional treatments similar to other benzimidazoles (Ref.).
Interestingly, when insulin stimulates glucose uptake in the cells, glucose transporter isoform 4 (GLUT4) translocates from intracellular vesicles to the plasma membrane ready to absorb glucose. This movement of GLUT4 towards the plasma membrane takes place via both rapid vibrations around a point and short linear movements (generally less than 10 microm). The linear movement seems to take place along microtubules. When disrupting the microtubules with drugs such as Fenbendazole, GLUT4 movements are disrupted as well strongly reducing insulin-stimulated glucose uptake (Ref.).
Another very interesting point coming from the Nature paper cited above is that Fenbendazole shows strong synergy when combined to DCA, a drug that I discussed earlier on this website https://www.cancertreatmentsresearch.com/dichloroacetate-dca-treatment-strategy/ So it may make very much sense to combine the two, and possibly 2DG (Ref.).
While Fenbendazole could be relevant for many types of cancers (as also suggested by the anecdotal reports listed above and by literature on the anticancer effects of benzimidazoles drugs) prior literature has so far indicated it’s anti cancer effects in
- Non-small Cell Lung Cancer Cells (NSCLC) (Ref.)
- Fenbendazole inhibits the cellular proteasome function dose- and time-dependently and leads to accumulation of ubiquitylated derivatives of various cellular proteins, including p53, which, in turn, leads to apoptosis via the mitochondrial pathway
- the cells first undergo G2/M arrest followed by apoptosis
- Fenbendazole induced endoplasmic reticulum stress, reactive oxygen species production, decreased mitochondrial membrane potential, and cytochrome c release that eventually led to cancer cell death.
- Lymphoma (Ref.)
- Prostate Cancer (Ref.) and taxane-resistant prostate cancer cells (Ref.)
- Glioblastoma (Ref.1, Ref.2)
The questions, is why I would consider using Fenbendazole, a drug used for animals, when we already have Mebendazole made for use in humans that is associated to similar anticancer mechanisms? There are three major reasons for me to do that and consider trying Fenbendazole as well:
- First, as discussed above, in some diseases, Fenbendazole was more effective than Mebendazole;
- Second, it is known that this type of drugs is not very well absorbed in the body and the absorption may differ from person to person (Ref.). Therefore switching between different drugs with similar expected mechanisms may make sense as one of them may be better absorbed in our specific case;
- Third, there is a good chance that the underlying anti-cancer mechanism is different for each of the drugs, even if the scientific observations suggest similar mechanisms of action (we should always remember that science represents not a complete understanding of nature, but only steps towards a better understanding).
Fenbendazole is well tolerated in humans
Although a drug that is used for animals, according to a report available at the European Medicine Agency “Fenbendazole seems to be well tolerated in humans after oral exposure (single oral dose up to 2,000 mg/per person; 500 mg/per person for 10 consecutive days)” (Ref.)
What type and how is Fenbendazole used
Taking Panacur C granules from Merck
There are people taking it for deworming and they seem to prefer the Fenbendazole version that is meant to be used for fish (Ref.). In this case, its is used in the range of 5mg/kg/day to 10mg/kg/day.
However, on his website, Joe Tippens, shows a picture of Panacur C box from Merck, sold as Canine Dewormer, containing Fenbendazole granules 22.2%. This means every gram of granules contains 222mg of pure Fenbendazole.
Dose and treatment regime
In his treatment protocol, following a discussion with one scientist from Merck animals who treated her brain cancer with Fenbendazole, Joe Tippens uses 1g granules (containing 222mg pure Fenbendazole) each day, and he is taking that 3 consecutive days. He than stops taking Fenbendazole for the next 4 days. After that he starts again, and he goes like this continuously during the year. So the drug administration is 3 days ON and 4 days OFF.
If due to any reason taking Fenbendazole for ever it’s not an option, I would at least consider taking it for 3 days, then repeat a three day course at three weeks and again at three months. This the minimum treatment schedule in my view and is inline with the rule of 3’s used when treating whipworms (Trichuris vulpis). The idea behind this treatment regime is that some warms such as Whipworms take 3 months to mature from an egg to an adult. If you kill adults at day 1, then three weeks later there will be some immature adults which will have matured, but you’ll still have eggs and larval worms present (Ref.). Nevertheless, this is the minimum regime I would use but I would probably better follow the treatment regime used by Joe Tippens (continuous 3 days ON and 4 days OFF) for 2-3 months and check if there is a response. If there is response, and tumors are shrinking I would continue, if not I would stop. Joe Tippens said he will take it for the rest of his life. He states there were no side effects for him or for over 50 people he knows taking it.
Since it has been shown that 500 mg/per person for 10 consecutive days is well tolerated in humans (Ref.), and since as discussed below the absorption of Fenbendazole in humans is poor, it may help to use from time to time a higher dose, such as 2g granules (each gram containing 222 mg pure Fenbendazole) each day, which would lead to a daily dose of 444 mg Fenbendazole.
Therefore, a suitable daily dose of Fenbendazole for longer term use may be between 220 mg (the dose that was effective for Joe Tippens) and 500mg (the dose shown tolerable in humans).
Since there are various produces for Fenbendazole under different brands, in different forms (granules, solution, capsules) and for different animals, it is best to check on the package to understand how much active ingredient (Fenbendazole) is in one gram (or ml) of the product we buy. And make sure that the daily dose of active ingredient (Fenbendazole) is somewhere between 220 mg and 500 mg.
Better to take it with or after food
Like many benzimidazoles, Fenbendazole is very poorly soluble in aqueous systems, which are found in the gastrointestinal tract, causing its low absorption to the bloodstream and thus very low bioavailability. Maximal plasma concentration levels of benzimidazoles in humans is known to be markedly increased if the substance is used immediately after a meal (Ref.1, Ref.2).
As for the case of Mebendazole, I expect another way to increase its absorption in the body is by combining it with Cimetidine (Ref.).
Add Vitamin E to possibly enable Fenbendazole effectiveness
During 2008, at the School of Medicine from Johns Hopkins University, it has been found that Fenbendazole could affect the growth of a human lymphoma cell line only when combined with vitamins (Ref.). Supplemented vitamins included B, D, K, E, and A.
Indeed, in his treatment regime, Joe Tippens also included the following: Tocotrienol form of Vitamin E (800IU per day, 7 days a week); Bio-Available Curcumin (600mg per day, 7 days a week), and CBD (25mg per day, 7 days a week) oil (Ref.).
The common vitamin that is both present in the supplement vitamins in the article cited above and Joe’s treatment regime is Vitamin E (800IU per day, 7 days a week). He uses a VITAMIN E (AS D-ALPHA TOCOPHEROL) complex of 400IU called Perfect E, containing:
- MIXED TOCOPHEROLS (~D-GAMMA TOCOPHEROL 400 mg; ~D-DELTA TOCOPHEROL 9 mg; ~D-BETA TOCOPHEROL 7 mg)
- TOCOTRIENOLS (FROM PALM) (~GAMMA TOCOTRIENOL 19 mg; ~DELTA TOCOTRIENOL 6 mg; ~ALPHA TOCOTRIENOL 12 mg; ~BETA TOCOTRIENOL 1 mg)
Given that each capsule has 400UI, 2capusles/day should match Joe’s schedule.
Indeed, other studies have also shown that the combination of Fenbendazole and Vitamin E can be effective against cancer (Ref.).
However, just to stay on the safe side, because of its anti oxidant properties I would not use Vit E during the chemo or radio therapy.
Where to buy
Panacure C can be found all over the world at online shops. It can be found in packages of 3 packets of 1g granules (or 222mg Fenbendazole, for small dogs) or 3 packets of 2g granules (or 444mg Fenbendazole, for adult dogs).
Fenbendazole should not be confused with Flubendazole.
In vitro anti-tubulin effects of mebendazole and fenbendazole on canine glioma cells. https://www.ncbi.nlm.nih.gov/pubmed/28078780
Benzimidazole anthelmintics have reported anti-neoplastic effects both in vitro and in vivo. The purpose of this study was to evaluate the in vitro chemosensitivity of three canine glioma cell lines to mebendazole and fenbendazole. The mean inhibitory concentration (IC50 ) (±SD) obtained from performing the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay after treating J3T, G06-A, and SDT-3G cells for 72 h with mebendazole were 0.030 ± 0.003, 0.080 ± 0.015 and 0.030 ± 0.006 μM respectively, while those for fenbendazole were 0.550 ± 0.015, 1.530 ± 0.159 and 0.690 ± 0.095 μM; treatment of primary canine fibroblasts for 72 h at IC50 showed no significant effect. Immunofluorescence studies showed disruption of tubulin after treatment. Mebendazole and fenbendazole are cytotoxic in canine glioma cell lines in vitro and may be good candidates for treatment of canine gliomas. Further in vivo studies are required.
Impairment of the Ubiquitin-Proteasome Pathway by Methyl N-(6-Phenylsulfanyl-1H-benzimidazol-2-yl)carbamate Leads to a Potent Cytotoxic Effect in Tumor Cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436308/
In recent years, there has been a great deal of interest in proteasome inhibitors as a novel class of anticancer drugs. We report that fenbendazole (FZ) (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl)carbamate) exhibits a potent growth-inhibitory activity against cancer cell lines but not normal cells. We show here, using fluorogenic substrates, that FZ treatment leads to the inhibition of proteasomal activity in the cells. Succinyl-Leu-Leu-Val-Tyr-methylcoumarinamide (MCA), benzyloxycarbonyl-Leu-Leu-Glu-7-amido-4-MCA, and t-butoxycarbonyl-Gln-Ala-Arg-7-amido-4-MCA fluorescent derivatives were used to assess chymotrypsin-like, post-glutamyl peptidyl-hydrolyzing, and trypsin-like protease activities, respectively. Non-small cell lung cancer cells transiently transfected with an expression plasmid encoding pd1EGFP and treated with FZ showed an accumulation of the green fluorescent protein in the cells due to an increase in its half-life. A number of apoptosis regulatory proteins that are normally degraded by the ubiquitin-proteasome pathway like cyclins, p53, and IκBα were found to be accumulated in FZ-treated cells. In addition, FZ induced distinct ER stress-associated genes like GRP78, GADD153, ATF3, IRE1α, and NOXA in these cells. Thus, treatment of human NSCLC cells with fenbendazole induced endoplasmic reticulum stress, reactive oxygen species production, decreased mitochondrial membrane potential, and cytochrome c release that eventually led to cancer cell death. This is the first report to demonstrate the inhibition of proteasome function and induction of endoplasmic reticulum stress/reactive oxygen species-dependent apoptosis in human lung cancer cell lines by fenbendazole, which may represent a new class of anticancer agents showing selective toxicity against cancer cells.
Unexpected antitumorigenic effect of fenbendazole when combined with supplementary vitamins. https://www.ncbi.nlm.nih.gov/pubmed/19049251
Diet containing the anthelminthic fenbendazole is used often to treat rodent pinworm infections because it is easy to use and has few reported adverse effects on research. However, during fenbendazole treatment at our institution, an established human lymphoma xenograft model in C.B-17/Icr-prkdcscid/Crl (SCID) mice failed to grow. Further investigation revealed that the fenbendazole had been incorporated into a sterilizable diet supplemented with additional vitamins to compensate for loss during autoclaving, but the diet had not been autoclaved. To assess the role of fenbendazole and supplementary vitamins on tumor suppression, 20 vendor-supplied 4-wk-old SCID mice were assigned to 4 treatment groups: standard diet, diet plus fenbendazole, diet plus vitamins, and diet plus both vitamins and fenbendazole. Diet treatment was initiated 2 wk before subcutaneous flank implantation with 3 x 107 lymphoma cells. Tumor size was measured by caliper at 4-d intervals until the largest tumors reached a calculated volume of 1500 mm3. Neither diet supplemented with vitamins alone nor fenbendazole alone caused altered tumor growth as compared with that of controls. However, the group supplemented with both vitamins and fenbendazoleexhibited significant inhibition of tumor growth. The mechanism for this synergy is unknown and deserves further investigation. Fenbendazoleshould be used with caution during tumor studies because it may interact with other treatments and confound research results.
We describe antitumor activities of vitamin E succinate (VES), an anti-oxidant and fenbendazole (FBZ), a commonly used veterinary anthelmintic. We used VES and FBZ, at low concentrations, singly and in combination, to test their inhibitory effects on proliferation of human and mouse prostate cancer cells in vitro. Administered alone, FBZ inhibited proliferation faster than VES in both mouse and human prostate cancer cell lines and a synergistic effect between both was also observed. Apoptosis was the likely mechanism for the observed effect. These drugs may deserve to be tested for their efficacy in the control of prostate cancer using in vivo models.
Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. https://www.ncbi.nlm.nih.gov/pubmed/21764822
Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer, and despite treatment advances, patient prognosis remains poor. During routine animal studies, we serendipitously observed that fenbendazole, a benzimidazole antihelminthic used to treat pinworm infection, inhibited brain tumor engraftment. Subsequent in vitro and in vivo experiments with benzimidazoles identified mebendazole as the more promising drug for GBM therapy. In GBM cell lines, mebendazole displayed cytotoxicity, with half-maximal inhibitory concentrations ranging from 0.1 to 0.3 µM. Mebendazole disrupted microtubule formation in GBM cells, and in vitro activity was correlated with reduced tubulin polymerization. Subsequently, we showed that mebendazole significantly extended mean survival up to 63% in syngeneic and xenograft orthotopic mouse glioma models. Mebendazole has been approved by the US Food and Drug Administration for parasitic infections, has a long track-record of safe human use, and was effective in our animal models with doses documented as safe in humans. Our findings indicate that mebendazole is a possible novel anti-brain tumor therapeutic that could be further tested in clinical trials.
Identification of selective therapeutic agents for metastatic prostate cancer by phenotype-based screening http://www.dtic.mil/dtic/tr/fulltext/u2/a545657.pdf
Background: As with many solid tumors, the prognosis for prostate cancer patients worsens when tumors metastasize to distant organs, such as the bone. Current chemotherapy is relatively limited for metastatic prostate cancer. Methods: We utilized a screening method consisting of multiple panels of highly metastatic and less metastatic prostate cancer cells to identify compounds that selectively target metastatic prostate cancer cells but not on less metastatic and normal prostate epithelial cells. Selected drugs from a library of 1120 FDA-approved drugs were then tested for their ability to improve the survival of mice in a highly aggressive Dunning rat prostate carcinoma lung metastasis model, and for anti-tumor activity on paclitaxel-resistant and experimental bone lesion of prostate tumors. To improve the bioavailability of agents for systemic administration, we
utilized a modified micelle preparation as well as nanoparticle (PLGA-PEG)-based formulation. Results: We identified fenbendazole, fluspirilene, clofazimine, niclosamide and suloctidil, which showed selective cytotoxicity on metastatic prostate cancer cells in vitro and in vivo. Such selectivity could explained by differential induction of apoptosis. Upon improvement in bioavailability, fenbendazole and albendazole significantly extended the survival of metastases bearing mice, and the extension of lifespan by albendazole was equivalent or greater than that provided by paclitaxel. These drugs were active in taxane-resistant tumors and in the bone microenvironment, two clinical conditions of men with advanced prostate cancer. Conclusion: Metastatic tumor cells differ in their responses to certain drug classes. Albendazole shows promise as a potential adjunct to standard therapy in patients with metastatic prostate cancer.
An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667160/
Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.
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