Author: Daniel S, PhD; Last update: January 31st, 2021
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. However, as we saw, it’s not only science. Instead, there are case reports published in peer review papers showing that patinets with some aggressive cancers have experienced great response to Mebendazole.
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.
Recommendation: when you finish reading this post, I recommend you read also this post I recently published (September 2020): 10 Cases of Complete Remission from Advanced Cancers after using Supplements or Repurposed Drugs In this post you will find more repurposed (off-label) drugs that have been shown to induce complete remission in various cancers (published in scientific journals by clinicians and scientists from major universities and hospitals).
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). In this case, it is used 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, Fenbendazole came out as 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.).
Scientific articles published during the past years, have indicated that Fenbendazole shows anti cancer effectiveness. Of these, 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 here. So it may make very much sense to combine the two, and possibly 2DG (Ref.). Could it be that the origin of this synergy comes from the possible glutathione depletion previously observed to be related to Fenbendazole? (Ref.)
Update April 2020: A recent scientific paper suggests yet another anti cancer activity related to Fenbendazole (Ref.). In this paper, the authors suggests that drugs such as Fenbendazole reactivate p53, known as the Guardian of the Genome. p53 functions as a tumor suppressor and it’s activity is inhibited in some cancers.
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.
- Update April 2020: Recently, it has been indicated that benzimidazole, including Methiazole and Fenbendazole play an important role in suppressing KRAS-mutant lung cancer cells (Ref.)
- 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).
Update December 2019: A recent study suggests that for Pancreatic Cancer, two other anti-worm drugs from the same category and used in animals, Parbendazol (brand name Verminum, Worm Guard and Helatac) and Oxibendazole, is more effective compared to Fenbendazole and Mebendazole (Ref.). While Parbendazole seems not to be on the market anymore, Oxibendazole can be found online. Here you can find this subject discussed a little more in details including discussions on what could be the relevant daily dose of Oxibendazole (Ref.).
Update September 2019: at the beginning of 2019, some months after I wrote this post, Joe’s story became viral. Here is a short interview on a TV station in US, with Joe https://www.youtube.com/watch?v=HYILnjc_wuY I am glad to see that I often addressed subjects on this website before they became known to most people.
Update May 2020: A man successfully using Fenbendazole and Artemisinin to treat his prostate cancer https://www.killingcancer.net/treatments
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
Below I discuss the dose and treatment regime but this is only visible to registered visitors. All visitors can easily register, for free, using the login options located at the right side of the page (when using a desktop) or at the bottom of the page (when using mobile), where login option via Facebook account is also available. It only takes one minute to registered on this website, while it may take much longer to collect the information addressed here.
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.
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Where to buy Fenbendazole
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.
Note that some Fenbendazole formulations (such as solutions and paste) may contain Parabens, that can have some weak estrogenic effects. Breast and Ovarian cancer patients may wont to avoid using such formulations.
Warning! To take advantage of the fact that Fenbendazole story spread across the world like wildfire, some people have seen this as an opportunity to take financial advantage of it. As a result, there are some “supplement” web-shops selling Fenbendazole in the most clever ways. With “the best and nicest stories” around them. I will not mention the names of those, but I would advise everyone to only buy Fenbendazole that has been manufactured by a registered and known manufacturer and sold via an authentic source such as a Pharmacy. Since it’s a matter of life, we want to be 100% sure we receive what we order. Don’t forget: over the internet everyone can claim anything, like GMP-approved source, etc, to sell their products. The best way is to follow what Joe did and use the Panacur C product only.
Update December 2019: Dear reader, many visitors of this website in search for information on Fenbendazole are reading this article and after that they leave this website. However, they leave behind important value. Continue reading this website and you will find other treatments that may have the same or better potential compared to Fenbendazole, but mostly known by specialised scientists and less by other people. The same was the story of Fenbendazole. The potential behind Fenbendazole was only known by scientists, until one day, Joe Tippers with his great success and communication skills succeeded to make out of his story a viral story.
For example, see here a case report recently published in scientific literature https://www.cancertreatmentsresearch.com/a-silver-bullet-to-kill-cancer/, of a man who had stage IV cancer with many sites’s of metastasis including liver and lungs. He was not responding to conventional treatments and he was sent home to die. He treated himself at home with an unconventional treatment approach and three months after that his medical doctors report that he obtained complete remission.
And here is another recent (2018) example: (Ref) the case of a medical doctor from US with stage 4 pancreatic cancer, who next to his conventional treatment added two repurposed drugs. With that he obtained complete remission. My point is: when you find time, explore this website. I share everything for free with you. All my search for new treatment options with potential is meant to help you with more treatment ideas and all are science based.
Here is another post that you want to read that many people appreciate: A post incorporating multiple repurposed drugs and supplements into a Metabolic anti-cancer treatment strategy: https://www.cancertreatmentsresearch.com/shutting-down-the-power-house-of-cancer/
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.
Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole (Ref.)
Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h.
Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases.
To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet.
These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.
The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer (Ref.)
Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents. Repurposing of non-anticancer drugs may expand the repertoire of effective molecules. Studies on repurposing of benzimidazole-based anthelmintics in PC and on their interaction with agents approved for PC therapy are lacking. We analyzed the effects of four Food and Drug Administration (FDA)-approved benzimidazoles on AsPC-1 and Capan-2 pancreatic cancer cell line viability.
Notably, parbendazole was the most potent benzimidazole affecting PC cell viability, with half maximal inhibitory concentration (IC50) values in the nanomolar range. The drug markedly inhibited proliferation, clonogenicity and migration of PC cell lines through mechanisms involving alteration of microtubule organization and formation of irregular mitotic spindles. Moreover, parbendazole interfered with cell cycle progression promoting G2/M arrest, followed by the emergence of enlarged, polyploid cells. These abnormalities, suggesting a mitotic catastrophe, culminated in PC cell apoptosis, are also associated with DNA damage in PC cell lines. Remarkably, combinations of parbendazole with gemcitabine, a drug employed as first-line treatment in PC, synergistically decreased PC cell viability. In conclusion, this is the first study providing evidence that parbendazole as a single agent, or in combination with gemcitabine, is a repurposing candidate in the currently dismal PC therapy.
Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells (Ref.)
Tumor suppressor p53 is mutated in about 50% of cancers. Most malignant melanomas carry wild-type p53, but p53 activity is often inhibited due to overexpression of its negative regulators Mdm2 or MdmX. We performed high throughput screening of 2448 compounds on A375 cells carrying p53 activity luciferase reporter construct to reveal compounds that promote p53 activity in melanoma. Albendazole and fenbendazole, two approved and commonly used benzimidazole anthelmintics, stimulated p53 activity and were selected for further studies. The protein levels of p53 and p21 increased upon the treatment with albendazole and fenbendazole, indicating activation of the p53-p21 pathway, while the levels of Mdm2 and MdmX decreased in melanoma and breast cancer cells overexpressing these proteins. We also observed a reduction of cell viability and changes of cellular morphology corresponding to mitotic catastrophe, i.e., G2/M cell cycle arrest of large multinucleated cells with disrupted microtubules.
In summary, we established a new tool for testing the impact of small molecule compounds on the activity of p53 and used it to identify the action of benzimidazoles in melanoma cells. The drugs promoted the stability and transcriptional activity of wild-type p53 via downregulation of its negative regulators Mdm2 and MdmX in cells overexpressing these proteins. The results indicate the potential for repurposing the benzimidazole anthelmintics for the treatment of cancers overexpressing p53 negative regulators.
Drug library screen reveals benzimidazole derivatives as selective cytotoxic agents for KRAS-mutant lung cancer. (Ref.)
KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancer (NSCLC). Mutations in KRAS are detected in 30% of NSCLC cases, with most of them occurring in codons 12 and 13 and less commonly in others. Despite intense efforts to develop drugs targeting mutant KRAS, no effective therapeutic strategies have been successfully tested in clinical trials. Here, we investigated molecular targets for KRAS-activated lung cancer cells using a drug library. A total of 1271 small molecules were screened in KRAS-mutant and wild-type lung cancer cell lines.
The screening identified the cytotoxic effects of benzimidazole derivatives on KRAS-mutant lung cancer cells. Treatments with two benzimidazole derivatives, methiazole and fenbendazole-both of which are structurally specific-yielded significant suppression of the RAS-related signaling pathways in KRAS-mutated cells. Moreover, combinatorial therapy with methiazole and trametinib, a MEK inhibitor, induced synergistic effects in KRAS-mutant lung cancer cells. Our study demonstrates that these benzimidazole derivatives play an important role in suppressing KRAS-mutant lung cancer cells, thus offering a novel combinatorial therapeutic approach against such cancer cells.
Update August 24th, 2019: several months after I wrote this article, the story of Joe Tippens made the news, and after that it went viral. Following that, some Facebook groups have been created where people are discussing the use of Fenbendazole against cancer. Here is one such group https://www.facebook.com/groups/429159131252194/ (Fenbendazole for Cancer Group)
Drug repurposing and relabeling for cancer therapy: Emerging benzimidazole antihelminthics with potent anticancer effects https://www.sciencedirect.com/science/article/abs/pii/S0024320520309413
Origin of drug and radio-refractory clones, cancer stem-like cells, and rapid angiogenesis and metastasis are among the primary concerns that limit the efficacy of anticancer treatments, emphasizing the urgency of developing new therapeutics. Factors like high attrition rates, huge investments, patients’ heterogeneity, and diverse molecular subtypes have challenged the rapid development of anticancer drugs. Treatment with repurposing pleiotropic benzimidazole antihelminthics, like mebendazole, albendazole, and flubendazole has recently opened a new window, owing to their easy access, low cost as a generic drug, and long track record of safe use in the human population. This review highlights the outcomes of preclinical and clinical studies of these drugs as a potent anticancer agent(s) conducted in the last two decades. Substantial preclinical studies, as well as limited clinical trials, suggest noteworthy anticancer potency of these pleiotropic benzimidazoles, particularly as potent microtubule disrupting, anti-angiogenic, and anti-metastatic agents, inhibitors of the immune checkpoint, hypoxia-inducible factor, epithelial-mesenchymal transition, cancer stemness, and multidrug resistance protein 1, and inducers of apoptosis and M1 polarization. These anticancer effects are attributed to multiple action points, including intrinsic apoptosis, canonical Wnt/β-catenin, JAK/STAT-3, JNK, MEK/ERK, and hedgehog signaling pathways. The effective anticancer properties of mebendazole, albendazole, and flubendazole either alone or synergistically with frontline drugs, warrant their validation through controlled clinical trials to use them as promising avenues to anticancer therapy.
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