The Testing Evidence for Using Fenbendazole for Treating Glioblastoma Multiforme

Executive Summary

• This article covers the evidence I could find for Fenbendazole as a treatment for Glioblastoma Multiforme.

Article Summary

Studies demonstrate that Fenbendazole is effective against cancer, we then cover how Fenbendazole works against cancer by explaining the mechanisms of action, and then the impacts of Fenbendazole on cancer.

Introduction

This article provides an overview covering the evidence for Fenbendazole and related drugs versus Glioblastoma Multiforme. 

Many articles on this website cover the evidence for the benefits of Fenbendazole for cancer. But the question of which specific cancers Fenbendazole has been proven effective is a constant source of questions.

The most common Benzimidazoles are Fenbendazole, Mebendazole and Albendazole. In our analysis, we include research for all three drugs together in articles as they are very similar to one another and it improves the ability to tie together different studies. You may see the following terms/acronyms used.

• FZ or FBZ means Fenbendazole
• MBZ means Mebendazole
• AZ means Albendazole

Cancer Type #8: Glioblastoma Multiforme

The following quote is from the article Benzimidazoles induce concurrent apoptosis and pyroptosis of human glioblastoma cells via arresting cell cycle.

Glioblastoma multiforme (GBM) is the most malignant and lethal primary brain tumor in adults accounting for about 50% of all gliomas. The only treatment available for GBM is the drug temozolomide, which unfortunately has frequent drug resistance issue. By analyzing the hub genes of GBM via weighted gene co-expression network analysis (WGCNA) of the cancer genome atlas (TCGA) dataset, and using the connectivity map (CMAP) platform for drug repurposing, we found that multiple azole compounds had potential anti-GBM activity. When their anti-GBM activity was examined, however, only three benzimidazole compounds, i.e. flubendazole, mebendazole and fenbendazole, potently and dose-dependently inhibited proliferation of U87 and U251 cells with IC50 values below 0.26 μM.

The three benzimidazole compounds have similar structures, but flubendazole has a slightly stronger effect than the other two compounds; therefore, RNA sequencing was performed on U87 and U251 cells treated with 0.25 μmol / L flubendazole for 24 h.

Flow cytometry was used to explore the effects of benzimidazoles on the cell cycle of GBM cells. The three compounds were able to arrest the cell cycle at the G2 / M phase of U87 and U251 cells (Fig. 4a, b) in a dose-dependent manner, but their effects were slightly greater in U251 cells. To explore the molecular mechanism of the compounds’ G2 / M phase arrest in GBM cells, samples of U87 and U251 cells treated with 0, 0.125, 0.25, and 0.5 μmol / L flubendazole for 12 and 24 h were collected and analyzed.

Flubendazole also downregulated the expression and phosphorylation of cdc2 in U251 cells, while this effect was not significant in U87 cells. Thus, benzimidazoles appear to arrest the GBM cell cycle at G2 / M phase via their effects on the P53 / P21 / cyclin B1 pathway.

Benzimidazoles induced mitochondria-dependent apoptosis of GBM cells JC-1 staining detected by flow cytometry showed that benzimidazoles dose-dependently reduced the mitochondrial membrane potential (MMP, ΔΨm) in U87 and U251 cells (Fig. 6a, b). Early apoptosis is usually accompanied by a decrease in mitochondrial membrane potential [23].

To explore the anti-GBM effect of benzimidazoles in vivo, flubendazole was selected for testing in a nude mouse xenograft model (Fig. 8a). Compared with mice injected with vehicle alone, those treated with flubendazole showed dose-dependent growth inhibition of the tumors. The weight and volume of tumors were significantly decreased with administration of flubendazole. In addition, the beneficial effect of flubendazole was almost equivalent to that of the positive control drug, TMZ, and the tumor had almost disappeared after 24 days of administration of 50 mg/kg flubendazole (Fig. 8b–d).

Here we found that all benzimidazole compounds had the ability to inhibit the proliferation and metastasis of GBM cells. To determine the molecular mechanism of their effects, RNA-sequencing analyses were performed. The data revealed that benzimidazole regulated cell migration, cell cycle, programmed cell death and other biological processes of GBM cells. Benzimidazoles inhibited the migration and invasion of GBM cells and regulated the expression of key EMT markers, which indicated that benzimidazoles could inhibit the metastasis of GBM. They also dose-dependently arrested the cell cycle at G2 / M phase of GBM cells through the P53 / P21 / cyclin B1 pathway.

The following quote is from the article Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme.

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.

There has been no shortage of clinical trials for GBM. More than 600 clinical trials related to GBM have been run or are actively recruiting, according to the US National Institutes of Health’s website (http://www.ClinicalTrials.gov). Unfortunately, few if any recent clinical trials show a clear survival benefit for patients with GBM. The present clinical trial system often does not address the difficulties of GBM therapy. Many therapies tried in the clinic were developed on the basis of results for other cancers, do not account for insufficient drug delivery to the brain, and do not address treatment-resistant migrating glioblastoma cells.

We accidentally found that fenbendazole, a benzimidazole, reduced brain tumor engraftment in nude mice after the mouse colony was treated for pinworms. Fenbendazole was previously reported to interfere with one lymphoma model in 2008,23 after we had already noted problems with fenbendazole disrupting brain tumor engraftment. We pursued this finding by evaluating whether the 2 most widely used human approved benzimidazoles showed efficacy against glioblastoma models.

The Multiple Mechanisms by Which Fenbendazole Works Against Cancer

There are many ways in which Fenbendazole works against cancer including.

• Reducing metastasis
• Increase autophagy
• Increase cancer cell death or apoptosis
• and much more

This topic is covered in the article By How Many Different Mechanisms Does Fenbendazole Fight Cancer?

Adding up the Studies of Fenbendazole Versus Cancer

There are many studies of Fenbendazole, Mebendazole, Albendazole, and other Benzimidazole derivatives versus cancer.

Due to the success of these studies and the information published in the study publications, the specific mechanisms by which these Benzimidazole-based Anthelmintics work against cancer are at this point well understood. There has not been a study published for every cancer type using one of the Benzimidazole derivatives. There are a very large number of different cancer types and limited funding for this type of research.

How Many Major Cancer Types Are There Studies For?

When I completed my analysis, I found 18 different types of cancer types which demonstrated effectiveness versus cancer. In many cases, these different cancer types had multiple cancer studies testing the different Benzimidazole derivatives.

Cancer centers do not apply the large body of published studies on the effectiveness of Benzimidazole derivatives to include as part of their treatment offerings. This is true even though Fenbendazole has been demonstrated to improve chemotherapy outcomes.

To understand the mechanisms by which Benzimidazole derivatives work against cancer, see the following few examples. To see all of the known mechanisms that I have compiled from all of the studies see the article on the mechanisms listed below.

The Multiple Mechanisms by Which Fenbendazole Works Against Cancer

There are many ways in which Fenbendazole works against cancer including.

• Reducing metastasis
• Increase autophagy
• Increase cancer cell death or apoptosis
• and much more

This topic is covered in the article By How Many Different Mechanisms Does Fenbendazole Fight Cancer?