The Testing Evidence for Using Mebendazole for Treating Lung Cancer

Executive Summary

• This article covers the evidence I could find for Mebendazole as a treatment for Lung Cancer.

Article Summary

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

Introduction

This article provides an overview covering the evidence for Mebendazole and related drugs versus Lung Cancer.

Many articles on this website cover the evidence for the benefits of Mebendazole for cancer. But the question of which specific cancers Mebendazole 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 #1: Lung Cancer

The following quote is from the article Network pharmacology and molecular docking study-based approach to explore mechanism of benzimidazole-based anthelmintics for the treatment of lung cancer.

Emerging studies have reported the potential anticancer activity of benzimidazole-based anthelmintics (BBA) against lung cancer (LC). However, mechanism underlying the anticancer activity of BBA is unclear. Therefore, in the current study, network pharmacology and molecular docking-based approach were used to explore the potential molecular mechanism for the treatment of LC. The potential targets for BBA were obtained from multiple databases including SwissTargetPrediction, Drug Bank, Therapeutic Target Database, and Comparative Toxicogenomics Database while LC targets were collected from DisGeNet gene discovery platform, Integrated Genomic Database of NSCLC, Catalogue of Somatic Mutations in Cancer and Online Mendelian Inheritance in Man database. Protein-protein interaction (PPI) diagram of common targets was constructed using STRING online platform. Topological analysis was performed using Cytoscape and gene enrichment analysis was conducted using FunRich software. Highest degree targets were then confirmed using molecular docking and molecular dynamics simulations.

That was the method employed, now here is the outcome.

The BBA were prioritized according to their S scores, with ricobendazole ranking highest followed by flubendazole, Mebendazole, mebendazole, triclabendazole, albendazole, oxibendazole, parbendazole, thiabendazole and oxfendazole. The potential targets of BBA identified using topological analysis and molecular docking were found to be CCND1 (cyclin D1), EGFR (Epidermal Growth Factor Receptor), ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2/CD340), PTGS2 (Prostaglandin-endoperoxide synthase 2), and SRC (Proto-oncogene tyrosine-protein kinase). Furthermore, molecular dynamics confirmed that CCND1 and EGFR are the potential targets of ricobendazole for the treatment of LC. BBA can be further explored as a therapeutic strategy for the treatment of lung cancer under in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

Of these drugs, fendbendazole came in second after flubendazole. Interestingly these other drugs are not generally available.

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

MBZ and other benzimidazoles seem to target cancer cells preferentially over normal cells, and this may suggest a favorable therapeutic index for in vivo applications. In vitro, MBZ displayed a slightly higher IC50 of 0.4 μM in mouse astrocytes, compared with those in various GBM cell lines, ranging 0.11 – 0.31 μM. In addition, our 2 different GBM animal models showed survival benefit for MBZ with minimal toxicity. Several other studies have shown in vivo success with benzimidazoles against cancers, including non–small cell lung cancer, adrenocortical carcinoma, leukemia, and colorectal cancer.11,12,23,35,36 There is evidence that MBZ’s mode of action in lung cancer cells involves prevention of polymerization of tubulin.

The following quote is from the article The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells.

Microtubules have a critical role in cell division, and consequently various microtubule inhibitors have been developed as anticancer drugs. In this study, we assess mebendazole (MZ), a microtubule-disrupting anthelmintic that exhibits a potent antitumor property both in vitro and in vivo. Treatment of lung cancer cell lines with MZ caused mitotic arrest, followed by apoptotic cell death with the feature of caspase activation and cytochrome c release. MZ induces abnormal spindle formation in mitotic cancer cells and enhances the depolymerization of tubulin, but the efficacy of depolymerization by MZ is lower than that by nocodazole.

Oral administration of MZ in mice elicited a strong antitumor effect in a s.c. model and reduced lung colonies in experimentally induced lung metastasis without any toxicity when compared with paclitaxel-treated mice. We speculate that tumor cells may be defective in one mitotic checkpoint function and sensitive to the spindle inhibitor MZ. Abnormal spindle formation may be the key factor determining whether a cell undergoes apoptosis, whereas strong microtubule inhibitors elicit toxicity even in normal cells.

The following quote is from the article Mebendazole prevents distant organ metastases in part by decreasing ITGβ4 expression and cancer stemness.

We expanded our preclinical models by orthotopically implanting a TNBC patient-derived xenograft (PDX), HCI-001, in NSG mice. Following 8 weeks of growth, the primary tumors reached an average tumor volume of ~ 150 mm3 (Additional file 2: Fig. S3F, G). The mice were then randomized into two treatment groups which were dosed 4 times per week: sesame oil as a vehicle gavage (Con, N = 8) or 30 mg/kg MBZ in sesame oil gavage (30 mg/kg; N = 9). After two weeks of treatment, there was no decrease in the size of tumors for the MBZ group nor a reduction (Fig. 4H; Additional file 2: Fig. S3H, I) of tumor weight (Fig. 4I). However, we did observe a twofold decrease in metastatic burden in the lung (Fig. 4J). We further confirmed a significant decrease in lung metastases by counting the number of nodules present in H & E stained mouse lungs. We observed a twofold reduction in lung nodules in mice treated with 30 mg/kg MBZ compared to mice given vehicle control (Fig. 4K, L; Additional file 2: Fig. S3J).

At the endpoint of the experiment, we extracted genomic DNA from mouse lungs and livers to measure metastatic spread using qPCR to quantify human HK2 DNA content. Mice treated with 215 ppm MBZ feed had significantly reduced lung (Fig. 4F; Additional file 2: Fig. S3D) and no detectable liver metastases (Fig. 4G; Additional file 2: Fig. S3E).

To rule out the effect of primary tumor size contributing to the difference in metastasis, we normalized HK2 DNA content by individual tumor weight and compared it to the mean of the control group. The results demonstrated that MBZ reduces lung metastasis to a greater extent than it inhibits tumor growth and MBZ completely abolishes liver metastases.

We did observe a twofold decrease in metastatic burden in the lung (Fig. 4J). We further confirmed a significant decrease in lung metastases by counting the number of nodules present in H & E stained mouse lungs. We observed a twofold reduction in lung nodules in mice treated with 30 mg/kg MBZ compared to mice given vehicle control (Fig. 4K, L; Additional file 2: Fig. S3J). The results highlight the ability of MBZ to reduce lung metastases in a TNBC PDX model, which has clinically relevant implications since PDX models closely match patients’ therapeutic responses. [38]

Our preclinical studies demonstrated that the anthelminthic, MBZ, decreased the growth of TNBC and significantly abrogated lung metastasis while eliminating liver metastases. We showed that MBZ decreased TNBC cell proliferation through previously described mechanisms of action, including G2 / M cell cycle arrest and apoptosis [16]. Using RNA sequencing, we discovered that MBZ also reduces ITGβ4 expression and previous studies have linked ITGβ4 expression with increased metastasis [41].

Adding up the Studies of Mebendazole 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 Mebendazole Works Against Cancer

There are many ways in which Mebendazole 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 Menbendazole Fight Cancer?