Mebendazole- A New Treatment For Colon Cancer: Know Its Safety, Effectiveness

Mebendazole (MBZ) is an anti-helminthic drug belonging to the class of benzimidazoles, approved by the FDA for getting rid of worm infections of many kinds- hookworms, whipworms, roundworms, and pinworms and echinococcosis (hydatid disease). Albendazole (ABZ) is a closely related anti-helminthic, and belongs to the same class of drugs.

These drugs act by binding tubulin, the structural protein of the cells, and preventing its polymerization, which prevents cell division and growth of the worm. The drugs specifically bind tubulin in the epithelium of the helminth gut. Many anti-cancer drugs unrelated to benzimidazoles also act on tubulin stalling the rapid growth of cancer cells. Albendazole (ABZ) has been found to be active against various cancers. Mebendazole (MBZ) has been shown to increase survival in a glioblastoma brain tumor mouse model. MBZ inhibited microtubule formation in and hence tubulin polymerization (Neuro-Oncology 13(9):974–982, 2011.).

This article describes how the drug Mebendazole (MBZ) that is approved in the clinic for killing parasitic worms, can be put to good use for treating colon cancer, and possibly other cancers (J Cancer Res Clin Oncol (2013) 139:2133–2140).

Researchers screened a drug library consisting of 1,600 molecules in clinical use, for their inhibitory effect on two colon cancer cell lines. The cytotoxic and antiproliferative effect was measured as a “survival index” or SI of <40%, where survival was indicated by fluorescence exhibited by live cells due to conversion of a pre-fluorescent dye fluorescein diacetate to fluorescein, which only occurs in cells with intact plasma membranes (an indication of cell viability). Sixty-eight hits were obtained, the largest number of drugs were anticancer agents. Anti-parasitic drugs, anti-infectives and cardiovascular drugs followed in decreasing order. Growth inhibition by the candidate molecules, of 60 cancer cell lines from the National Cancer Institute (NCI 60 GI 50 data) was screened. Based on analysis of chemical structure of molecules with anti-cancer activity the benzimidazole drug group was found to be highly active, with equal activity of oxibendazole and Mebendazole (MBZ), followed by Albendazole (ABZ), and fenbendazole. The cytotoxic effect of Mebendazole (MBZ) was further tested in three colon cancer cell lines and two untransformed cell lines. Mebendazole (MBZ) showed a highly selective inhibitory effect at concentrations as low as <5 μM on the colon cancer cell lines, while sparing the normal, untransformed cell lines completely, indicating that in the clinical setting side-effects or by-stander effects should be minimal. Thus Mebendazole (MBZ) promises to have an encouraging safety profile in cancer patients. It is already established for its safety and efficacy in eradicating helminth infections.

While Albendazole (ABZ) and Mebendazole (MBZ) are both active against metastatic colon cells, the authors found differences in the mechanism of action (MoA) of the drugs. Mebendazole (MBZ) has a safer toxicity profile than Albendazole (ABZ), which may be due to differences in mechanism of action. There are several lines of reasoning supporting this conclusion:

• First, genome-wide expression analysis of genes induced by 1,309 compounds called connectivity map or CMAP was used to compare relative gene induction between Albendazole (ABZ), Mebendazole (MBZ) and other benzamidazoles. Using Mebendazole (MBZ) induced expression signature as the query in CMAP, ABZ ranked 222, indicating a very low correlation score between the two drugs. In other words the overall gene expression pattern/signature induced by the two drugs is very different.
• Second, using the NCI 60 GI 50 data the comparability of the activity of the two drugs was modest, based on the Pearson’s correlation coefficient which was 0.64.
• Third, glioblastoma is a highly invasive brain tumor. The activity of Albendazole (ABZ) and Mebendazole (MBZ) was tested in two different glioblastoma preclinical mouse models. Mebendazole (MBZ) significantly increased survival unlike ABZ in both orthotopic mouse models.
• Fourth, Albendazole (ABZ) is known to generate reactive oxygen species (ROS), which is known to cause cellular- and hence tissue- damage through oxidation of lipids, proteins and DNA which destroys these biomolecules.
• Fifth, Albendazole (ABZ) induces neutropenia and anemia unlike Mebendazole (MBZ).
• Sixth, protein kinases especially those known to be associated with cancers, were found to be inhibited by Mebendazole (MBZ), but not by Albendazole (ABZ). Protein kinases are enzymes which play a critical role in intracellular molecular communication via signal transduction pathways within cells, eventually effecting all the cellular activities and functions. In the cancer scenario, aberrant protein kinase activity associated with mutant forms of protein kinases has a major impact on the cell growth leading to malignant tumors. Drug-targeting of such kinases is a widely sought approach for cancer control. KINOMEscan (Discoverx, CA, USA) is a high throughput assay designed to test the binding of an array of 97 protein kinases to their corresponding ligand immobilized on inert support. The kinases are conjugated to DNA tags, whose amplification by quantitative PCR serves as the readout. The amplified product correlates directly with the extent of kinase bound to its ligand. This assay was used to measure the binding affinity of Mebendazole (MBZ) and Albendazole (ABZ) to the kinases as binding to the active site of the drug will inhibit the kinase activity. In this case the readout correlates inversely with drug binding as the binding of the kinase by a drug prevents the kinase from binding its ligand, and hence consequent amplification of DNA tag on captured kinase. The control and drugs that do not bind the kinase will therefore give maximal readout. Binding of a test drug to a kinase is represented as percentage of the control (POC) readout. The selectivity score or S(35) is calculated as number of non-mutant kinases with POC <35/number of non-mutant kinases tested. This score is a measure of binding of a drug to a non-mutant kinase. Albendazole and Mebendazole each were tested at 10 M concentration. Albendazole (ABZ) did not bind any kinase in this assay, while Mebendazole (MBZ) bound strongly to multiple protein kinases with a POC<22, namely PDFRB, PDGFRA, MEK2, MEK1, KIT, JNK 3, 2 and 1, BRAF, ABL1- phosphorylated and non-phosphorylated; and the mutant kinases BRAF (V600E) and ABL1 (T315I)-phosphorylated. The S(35) score of MBZ was 0.19 i.e. 20 out of 97 kinases were inhibited by Mebendazole (MBZ) with a POC of <35. The binding constant Kd of MBZ-binding kinases was also calculated through a dose-response curve. Mebendazole bound strongest in nanomolar range to ABL1 –phosphorylated, its two variant mutant forms ABL1 (E225K)-phosphorylated and ABL1 (T315I)-phosphorylated; and BRAF and its mutant form BRAF (V600E). In addition Mebendazole bound JNK3, KIT, PDGFRA and B in the nanomolar range. It is important to stress that ABL kinases are associated with various cancers, especially the mutant ABL1 (T315I) which is associated with chronic myeloid leukemia (CML). This mutation is recalcitrant to ABL- targeting drugs available for treatment of chronic myeloid leukemia (CML). Therefore further studies are warranted to investigate whether Mebendazole may be effective in chronic myeloid leukemia (CML) treatment. BRAF and particularly mutant BRAF (V600E) are associated with melanoma and colon cancer. Thus Mebendazole may also be useful in treating melanoma as well.
• Seventh, using Mebendazole (MBZ) induced gene expression signature as the query in CMAP nocodazole ranked 3, indicating a very tight correlation score between the two drugs, indicating the overall gene expression pattern/signature induced by the two drugs is very similar, and the gene targets are therefore similar. Nocodazole has been shown to inhibit multiple protein kinases including ABL, c-KIT, BRAF, and MEK, and Bcr–Abl. It is speculated that Mebendazole is likely to inhibit these kinases.

In the clinical setting, a case study validated the safety and efficacy of Mebendazole in colon cancer that was found in preclinical in vitro experiments described above. A patient with refractory metastatic colon cancer was previously treated with capecitabine, oxaliplatin and bevacizumab. The treatment was stopped due to intolerable oxaliplatin-induced neuropathy. Second-line treatment with apecitabine and irinotecan followed, but failed as advanced tumor progression and treatment-induced neuropathy occurred. The patient was then treated with Mebendazole at the standard anti-helminthic dose of 100 mg two times per day. No significant drug-related adverse events were seen. Computerized tomography (CT) scans at six weeks on Mebendazole (MBZ) treatment indicated complete tumor remission in the lungs and lymph nodes and a significant remission in the liver (Acta Oncol 2014 Mar 28;53(3):427-8.).