Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer

Abstract

Purpose In the present study, we screened a compound library containing 1,600 clinically used compounds with the aim to identify compounds, which potentially could be repositioned for colon cancer therapy.Methods Two established colon cancer cell lines were tested using the fluorometric microculture cytotoxicity assay (FMCA). For compound comparison connectivity map (CMAP) analysis, NCI 60 data mining and protein kinase binding measurements were performed.ResultsSixty-eight compounds were defined as hits with activity in both of these cell lines (<40 % cell survival compared with control) at 10 μM drug concentration. Analysis of chemical similarity of the hit compounds revealed several distinct clusters, among them the antiparasitic benzimidazole group. Two of these compounds, mebendazole (MBZ) and albendazole (ABZ) are registered for human use. Data from the NCI 60 cell line panel revealed only modest correlation between MBZ and ABZ, indicating differences in mechanism of action. This was further supported when gene expression signatures were compared in the CMAP database; ABZ ranked very low when MBZ was used as the query signature. Furthermore, MBZ, but not ABZ, was found to significantly interact with several protein kinases including BCR–ABL and BRAF. Analysis of the diagnosis-specific activity of MBZ showed activity in 80 % of the colon cancer cell lines in the NCI 60 panel. Three additional colon cancer cell lines and three cell models with non-malignant phenotypes were subsequently tested, confirming selective colon cancer activity of MBZ.ConclusionMBZ seemingly has repositioning potential for colorectal cancer therapy.

Anthelmintic Flubendazole and Its Potential Use in Anticancer Therapy

“…Another benzimidazole carbamate mebendazole was found effective in a number of in vitro models including adrenocortical carcinoma cell lines (26), non-small lung cancer cells (27), cholangiocarcinoma cancer cells (in vivo activity was noted too) (28), malignant melanoma cells (29), colon cancer cells (30,31) and gastric cancer cells, where it could not only inhibit their growth but also migration and invasion (32).…”

In Vitro Screening for Drug Repositioning

“…85 Among other examples of the use of in vitro screening models to reposition existing drugs into oncological disorders, the following are noteworthy due to the diversity of compounds tested and the potential for near-term therapeutic utility. Using a library of 1600 annotated clinical compounds (Pharmakon 1600 from MicroSource Inc.) initially tested at 10 µM, Nygren et al (2013) 86 identified mebendazole, an antihelminthic drug used to treat gut worm infections, as having cytotoxic activity in the RKO and HCT 116 colon cancer cell lines. To determine the mechanism of this cytotoxic activity, mebendazole was tested against a panel of kinases; this revealed potent inhibitory action against Abl and BRAF.…”

ecancermedicalscience

“…Screening of compounds for activity against colon cancer cell lines also identified MBZ as a candidate molecule in work by Nygren and colleagues [20]. The authors set out to screen 1600 existing drugs for activity against two well-established colon cancer cell lines (HCT 116 and RKO) and found 64 candidate drugs, including a cluster of benzimidazoles (albendazole, mebendazole, oxybendazole and fenbendazole).…”

“…Here, a 74-year-old patient suffering from progressive metastatic colon cancer had been treated first with capecitabine, oxaliplatin, and bevacizumab, and then by capecitabine and irinotecan in the face of disease progression, and who had no standard treatment options available was started on an oral dose of MBZ of 100 mg twice a day. MBZ was selected based on the author’s previous pre-clinical work with MBZ [20]. After six weeks of monotherapy, radiological evaluation showed near complete remission of metastatic lesions in the lungs and lymph nodes and a good partial remission in the liver.…”

“…While there is evidence that perioperative or intraoperative diclofenac may be associated with lower risk of cancer recurrence or metastases following surgery [20], there are also active investigations of its direct anticancer role. In particular, diclofenac has shown pre-clinical activity in a range of cancer types, with in vivo evidence in melanoma [21] and ovarian cancer [22] in particular.…”