Fenbendazole acts as a moderate microtubule destabilizing agent and causes cancer cell death by modulating multiple cellular pathways

Abstract

Drugs that are already clinically approved or experimentally tested for conditions other than cancer, but are found to possess previously unrecognized cytotoxicity towards malignant cells, may serve as fitting anti-cancer candidates. Methyl N-(6-phenylsulfanyl-1H benzimidazol-2-yl) carbamate [Fenbendazole, FZ], a benzimidazole compound, is a safe and inexpensive anthelmintic drug possessing an efficient anti-proliferative activity. In our earlier work, we reported a potent growth-inhibitory activity of FZ caused partially by impairment of proteasomal function. Here, we show that FZ demonstrates moderate affinity for mammalian tubulin and exerts cytotoxicity to human cancer cells at micromolar concentrations. Simultaneously, it caused mitochondrial translocation of p53 and effectively inhibited glucose uptake, expression of GLUT transporters as well as hexokinase (HK II) - a key glycolytic enzyme that most cancer cells thrive on. It blocked the growth of human xenografts in nu/nu mice model when mice were fed with the drug orally. The results, in conjunction with our earlier data, suggest that FZ 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.

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

“…The prolonged cell cycle arrest in G2/M phase, together with the slower emergence of polyploid cells in the p53-wild type Capan-2, as compared to the p53-mutant AsPC-1, is likely to be related to their distinct p53 status. A similar G2/M cell cycle arrest associated with a transient accumulation of cyclin B1 had been previously described in the p53-wild type A549 lung cancer cell line treated with fenbendazole [26]. In this regard, it has been reported that cell cycle checkpoint protein cyclin B1 accumulates in the presence of aberrant mitosis and that the cyclin is then slowly degraded allowing cell cycle progression [37,38].…”

“…This dynamics of cyclin B1 expression was in line with flow cytometry analysis that revealed a prolonged G2/M arrest in Capan-2, followed by a gradual increase in the proportion of polyploid cells at later time points. A similar early transient accumulation of cyclin B1, followed by its decreased expression was previously described in lung carcinoma cells undergoing G2/M arrest after fenbendazole treatment [26]. Overall, in both AsPC-1 and Capan-2 parbendazole induced cell cycle arrest, appearance of enlarged polyploid cells and altered cyclin B1 expression.…”

“…Conversely, the effects of the four benzimidazoles on PC cell viability did not appear to correlate with the lipophilicity of the anthelmintic drugs. Despite the different activities of the compounds, all of these drugs affected PC viability with IC 50 values in the range achieved by standard therapeutic dosages [17,[25][26][27][28].…”

“…19) µM in Capan-2 ( Figure 1B,C). These IC 50 values were all in the range or even lower than the therapeutic plasma concentrations reached after administration of standard dosages [17,[25][26][27][28]. Notably, parbendazole showed the lowest IC 50 values as compared to other benzimidazoles tested in both cell lines ( Figure 1C), suggesting that the specific substituent at the C5 might be relevant for anti-proliferative activities.…”

Design and Synthesis of New Tubulin Polymerization Inhibitors Inspired from Combretastatin A‐4: An Anticancer Agent

“…MDA-MB-231 cells were treated with the compounds for 24 h at 200 nM doses, and the equal number of cells were processed for purification of polymerized as well as depolymerized tubulin fractions and proceeded for western blot analysis using anti-αtubulin antibody. [59] The results showed that compounds 2 f-3, 2 f-6, 5 f-5, 5 f-6, and 4 f-3 were potent depolymerizing agents, while 1 f-5 and 1 f-6 also showed significant disruption of tubulin polymerization ( Figure 5A). The compound 4 f-2 did not show much depolymerizing activity while Colchicine was used as a positive control.…”