The effect of MZ as an antitumor agent has never been tested before. This gives rise to the question of whether these mechanisms are directly or indirectly related. Because MZ could inhibit the growth of p53-null cell lines and other p53-mutated cells, although at a higher dose, we examined the other p53-independent pathways. 2I)⇓ ; Allan, R.J.; Watson, T.R. Not specified. MZ treatment also resulted in mitochondrial cytochrome c release, followed by apoptotic cell death. Educational Resources. ; Riggins, G.J. ; Joe, Y.A. Lung cancer has become the leading cause of cancer death in the world (1). Our results demonstrate for the first time the antitumor and antiangiogenetic effects of MZ both in vitro and in vivo. Of these mechanisms, fumarate reductase, glucose uptake, and microtubule inhibition satisfy many of the criteria considered relevant for a putative site of action. Con, control; MZ, treated. Fry, E.A. Print Reset. . ; Rodriguez-Bravo, V.; Galsky, M.; Cordon-Cardo, C.; Domingo-Domenech, J. Inhibition of several kinases (including BCR–ABL and BRAF) in the nanomolar range. those of the individual authors and contributors and not of the publisher and the editor(s). Targeting acute myeloid leukemia by drug-induced c-MYB degradation. . Lung cancer. It was a phase one study with a primary focus on drug safety. Mebendazole Elicits a Potent Antitumor Effect on Human Cancer Cell Lines Both in Vitro and in Vivo1 Tapas Mukhopadhyay,2 Ji-ichiro Sasaki, Rajagopal Ramesh, and Jack A. Roth ... that mebendazole (MZ), a derivative of benzimidazole, induces a dose- and time-dependent apo-ptotic response in human lung cancer cell lines. Pinto, L.C. 1D)⇓ Bars, SE. ; Yazal, T.; Dong, K.; Nguyen, A.; Yu, G.; Dao, A.; Bochkur, D.M. Targeting cancer stem cells to suppress acquired chemotherapy resistance. The experiment was repeated twice using 10 animals in both the control and treatment groups. ; Riggins, G.J. BZ interacts weakly with host tubulin and affects the microtubule assembly only at high concentrations, whereas MZ is an anthelmintic drug that is used extensively for gastrointestinal parasitic infections in humans. This paper follows a comprehensive review, published in 2014 by Pantziarka et al. Zhao, J. Kralova, V.; Hanušová, V.; Caltová, K.; Špaček, P.; Hochmalová, M.; Skálová, L.; Rudolf, E. Flubendazole and mebendazole impair migration and epithelial to mesenchymal transition in oral cell lines. Predicting New Indications for Approved Drugs Using a Proteo-Chemometric Method. Hiscutt, E.L.; Hill, D.S. Dakshanamurthy, S.; Issa, N.T. A considerable increase in cytochrome c was noticed, which correlated with the MZ dose. Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer. Davis, R.J.; Van Waes, C.; Allen, C.T. The costs of publication of this article were defrayed in part by the payment of page charges. Mebendazole, an antiparasitic drug, inhibits drug transporters expression in preclinical model of gastric peritoneal carcinomatosis. The effect of MZ on the proliferation of tumor cell lines in vitro prompted us to investigate its antitumor activity in a nu/nu mouse model. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. ; Peters, O.J. Zhang, F.; Li, Y.; Zhang, H.; Huang, E.; Gao, L.; Luo, W.; Wei, Q.; Fan, J.; Song, D.; Liao, J.; et al. Lien, K.; Georgsdottir, S.; Sivanathan, L.; Chan, K.; Emmenegger, U. Low-dose metronomic chemotherapy: A systematic literature analysis. De Witt, M.; Gamble, A.; Hanson, D.; Markowitz, D.; Powell, C.; Symons, M.; Atlas, M.; Boockvar, J.; Ruggieri, R.; Symons, M. Repurposing Mebendazole as a Replacement for Vincristine for the treatment of Brain tumors. The experiments were conducted in triplicate. Effect of MZ treatment on lung colony formation in an experimental metastasis. NSCLC cell lines: ~0.16 µM. Such microtubule disruption is associated with G2-M-phase blockage (3, 4, 5, 6, 7) The results indicated that the control and MZ-treated mice had similar cell densities on the membrane filters (Fig. Corti, N.; Heck, A.; Rentsch, K.; Zingg, W.; Jetter, A.; Stieger, B.; Pauli-Magnus, C. Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: An interaction study in healthy volunteers. G, plot of milligrams of hemoglobin/ml of tumor tissue obtained from control and treated animals after hemoglobin assay. , 24) A. R.); Specialized Program of Research Excellence Grant 2P50-CA70970-04); gifts from Tenneco and Exxon to the Division of Surgery at M. D. Anderson Cancer Center for its Core Laboratory Facility; M. D. Anderson Support Core Grant CA 16672; a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8); the W. M. Keck Foundation; and Sponsored Research Agreement SR93-004-1 with Introgen Therapeutics. Inhibition of VEGFR2 autophosphorylation, at 1–10 μM in cultured HUVECs and with an IC50 of 4.3 μM in a cell-free kinase assay. However, data exist that support a general concept of primary microtubule action leading to a series of biochemical effects that either directly or indirectly elicit a number of changes; as we demonstrate here, these changes vary in normal and cancer cells. 1D)⇓ You seem to have javascript disabled. [, Although MBZ possesses many characteristics attractive for drug repurposing, there are still some possible drawbacks to be cleared. The experiments were performed three times, and data were analyzed and interpreted as being statistically significant if P < 0.05, according to the Mann-Whitney test. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Both cell lines showed an increase in cytochrome c protein in the cytoplasm after MZ treatment in a dose-dependent manner. ), which are all responsive to Mebendazole, as discussed above. ; Hong, Y.K. ; Dakshanamurthy, S. Repurpose VS: A Drug Repurposing-Focused Computational Method for Accurate Drug-Target Signature Predictions. ; Jones, T.; Bear, R. Anti-Neoplastic Cytotoxicity of Gemcitabine-(C4-amide)-[anti-EGFR] in Dual-combination with Epirubicin-(C3-amide)-[anti-HER2/neu] against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3) and the Complementary Effect of Mebendazole. Significantly, there are also two case reports of anti-cancer activity in humans. Colle, I.; Naegels, S.; Hoorens, A.; Hautekeete, M. Granulomatous hepatitis due to mebendazole. Received: 29 July 2019 / Revised: 27 August 2019 / Accepted: 28 August 2019 / Published: 31 August 2019. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Structurally different from other anticancer drugs, MZ is remarkably safe at high doses in humans. The paper on KRAS mutated lung cancer (screeining in cell lines) "Drug library screen reveals benzimidazole derivatives as selective cytotoxic agents for KRAS-mutant lung … In this study, we were interested in determining the effect of MZ on solid tumor growth and angiogenesis. ; Martin, S.; Kerr, R.; Harbottle, A.; Lovat, P.E. This will allow us to conclude whether MZ-induced tumor growth inhibition is attributable to inhibition of nasovascularization or is a consequence of reduced tumor cell growth. ; Bunz, F. Repurposing the antihelmintic mebendazole as a hedgehog inhibitor. ... Liver Cancer; Lung Cancer; Lymphoma; Pancreatic Cancer; Prostate Cancer; Skin Cancer; Thyroid Cancer; Uterine Cancer; All Cancer Types. Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer. Mebendazole meets many of the characteristics desirable for a repurposed drug: good and proven toxicity profile, pharmacokinetics allowing to reach therapeutic concentrations … The H460, A549, HUVEC, and WI38 cell lines were used in this assay. ; Tormos, R.; Miranda, M.A. It should be noted that the control implant had a tree-like architecture of major vessels (arrow) connecting to minor branches but that the MZ-treated implants had scarce vessels. . Inhibition of MAPK/ERK pathway, induction of apoptosis, synergy with trametinib, Human head and neck squamous cell carcinoma CAL27 and SCC15, Apoptosis induction as a single drug. We found that the cells were blocked at the G2-M phase 12 h after MZ treatment before undergoing apoptosis. Markowitz, D.; Ha, G.; Ruggieri, R.; Symons, M. Microtubule-targeting agents can sensitize cancer cells to ionizing radiation by an interphase-based mechanism. 1E)⇓ Phone: (713) 745-4542; Fax: (713) 794-4901; E-mail: tmukhopa{at}mdanderson.org. 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.