Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer, and despite treatment advances, patient prognosis remains poor. During routine animal studies, we serendipitously observed that fenbendazole, a benzimidazole antihelminthic used to treat pinworm infection, inhibited brain tumor engraftment. Subsequent in vitro and in vivo experiments with benzimidazoles identified mebendazole as the more promising drug for GBM therapy. In GBM cell lines, mebendazole displayed cytotoxicity, with half-maximal inhibitory concentrations ranging from 0.1 to 0.3 µM. Mebendazole disrupted microtubule formation in GBM cells, and in vitro activity was correlated with reduced tubulin polymerization. Subsequently, we showed that mebendazole significantly extended mean survival up to 63% in syngeneic and xenograft orthotopic mouse glioma models. Mebendazole has been approved by the US Food and Drug Administration for parasitic infections, has a long track-record of safe human use, and was effective in our animal models with doses documented as safe in humans. Our findings indicate that mebendazole is a possible novel anti-brain tumor therapeutic that could be further tested in clinical trials.

[1]  Lisa I. Wang,et al.  Antitumor activity of albendazole against the human colorectal cancer cell line HT-29: in vitro and in a xenograft model of peritoneal carcinomatosis , 2005, Cancer Chemotherapy and Pharmacology.

[2]  P. Schantz,et al.  Long term follow-up of human hydatid disease (Echinococcus granulosus) treated with a high-dose mebendazole regimen. , 1984, The American journal of tropical medicine and hygiene.

[3]  Giovanni Mazzoni,et al.  Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice , 2008, Cancer Chemotherapy and Pharmacology.

[4]  D. Morris,et al.  Pilot Study of Albendazole in Patients with Advanced Malignancy , 2001, Oncology.

[5]  Mustafa Khasraw,et al.  Advances in the Treatment of Malignant Gliomas , 2010, Current oncology reports.

[6]  E. Lacey The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles. , 1988, International journal for parasitology.

[7]  D. Vuitton Benzimidazoles for the treatment of cystic and alveolar echinococcosis: what is the consensus? , 2009, Expert review of anti-infective therapy.

[8]  K. Katzarov,et al.  The types and timing of the degenerative changes seen in the cysts during and after benzimidazole treatment of cystic echinococcosis , 2005, Annals of tropical medicine and parasitology.

[9]  P. Köhler,et al.  The biochemical basis of anthelmintic action and resistance. , 2001, International journal for parasitology.

[10]  P. Georgiev,et al.  Effect of mebendazole on human cystic echinococcosis: the role of dosage and treatment duration. , 1999, Annals of tropical medicine and parasitology.

[11]  D. Rall,et al.  Studies on the chemotherapy of experimental brain tumors: development of an experimental model. , 1970, Cancer research.

[12]  J. Bircher,et al.  Plasma concentrations of mebendazole during treatment of echinococcosis , 1980, European Journal of Clinical Pharmacology.

[13]  S. Badar,et al.  Potent inhibition of tubulin polymerisation and proliferation of paclitaxel-resistant 1A9PTX22 human ovarian cancer cells by albendazole. , 2009, Anticancer research.

[14]  M. Kwa,et al.  Benzimidazole resistance in Haemonchus contortus is correlated with a conserved mutation at amino acid 200 in β-tubulin isotype 1 , 1994 .

[15]  L. J. Eldik,et al.  Targeting protein kinases in central nervous system disorders , 2009, Nature Reviews Drug Discovery.

[16]  Lisa I. Wang,et al.  Albendazole: a Potent Inhibitor of Vascular Endothelial Growth Factor and Malignant Ascites Formation in OVCAR-3 Tumor-Bearing Nude Mice , 2006, Clinical Cancer Research.

[17]  Steve D. M. Brown,et al.  Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans , 2007, Cell.

[18]  R. Kiss,et al.  Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. , 2007, The oncologist.

[19]  R. Kiss,et al.  Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  J. El-on Benzimidazole treatment of cystic echinococcosis. , 2003, Acta tropica.

[21]  M. Kwa,et al.  Beta-tubulin genes from the parasitic nematode Haemonchus contortus modulate drug resistance in Caenorhabditis elegans. , 1995, Journal of molecular biology.

[22]  T. Karpathios,et al.  High mebendazole doses in pulmonary and hepatic hydatid disease. , 1991, Archives of disease in childhood.

[23]  S. Morris,et al.  Nucleophosmin-Anaplastic Lymphoma Kinase of Large-Cell Anaplastic Lymphoma Is a Constitutively Active Tyrosine Kinase That Utilizes Phospholipase C-γ To Mediate Its Mitogenicity , 1998, Molecular and Cellular Biology.

[24]  A. Verma MGMT Gene Silencing and Benefit From Temozolomide in Glioblastoma , 2006 .

[25]  Y. Erşahin,et al.  Intracranial hydatid cysts in children. , 1993, Neurosurgery.

[26]  Q. Quick,et al.  The microtubule inhibiting agent epothilone B antagonizes glioma cell motility associated with reorganization of the actin-binding protein α-actinin 4. , 2011, Oncology reports.

[27]  R. Mirimanoff,et al.  Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. , 2009, The Lancet. Oncology.

[28]  N. Doudican,et al.  Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells , 2008, Molecular Cancer Research.

[29]  Jack A Roth,et al.  Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  A. Bryceson,et al.  Bioavailability and tolerability of mebendazole in patients with inoperable hydatid disease. , 1982, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[31]  K. Gull,et al.  The interaction of benzimidazole carbamates with mammalian microtobule protein. , 1979, Biochemical pharmacology.

[32]  Jack A Roth,et al.  The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells. , 2002, Molecular cancer therapeutics.

[33]  M. Poruchynsky,et al.  Potent inhibition of tumoral hypoxia-inducible factor 1α by albendazole , 2010, BMC Cancer.

[34]  S. Govender,et al.  Echinococcal Infection of the Spine with Neural Involvement , 1988, Spine.

[35]  E. Lacey,et al.  Structure-activity relationships of benzimidazole carbamates as inhibitors of mammalian tubulin, in vitro. , 1985, Biochemical pharmacology.

[36]  Nihal Ahmad,et al.  Dose translation from animal to human studies revisited , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  A D Dayan,et al.  Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics. , 2003, Acta tropica.

[38]  P. Erdinçler,et al.  The role of mebendazole in the surgical treatment of central nervous system hydatid disease. , 1997, British journal of neurosurgery.

[39]  M. Sukhai,et al.  The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. , 2009, Blood.

[40]  A. Armson,et al.  Characterisation of benzimidazole binding with recombinant tubulin from Giardia duodenalis, Encephalitozoon intestinalis, and Cryptosporidium parvum. , 2004, Molecular and biochemical parasitology.

[41]  D. Morris,et al.  The influence of ovarian cancer induced peritoneal carcinomatosis on the pharmacokinetics of albendazole in nude mice. , 2010, Anticancer research.

[42]  J. D. Smyth,et al.  Experience with mebendazole in the treatment of inoperable hydatid disease in England. , 1982, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[43]  G. Riggins,et al.  Establishment of a human glioblastoma stemlike brainstem rodent tumor model. , 2010, Journal of neurosurgery. Pediatrics.

[44]  P. Kleihues,et al.  Intratumoral Patterns of Genomic Imbalance in Glioblastomas , 2010, Brain pathology.

[45]  G. Riggins,et al.  Evaluation of retinoic acid therapy for OTX2-positive medulloblastomas. , 2010, Neuro-oncology.

[46]  C. Dang,et al.  Unexpected antitumorigenic effect of fenbendazole when combined with supplementary vitamins. , 2008, Journal of the American Association for Laboratory Animal Science : JAALAS.