title: Carbendazim inhibits cancer cell proliferation by suppressing microtubule dynamics.
abstract: Carbendazim (methyl 2-benzimidazolecarbamate) is widely used as a systemic fungicide in human food production and appears to act on fungal tubulin. However, it also inhibits proliferation of human cancer cells, including drug- and multidrug-resistant and p53-deficient cell lines. Because of its promising preclinical anti-tumor activity, it has undergone phase I clinical trials and is under further clinical development. Although it weakly inhibits polymerization of brain microtubules and induces G(2)/M arrest in tumor cells, its mechanism of action in human cells has not been fully elucidated. We examined its mechanism of action in MCF7 human breast cancer cells and found that it inhibits proliferation (IC(50), 10 microM) and half-maximally arrests mitosis at a similar concentration (8 microM), in concert with suppression of microtubule dynamic instability without appreciable microtubule depolymerization. It induces mitotic spindle abnormalities and reduces the metaphase intercentromere distance of sister chromatids, indicating reduction of tension on kinetochores, thus leading to metaphase arrest. With microtubules assembled in vitro from pure tubulin, carbendazim also suppresses dynamic instability, reducing the dynamicity by 50% at 10 microM, with only minimal (21%) reduction of polymer mass. Carbendazim binds to mammalian tubulin (K(d), 42.8 +/- 4.0 microM). Unlike some benzimidazoles that bind to the colchicine site in tubulin, carbendazim neither competes with colchicine nor competes with vinblastine for binding to brain tubulin. Thus, carbendazim binds to an as yet unidentified site in tubulin and inhibits tumor cell proliferation by suppressing the growing and shortening phases of microtubule dynamic instability, thus inducing mitotic arrest.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9610, USA.
authors.forename: Mythili
authors.initials: M
authors.lastname: Yenjerla
authors.forename: Corey
authors.initials: C
authors.lastname: Cox
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jordan
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D002219:Carbamates / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003078:Colchicine; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology; D008938:Mitosis / Q000187:drug effects*; D014404:Tubulin / Q000187:drug effects / Q000502:physiology
chemical_list: D001562:Benzimidazoles; D002219:Carbamates; D014404:Tubulin; C006698:carbendazim; D003078:Colchicine