title: Amitozyn impairs chromosome segregation and induces apoptosis via mitotic checkpoint activation.
abstract: Amitozyn (Am) is a semi-synthetic drug produced by the alkylation of major celandine (Chelidonium majus L.) alkaloids with the organophosphorous compound N,N'N'-triethylenethiophosphoramide (ThioTEPA). We show here that the treatment of living cells with Am reversibly perturbs the microtubule cytoskeleton, provoking a dose-dependent cell arrest in the M phase. Am changed the dynamics of tubulin polymerization in vitro, promoted the appearance of aberrant mitotic phenotypes in HeLa cells and induced apoptosis by the activation of caspase-9, caspase-3 and PARP, without inducing DNA breaks. Am treatment of HeLa cells induced changes in the phosphorylation of the growth suppressor pRb that coincided with maximum mitotic index. The dose-dependent and reversible anti-proliferative effect of Am was observed in several transformed cell lines. Importantly, the drug was also efficient against multidrug-resistant, paclitaxel-resistant or p53-deficient cells. Our results thus open the way to further pre-clinical evaluation of Am.
authors.forename: Bastien
authors.initials: B
authors.lastname: Hermant
authors.affiliation: Institut de Biologie Structurale, Centre National de la Recherche Scientifique (CNRS), Grenoble, France.
authors.forename: Bastien
authors.initials: B
authors.lastname: Herman
authors.forename: Aldrian
authors.initials: A
authors.lastname: Gudrun
authors.forename: Anatoly I
authors.initials: AI
authors.lastname: Potopalsky
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Chroboczek
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Tcherniuk
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053119:Benzophenanthridines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020090:Chromosome Segregation / Q000187:drug effects*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010641:Phenotype; D055503:Protein Multimerization / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D009946:Organothiophosphorus Compounds; D016160:Retinoblastoma Protein; D014404:Tubulin