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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects*
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Benzophenanthridines / chemistry
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Benzophenanthridines / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromosome Segregation / drug effects*
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DNA Breaks, Double-Stranded / drug effects
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HeLa Cells
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Humans
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M Phase Cell Cycle Checkpoints / drug effects*
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Organothiophosphorus Compounds / chemistry
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Organothiophosphorus Compounds / pharmacology*
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Phenotype
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Protein Multimerization / drug effects
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Retinoblastoma Protein / metabolism
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Signal Transduction / drug effects
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Tubulin / chemistry
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Tubulin / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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Benzophenanthridines
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Organothiophosphorus Compounds
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Retinoblastoma Protein
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Tubulin
Grants and funding
This study was in part supported by CNRS (France), by the Gefluc Association (France) and by the Academy of Young Scientists of Ukraine (Grant 4791/05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.