Publication details

Microtubules as targets of alkaloids in cancer treatment

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Year of publication 2005
Type Article in Proceedings
Conference Sborník XIII. Cytoskeletálního klubu
MU Faculty or unit

Faculty of Medicine

Field Oncology and hematology
Keywords benzophenanthridine alkaloids; cancer; cytostatics; anti-mitotic drugs; microtubules
Description A large number of chemical compounds, many of which are derived from natural products, bind to tubulin and inhibit cell proliferation at the metaphase/anaphase transition of mitosis by acting on the mitotic spindle. In our contribution, we briefly summarize the current understanding of interactions of microtubules with alkaloids using as anti-tumor agents, i.e. Vinca alkaloides, taxanes, colchicine and others. Microtubule-interacting drugs are important agents in cancer chemotherapy. Not only the presence of MT, but also theirs dynamics are important for cell processes dependent on MT (intracellular transport, motility, morphogenesis, mitosis). Dynamic properties of MTs include dynamic instability and treadmilling. Disruption of tubulin-MT equlibrium and/or MT stabilization can lead to the same consequences as microtubule disruption. Two classes of anti-tumor drugs was found to inhibit cell division by acting on microtubules: 1) taxanes that block MT depolymerization and stabilize MT; 2) vinca alkaloids and colchicine that inhibit MT polymerization. Three types of toxins according to binding site on b-tubulin are recognized to date: 1) colchicine site (close to a/b interface); 2) vinca alkaloids area; 3) taxane binding pocket. Several new compounds with anti-mitotic properties are effective chemoterapeutic agents and thus the search for new tubulin-binding drugs is important for the cancer therapy. Recently we study antiproliferative properties of benzo[c]phenanthridine alkaloids. Anti-microtubular effect is one of the discussed mechanism of these alkaloids action. Wolf and Knippling (1993) described that benzo[c]phenanthridine derivatives chelidonine, sanguinarine and chelerythrine inhibit taxol-mediated polymerisation of rat brain tubulin in vitro and that sanguinarine and chelerythrine affect colchicine and podophyllotoxine binding on MT. We described the effect of sanguinarine, chelerythrine, sanguilutine, chelilutine (Slaninová et al., 2001) and recently also other derivatives sanguirubine and chelirubine on microtubules of HeLa cells. In cells cultivated with these alkaloids the microtubular network thining out from the cell periphery and at higher alkaloid concentrations MTs completely disappear. References: Slaninová, I., Táborská, E., Bochořáková, H., Slanina, J. Cell Biology and Toxicology: 17: 51-63. 2001. Wolf J, Knipling L. Biochemistry.32: 13334-13339.1993 Reviews for further reading: Checchi, P.M. et al., Ttrends in Pharmacol Sci:24. 361-365. 2003. Hadfield, J.A et al., Progress in Cell Cycle Research:5, 309-325. 2003. Wood, K.W. et al., Current Opin in Pharmacol.:1. 370-377.2001. Jordan, A.M. et al. Current Opin in Cell Biol. 10: 123-130. 1998. Sorger, P.K. et al. Current Opin in Cell Biol. 9: 807-814.1997. This work was supported by grants from Grant Agency of the Czech Republic (No. 525/04/0017 and 301/03/H005).
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