Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives

Molecular Cancer

Research

Elzbieta Izbicka¹  Richard F Luduena²  Jonathan Y Mane³  Torin Huzil³  Philip Winter³  Chih-Yuan Tseng³  Lorelei Johnson³  Jack A Tuszynski⁴ 

[1] Cancer Therapy and Research Center, The Institute for Drug Development, 14960 Omicron Drive, 78245, San Antonio, TX, USA;Department of Biochemistry, University of Texas Health Science Center, 78229, San Antonio, TX, USA;Department of Oncology, Cross Cancer Institute, University of Alberta, T6G 1Z2, Edmonton, AB, Canada;Department of Oncology, Cross Cancer Institute, University of Alberta, T6G 1Z2, Edmonton, AB, Canada;Department of Physics, University of Alberta, Edmonton, AB, Canada;

关键词: Colchicine;    Free Energy;    Maximum Entropy Method;    Binding Free Energy;    Ixabepilone;   

DOI  :  10.1186/1476-4598-9-131

 received in 2009-12-22, accepted in 2010-05-30,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundA maximum entropy approach is proposed to predict the cytotoxic effects of a panel of colchicine derivatives in several human cancer cell lines. Data was obtained from cytotoxicity assays performed with 21 drug molecules from the same family of colchicine compounds and correlate these results with independent tubulin isoform expression measurements for several cancer cell lines. The maximum entropy method is then used in conjunction with computed relative binding energy values for each of the drug molecules against tubulin isotypes to which these compounds bind with different affinities.ResultsWe have found by using our analysis that αβ I and αβ III tubulin isoforms are the most important isoforms in establishing predictive response of cancer cell sensitivity to colchicine derivatives. However, since αβ I tubulin is widely distributed in the human body, targeting it would lead to severe adverse side effects. Consequently, we have identified tubulin isotype αβ III as the most important molecular target for inhibition of microtubule polymerization and hence cancer cell cytotoxicity. Tubulin isotypes αβ I and αβ II are concluded to be secondary targets.ConclusionsThe benefit of being able to correlate expression levels of specific tubulin isotypes and the resultant cell death effect is that it will enable us to better understand the origin of drug resistance and hence design optimal structures for the elimination of cancer cells. The conclusion of the study described herein identifies tubulin isotype αβ III as a target for optimized chemotherapy drug design.

【 授权许可】

Unknown   
© Tseng et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.