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

Abstract

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 αβI and αβIII tubulin isoforms are the most important isoforms in establishing predictive response of cancer cell sensitivity to colchicine derivatives. However, since αβI tubulin is widely distributed in the human body, targeting it would lead to severe adverse side effects. Consequently, we have identified tubulin isotype αβIII as the most important molecular target for inhibition of microtubule polymerization and hence cancer cell cytotoxicity. Tubulin isotypes αβI and αβII 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 αβIII as a target for optimized chemotherapy drug design.

The Tubulin Colchicine Domain: a Molecular Modeling Perspective

“…[53] Several research groups have investigated the possibility of designing a compound that can selectively bind to a specific isotype. [55] The current microtubule-disrupting agents bind to all isotypes, having only a slight preference for one over another. The vinca alkaloids bind preferentially to bII, providing an explanation for their good activity against leukemia and Hodgkin's lymphoma, as these cancerous cells express high levels of the bII isotype.…”

Tubulin-interactive stilbene derivatives as anticancer agents

“…A set of novel colchicine derivatives with selective affinity to the colchicine domain of the αβIII isoform was synthesized. Their cytotoxic action correlated with the expression levels of specific tubulin isotypes [45,111]. The discovery of novel tubulin-binding agents that could selectively bind specific isoforms will be the aim of further research with the use of molecular modeling.…”

Using Entropy Leads to a Better Understanding of Biological Systems

“…In the first example, we will show that the incorporation of the laws of physics and principles of inference provides a more comprehensive method to investigate and reveal protein folding dynamics compared to conventional approaches [14]. Second, a maximum entropy method is developed to predict tubulin isotype expression levels in a cell when the cell is exposed to various cytotoxic derivatives of the anti-cancer drug, colchicine [15]. The last example discussed here aims to provide a theoretical method based on the maximum entropy approach to design short nucleic acid sequences, aptamers that specifically bind to bio-molecular targets of interest [16].…”

“…In order to understand the complex behavior of various cancer cells exposed to a novel family of tubulin-binding compounds created as derivatives of colchicine, we propose to apply the ME approach to predict the expression levels of specific isotypes of tubulin in response to cytotoxic agents [15]. Six cancer cell lines as listed in Table 1, A549, MCF7, CEM, HeLa, M006X, and M010B, were used in this study and they were subjected to colchicine and 20 of its novel derivatives with significantly different binding affinities for each tubulin isotype, particularly, αβI, αβII, αβIII, and αβIV.…”