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

Chih Yuan Tseng, Jonathan Y. Mane, Philip Winter, Lorelei Johnson, Torin Huzil, Elzbieta Izbicka, Richard F. Luduena, Jack A. Tuszynski

Research output: Contribution to journalArticle

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Abstract

Background: A 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.Results: We 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.Conclusions: The 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.

Original languageEnglish (US)
Article number131
JournalMolecular Cancer
Volume9
DOIs
StatePublished - May 30 2010

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Colchicine
Tubulin
Cell Line
Neoplasms
Protein Isoforms
Entropy
Drug Design
Human Body
Drug Resistance
Microtubules
Polymerization
Pharmaceutical Preparations
Cell Death
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology

Cite this

Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives. / Tseng, Chih Yuan; Mane, Jonathan Y.; Winter, Philip; Johnson, Lorelei; Huzil, Torin; Izbicka, Elzbieta; Luduena, Richard F.; Tuszynski, Jack A.

In: Molecular Cancer, Vol. 9, 131, 30.05.2010.

Research output: Contribution to journalArticle

Tseng, Chih Yuan ; Mane, Jonathan Y. ; Winter, Philip ; Johnson, Lorelei ; Huzil, Torin ; Izbicka, Elzbieta ; Luduena, Richard F. ; Tuszynski, Jack A. / Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives. In: Molecular Cancer. 2010 ; Vol. 9.
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