High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction

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High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction

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Title: High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction
Author: Goldmacher, Victor S.; Audette, Charlene A.; Guan, Yinghua; Sidhom, Eriene-Heidi; Shah, Jagesh V.; Whiteman, Kathleen R.; Kovtun, Yelena V.

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Citation: Goldmacher, Victor S., Charlene A. Audette, Yinghua Guan, Eriene-Heidi Sidhom, Jagesh V. Shah, Kathleen R. Whiteman, and Yelena V. Kovtun. 2015. “High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction.” PLoS ONE 10 (2): e0117523. doi:10.1371/journal.pone.0117523. http://dx.doi.org/10.1371/journal.pone.0117523.
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Abstract: The microtubule-targeting maytansinoids accumulate in cells and induce mitotic arrest at 250- to 1000-fold lower concentrations than those required for their association with tubulin or microtubules. To identify the mechanisms of this intracellular accumulation and exceptional cytotoxicity of maytansinoids we studied interaction of a highly cytotoxic maytansinoid, S-methyl DM1 and several other maytansinoids with cells. S-methyl DM1 accumulated inside the cells with a markedly higher apparent affinity than to tubulin or microtubules. The apparent affinities of maytansinoids correlated with their cytotoxicities. The number of intracellular binding sites for S-methyl DM1 in MCF7 cells was comparable to the number of tubulin molecules per cell (~ 4–6 × 107 copies). Efflux of 3 [H]-S-methyl DM1 from cells was enhanced in the presence of an excess of non-labeled S-methyl DM1, indicating that re-binding of 3 [H]-S-methyl DM1 to intracellular binding sites contributed to its intracellular retention. Liposomes loaded with non-polymerized tubulin recapitulated the apparent high-affinity association of S-methyl DM1 to cells. We propose a model for the intracellular accumulation of maytansinoids in which molecules of the compounds diffuse into a cell and associate with tubulin. Affinities of maytansinoids for individual tubulin molecules are weak, but the high intracellular concentration of tubulin favors, after dissociation of a compound-tubulin complex, their re-binding to a tubulin molecule, or to a tip of a microtubule in the same cell, over their efflux. As a result, a significant fraction of microtubule tips is occupied with a maytansinoid when added to cells at sub-nanomolar concentrations, inducing mitotic arrest and cell death.
Published Version: doi:10.1371/journal.pone.0117523
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324968/pdf/
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:14065542
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