Molecular Mechanisms of Microtubule Acting Cancer Drugs

Correia, John J.; Lobert, Sharon

doi:10.1007/978-1-59745-336-3_2

Cited by 5 publications

(16 citation statements)

References 115 publications

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“…Taxol and other taxane drugs bind to and stabilize MTs preventing depolymerization, while demecolcine depolymerizes MTs. 278,279 As previously noted, anesthetics are also known to interact with the cytoskeleton [76][77][78] and Figure 4. Varicosities and mt changes due to anesthetics: (A) light photomicrographs of the effect of 2 × 10 -3 m procaine on varicosity formation in cultured neurites from time zero to (a) two hours (b), three hours (c), and four hours (d); 79 (B) scanning electron micrograph of swellings (s) in the neurite in response to 1 × 10 -3 m procaine; 79 (C) electron micrograph showing the formation of blebs on 3t3 cell surface, due to the disruption of membraneassociated MT and microfilaments after treatment with 0.6 mM tetracaine.…”

Section: Mt and Cytoskeleton Modulationmentioning

confidence: 73%

Neuroprotective Effects against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton

et al. 2016

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Postoperative cognitive dysfunction (POCD) is a decline in memory following anaesthesia and surgery in elderly patients. While often reversible, it consumes medical resources, compromises patient well-being, and possibly accelerates progression into Alzheimer’s disease. Anesthetics have been implicated in POCD, as has neuroinflammation, as indicated by cytokine inflammatory markers. Photobiomodulation (PBM) is an effective treatment for a number of conditions, including inflammation. PBM also has a direct effect on microtubule disassembly in neurons with the formation of small, reversible varicosities, which cause neural blockade and alleviation of pain symptoms. This mimics endogenously formed varicosities that are neuroprotective against damage, toxins, and the formation of larger, destructive varicosities and focal swellings. It is proposed that PBM may be effective as a preconditioning treatment against POCD; similar to the PBM treatment, protective and abscopal effects that have been demonstrated in experimental models of macular degeneration, neurological, and cardiac conditions.

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Section: Mt and Cytoskeleton Modulationmentioning

confidence: 73%

Neuroprotective Effects against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton

et al. 2016

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“…This trend suggests a higher tubulin concentration can shift the equilibrium back toward oligomer formation in the presence of eribulin, but eribulin clearly weakens oligomer stability. 2 Thus, unlike vinca alkaloids, eribulin does not stimulate large nonmicrotubule polymer formation but rather binds to tubulin and suppresses or weakens oligomer formation.…”

Section: Resultsmentioning

confidence: 98%

Macromolecular Interaction of Halichondrin B Analogues Eribulin (E7389) and ER-076349 with Tubulin by Analytical Ultracentrifugation

Alday

Correia

2009

Biochemistry

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Halichondrin B is an antimitotic drug that inhibits microtubule assembly. To understand the molecular details of its interaction with tubulin, we investigated the binding of two halichondrin B analogues, eribulin (previously, ER-086526, E7389) and ER-076349, to tubulin by quantitative analytical ultracentrifugation. Eribulin is currently undergoing phase III clinical trials for cancer; ER-076349 is a closely related analogue with C.35 hydroxyl instead of C.35 primary amine [Towle, M. J., et al. (2001) Cancer Res. 61, 1013]. Below the critical concentration for microtubule assembly and in the presence of GDP, tubulin undergoes weak self-association into short curved oligomers. Eribulin inhibits this oligomer formation 4-6-fold, while ER-076349 slightly stimulates oligomer formation by 2-fold. This is in contrast to vinblastine which strongly stimulates large spiral polymers by 1000-fold under these same conditions. Vinblastine-induced spiral formation is strongly inhibited by both eribulin and ER-076349. Colchicine binding to the intradimer interface has no significant effect on small oligomer formation or the inhibitory activity of eribulin on this process. These results suggest that halichondrin B analogues bind to the interdimer interface or to the beta-subunit alone, disrupt polymer stability, and compete with vinblastine-induced spiral formation. Stathmin is known to form a tight 1:2 complex with tubulin. Eribulin strongly inhibits formation of the 1:2 stathmin-tubulin complex (>3.3 kcal/mol), while ER-076349 weakens formation of the 1:2 complex by approximately 1.9 kcal/mol. These results suggest that eribulin is a global inhibitor of tubulin polymer formation, disrupting tubulin-tubulin contacts at the interdimer interface. ER-076349 also perturbs tubulin-tubulin contacts, but in a more polymer specific manner, reflecting adaptability of the interdimer interface to drug and polymer polymorphism. These results suggest halichondrin B analogues exhibit unique tubulin-based activities that may underlie the clinical utility of these compounds.

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“…Maytansinoids and vinblastine share many similarities: both bind to β-tubulin and tips of microtubules, both, at high concentrations, inhibit microtubule polymerization, both accumulate in cells, and both appear to cause cell cycle arrest and cell death via a similar mode—suppression of dynamic instability of microtubules [ 4 , 5 , 7 , 8 , 30 , 31 ]. On the other hand, while S -methyl DM1 and maytansine do not seem to induce significant aggregation of tubulin in cell-free systems [ 6 , 8 ], or oligomerization in cells (this study), vinblastine and other vinca alkaloids increase the affinity of tubulin for itself inducing its extensive oligomerization in cell-free syslems [ 19 , 32 ] and in cells (this study).…”

Section: Discussionmentioning

confidence: 99%

“…These compounds have affinity to both nonpolymerized tubulin (αβ-heterodimer), and to the tips of microtubules, and are believed to arrest mitosis through their interaction with the mitotic spindle microtubule tips, which leads to suppression of the dynamic instability of the microtubules [ 4 , 6 ]. Among the hypothetical explanations for the high cytotoxicity of tubulin-binding agents are: (i) their ability to accumulate inside cells at low concentrations, seemingly lower than their affinities to both tubulin and microtubules, and (ii) their ability to induce cell death by binding to only a fraction of microtubules, because cells may be arrested at mitosis when only one or several chromosomes fail to segregate due to suppression of dynamic instability of their mitotic spindle microtubules [ 4 , 5 , 7 ]. While interactions of maytansinoids with tubulin and microtubules in solution have been examined [ 6 , 8 ], the reasons for their ability to accumulate in cells at concentrations lower than those at which they associate with either tubulin or microtubules have not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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Molecular Mechanisms of Microtubule Acting Cancer Drugs

Cited by 5 publications

References 115 publications

Neuroprotective Effects against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton

Neuroprotective Effects against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton

Macromolecular Interaction of Halichondrin B Analogues Eribulin (E7389) and ER-076349 with Tubulin by Analytical Ultracentrifugation

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

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