Differential in vitro association of vinca alkaloid-induced tubulin spiral filaments into aggregated spirals

Verdier-Pinard, Pascal; Garès, Michèle; Wright, Michel

doi:10.1016/s0006-2952(99)00190-2

Cited by 16 publications

(8 citation statements)

References 35 publications

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“…Vinorelbine induces tubulin paracrystals and acts on interphase microtubules, which might be linked to this phenomenon (Lobert et al, 1998;Verdier-Pinard et al, 1999;Jean-Decoster et al, 1999) (supplementary material Fig. S2).…”

Section: Discussionmentioning

confidence: 99%

“…Their mode of action relies on changing microtubule dynamics, which disrupts formation of mitotic spindles. Taxol stabilizes microtubules and prevents microtubule depolymerization, whereas nocodazole and vinca alkaloids, such as vinorelbine, prevent polymerization (Beswick et al, 2006;Verdier-Pinard et al, 1999). In each case, loss of dynamic instability results in lack of normal microtubule function, which can lead to cell death following prolonged mitotic arrest (Gascoigne and Taylor, 2008;Varetti and Musacchio, 2008).…”

Section: Introductionmentioning

confidence: 99%

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The microtubule poison vinorelbine kills cells independently of mitotic arrest and targets cells lacking the APC tumour suppressor more effectively

Klotz

Nelson

Kroboth

et al. 2012

Journal of Cell Science

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SummaryColorectal cancers commonly carry truncation mutations in the adenomatous polyposis coli (APC) gene. The APC protein contributes to the stabilization of microtubules. Consistently, microtubules in cells lacking APC depolymerize more readily in response to microtubule-destabilizing drugs. This raises the possibility that such agents are suitable for treatment of APC-deficient cancers. However, APC-deficient cells have a compromised spindle assembly checkpoint, which renders them less sensitive to killing by microtubule poisons whose toxicity relies on the induction of prolonged mitotic arrest. Here, we describe the novel discovery that the clinically used microtubule-depolymerizing drug vinorelbine (Navelbine) kills APC-deficient cells in culture and in intestinal tissue more effectively than it kills wild-type cells. This is due to the ability of vinorelbine to kill cells in interphase independently of mitotic arrest. Consistent with a role for p53 in cell death in interphase, depletion of p53 renders cells less sensitive to vinorelbine, but only in the presence of wild-type APC. The pro-apoptotic protein BIM (also known as BCL2L11) is recruited to mitochondria in response to vinorelbine, where it can inhibit the anti-apoptotic protein BCL2, suggesting that BIM mediates vinorelbine-induced cell death. This recruitment of BIM is enhanced in cells lacking APC. Consistently, BIM depletion dampens the selective effect of vinorelbine on these cells. Our findings reveal that vinorelbine is a potential therapeutic agent for colorectal cancer, but they also illustrate the importance of the APC tumour suppressor status when predicting therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The microtubule poison vinorelbine kills cells independently of mitotic arrest and targets cells lacking the APC tumour suppressor more effectively

Klotz

Nelson

Kroboth

et al. 2012

Journal of Cell Science

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“…Characterization of biomolecular complexes interactions, and macromolecular conformational changes, by sedimentation velocity and sedimentation equilibrium [11], [62], [72], [74], [75], [77] [147] Differential scanning calorimetry (DSC)…”

Section: Analytical Ultracentrifugationmentioning

confidence: 99%

“…Magnification is 250 higher than optical microscopy; 5-10 nM objects can be imaged [5], [11], [22], [23], [34], [62], [74], [86], [125] Fluorescence anisotropy Characterization of the interaction between two molecules one being fused to a fluorophore. The fluorophore is excited by polarized light but also emit.…”

Section: Analytical Ultracentrifugationmentioning

confidence: 99%

“…Authors have shown that a correlation exists between binding parameters and cytotoxicity for most of the existing taxane/epothilone analogues [74]. Lobert et al also provide the thermodynamic direction for drug improvement since they assume that compounds with a favorable entropic contribution to binding are less effective in killing cells than those with a favorable enthalpic contribution.…”

Section: Is Affinity Improvement a Real Benefit?mentioning

confidence: 99%

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Microtubule targeting agents: from biophysics to proteomics

Calligaris

Verdier-Pinard

Devred

et al. 2010

Cell. Mol. Life Sci.

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This review explores various aspects of the interaction between microtubule targeting agents and tubulin, including binding site, affinity, and drug resistance. Starting with the basics of tubulin polymerization and microtubule targeting agent binding, we then highlight how the three-dimensional structures of drug-tubulin complexes obtained on stabilized tubulin are seeded by precise biological and biophysical data. New avenues opened by thermodynamics analysis, high throughput screening, and proteomics for the molecular pharmacology of these drugs are presented. The amount of data generated by biophysical, proteomic and cellular techniques shed more light onto the microtubule-tubulin equilibrium and tubulin-drug interaction. Combining these approaches provides new insight into the mechanism of action of known microtubule interacting agents and rapid in-depth characterization of next generation molecules targeting the interaction between microtubules and associated modulators of their dynamics. This will facilitate the design of improved and/or alternative chemotherapies targeting the microtubule cytoskeleton.

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Methods for Studying Vinca Alkaloid Interactions With Tubulin

Lobert

Correia

2007

Methods in Molecular Medicine™

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Differential in vitro association of vinca alkaloid-induced tubulin spiral filaments into aggregated spirals

Cited by 16 publications

References 35 publications

The microtubule poison vinorelbine kills cells independently of mitotic arrest and targets cells lacking the APC tumour suppressor more effectively

The microtubule poison vinorelbine kills cells independently of mitotic arrest and targets cells lacking the APC tumour suppressor more effectively

Microtubule targeting agents: from biophysics to proteomics

Methods for Studying Vinca Alkaloid Interactions With Tubulin

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