Fluorescent Taxoid Probes for Microtubule Research

Barasoaín, Isabel; Díaz, J. Fernando; Andreu, José Manuel

doi:10.1016/s0091-679x(10)95019-x

Cited by 21 publications

(22 citation statements)

References 52 publications

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“…To evaluate whether ERG overexpression interferes with taxane binding to MTs, we treated live ERG-positive and ERG-negative DU-145 cells with fluorescently labelled paclitaxel (Flutax) and monitored the extent and stability of Flutax binding to the microtubule network 38 . We found that the ERG-positive DU145 cells had significantly fewer MTs labelled with Flutax as compared with ERG-negative cells, in which Flutax labelled an extensive and intricate microtubule network throughout the cell cytoplasm ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

ERG induces taxane resistance in castration-resistant prostate cancer

et al. 2014

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Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG over-expression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane in sensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.

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Section: Resultsmentioning

confidence: 99%

ERG induces taxane resistance in castration-resistant prostate cancer

et al. 2014

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“…To probe the anticancer effects of Taxol, fluorescent analogues [4–15] have been reported. The most extensively studied derivative, a commercially available compound termed Flutax-2 (Figure 1), comprises Taxol linked at the 7-position through a β-Ala ester to the fluorophore Oregon Green (OG).…”

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confidence: 99%

Synthesis of a Fluorescent Analogue of Paclitaxel That Selectively Binds Microtubules and Sensitively Detects Efflux by P‐Glycoprotein

2017

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The anticancer drug paclitaxel (Taxol) exhibits paradoxical and poorly understood effects against slow growing tumors. To investigate its biological activity, fluorophores such as Oregon Green have been linked to this drug. However, this modification increases its polarity by ~ 1000-fold and reduces the toxicity of Taxol towards cancer cell lines by over 200-fold. To construct more drug-like fluorescent probes suitable for imaging by confocal microscopy and analysis by flow cytometry, we synthesized derivatives of Taxol linked to the drug-like fluorophore Pacific Blue (PB). We found that PB-Gly-Taxol bound the target protein beta-tubulin both with high affinity in vitro and with high specificity in living cells, exhibited substantial cytotoxicity towards HeLa cells, and it was a highly sensitive substrate of the multidrug resistance transporter P-glycoprotein (P-gp). This probe provides a new tool for investigation of the proliferation rate paradox associated with Taxol.

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“…Despite their success in monitoring microtubules in vitro, these reagents were unable to trace microtubules in living cells due to the lack of specificity and the complexity of cellular contents. Microtubule‐targeting agents, such as taxol or colchicine, were able to label microtubules in living cells due to their specificity to microtubules; however, the microtubule‐targeting agent‐based molecules are detrimental to microtubule dynamics, making it unsuitable for monitoring microtubule behaviors in living cells 34–37 . In this study, we sought to adopt a peptide‐based strategy to develop fluorescent molecules that monitor microtubule behavior in living cells.…”

Section: Discussionmentioning

confidence: 99%

Modified heptapeptide from tau binds both tubulin and microtubules

Liu

et al. 2020

Thoracic Cancer

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Background: Microtubules are the major cytoskeletal component in eukaryotes which are essential for a large spectrum of cellular activities. Monitoring the behavior of microtubules is helpful for a better understanding of the regulatory mechanism governing microtubule architecture and microtubule-based activities. Here, we characterized the binding capability of a modified heptapeptide from tau to both tubulin and microtubules and sought to develop it as a fluorescent peptide for monitoring microtubules. Methods: To deliver the fluorescent peptide into the cells, a cell-penetrating peptide was conjugated to the modified heptapeptide from tau and synthesized. The affinity of the modified heptapeptide was determined by microscale thermophoresis. The microtubule labeling ability was determined by adding the peptide into the polymerized microtubule solutions or cultured HeLa cells.; Results: Affinity determination revealed that the tau-derived peptide specifically bound to tubulin. In addition, the peptide was able to label polymerized microtubules in solution, although no obvious microtubule filaments were observed clearly in living cells, probably due to the inadequate affinity. Conclusions: These results suggest that using a peptide-based strategy for imaging microtubules might be plausible and attempts to improve its affinity is warranted in the future.

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Fluorescent Taxoid Probes for Microtubule Research

Cited by 21 publications

References 52 publications

ERG induces taxane resistance in castration-resistant prostate cancer

ERG induces taxane resistance in castration-resistant prostate cancer

Synthesis of a Fluorescent Analogue of Paclitaxel That Selectively Binds Microtubules and Sensitively Detects Efflux by P‐Glycoprotein

Modified heptapeptide from tau binds both tubulin and microtubules

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