Binding of Indanocine to the Colchicine Site on Tubulin Promotes Fluorescence, and Its Binding Parameters Resemble Those of the Colchicine Analogue AC

Das, Lalita; Gupta, Suvroma; Dasgupta, Dipak; Poddar, Asim; Janik, Mark E.; Bhattacharyya, Bhabatarak

doi:10.1021/bi801575e

Cited by 27 publications

(18 citation statements)

References 32 publications

(46 reference statements)

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“…Third, globular protein unfolding usually has a positive DC p . This type of analysis has been applied to ligand binding to tubulin by Das et al (2009) who have shown that that the enthalpy of association of indanocine with tubulin is negative and occurs with a negative heat capacity change (DC p = -175.1 cal mol À1 K À1 ). It has also been applied to stathmin binding to tubulin to form a T2S complex (Honnappa et al, 2003).…”

Section: B Thermodynamic Parameters Determination Of Map-tubulin Intmentioning

confidence: 99%

Microtubule and MAPs

Devred¹,

Barbier²,

Lafitte³

et al. 2010

Methods in Cell Biology

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Microtubules are implicated in many essential cellular processes such as architecture, cell division, and intracellular traffic, due to their dynamic instability. This dynamicity is tightly regulated by microtubule-associated proteins (MAPs), such as tau and stathmin. Despite extensive studies motivated by their central role in physiological functions and pathological role in neurodegenerative diseases and cancer, the precise mechanisms of tau and stathmin binding to tubulin and their consequences on microtubule stability are still not fully understood. One of the most crucial points missing is a quantitative thermodynamic description of their interaction with tubulin/microtubules and of the tubulin complexes formed upon these interactions. In this chapter, we will focus on the use of analytical ultracentrifugation, isothermal titration calorimetry, and nuclear magnetic resonance-three powerful and complementary techniques in the field of MAP-tubulin/microtubule interactions, in addition to the spectrometric techniques and co-sedimentation approach. We will present the limits of these techniques to study this particular interaction and precautions that need to be taken during MAPs preparation. Understanding the molecular mechanisms that govern MAPs action on microtubular network will not only shed new light on the role of this crucial family of protein in the biology of the cell, but also hopefully open new paths to increase the therapeutic efficiency of microtubule-targeting drugs in cancers therapies and neurodegeneratives diseases prevention.

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Section: B Thermodynamic Parameters Determination Of Map-tubulin Intmentioning

confidence: 99%

Microtubule and MAPs

Devred¹,

Barbier²,

Lafitte³

et al. 2010

Methods in Cell Biology

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“…4 Indanocine 1 is a potent microtubule-destabilizing agent and binds to the colchicine binding site of tubulin. [7][8][9] Recent reports have shown that indanocine reduces dynamic instability of microtubules at low concentrations and inhibits migration of metastatic cancer cells. 10 Therefore indanocine and associated analogues are of great interest as they not only have promise as potential chemotherapeutic agents, 11 but could also be used to prevent the spread of cancer through metastasis.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and antiproliferative activity of indole analogues of indanocine

2013

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The design and synthesis of a novel series of indole-analogues of indanocine is reported, together with their antiproliferative activity in the NCI's panel of cancer cell lines. Indanocine displays potent activity against a wide range of cancer cell lines (mean GI 50 < 20 nM), including drug-resistant cancer cell lines, and also inhibits the migration of metastatic cancer cells. A number of the described indole-analogues display a similar activity profile to indanocine, exhibiting potent antiproliferative activities in several cancer cell lines, and offer new leads for further development.

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“…The ability of polygamain to displace colchicine binding to tubulin was evaluated using a fluorescent colchicine displacement assay (Das et al, 2009) as described previously . In brief, a solution containing 2 M tubulin alone or 2 M colchicine and 2 M tubulin was incubated for 2 h at 37°C with vehicle or competing drug.…”

Section: Methodsmentioning

confidence: 99%

Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site

et al. 2011

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Bioassay-guided fractionation was used to isolate the lignan polygamain as the microtubule-active constituent in the crude extract of the Mountain torchwood, Amyris madrensis. Similar to the effects of the crude plant extract, polygamain caused dose-dependent loss of cellular microtubules and the formation of aberrant mitotic spindles that led to G 2 /M arrest. Polygamain has potent antiproliferative activities against a wide range of cancer cell lines, with an average IC 50 of 52.7 nM. Clonogenic studies indicate that polygamain effectively inhibits PC-3 colony formation and has excellent cellular persistence after washout. In addition, polygamain is able to circumvent two clinically relevant mechanisms of drug resistance, the expression of P-glycoprotein and the ␤III isotype of tubulin. Studies with purified tubulin show that polygamain inhibits the rate and extent of purified tubulin assembly and displaces colchicine, indicating a direct interaction of polygamain within the colchicine binding site on tubulin. Polygamain has structural similarities to podophyllotoxin, and molecular modeling simulations were conducted to identify the potential orientations of these compounds within the colchicine binding site. These studies suggest that the benzodioxole group of polygamain occupies space similar to the trimethoxyphenyl group of podophyllotoxin but with distinct interactions within the hydrophobic pocket. Our results identify polygamain as a new microtubule destabilizer that seems to occupy a unique pharmacophore within the colchicine site of tubulin. This new pharmacophore will be used to design new colchicine site compounds that might provide advantages over the current agents.

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Binding of Indanocine to the Colchicine Site on Tubulin Promotes Fluorescence, and Its Binding Parameters Resemble Those of the Colchicine Analogue AC

Cited by 27 publications

References 32 publications

Microtubule and MAPs

Microtubule and MAPs

Design, synthesis and antiproliferative activity of indole analogues of indanocine

Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site

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