Drugs that target dynamic microtubules: a new molecular perspective.

doi:10.1002/MED.20242

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Drugs that target dynamic microtubules: a new molecular perspective.

Journal Article•DOI•

Drugs that target dynamic microtubules: a new molecular perspective.

Richard A. Stanton¹, Kim M. Gernert², James H. Nettles², Ritu Aneja¹•Institutions (2)

Georgia State University¹, Emory University²

01 May 2011-Medicinal Research Reviews (NIH Public Access)-Vol. 31, Iss: 3, pp 443-481

TL;DR: The effects of microtubule‐binding chemotherapeutic agents are reviewed from a new perspective, considering how their mode of binding induces conformational changes and alters biological function relative to the molecular vectors of micro Tubule assembly or disassembly.

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Abstract: Microtubules have long been considered an ideal target for anticancer drugs because of the essential role they play in mitosis, forming the dynamic spindle apparatus. As such, there is a wide variety of compounds currently in clinical use and in development that act as antimitotic agents by altering microtubule dynamics. Although these diverse molecules are known to affect microtubule dynamics upon binding to one of the three established drug domains (taxane, vinca alkaloid, or colchicine site), the exact mechanism by which each drug works is still an area of intense speculation and research. In this study, we review the effects of microtubule-binding chemotherapeutic agents from a new perspective, considering how their mode of binding induces conformational changes and alters biological function relative to the molecular vectors of microtubule assembly or disassembly. These “biological vectors” can thus be used as a spatiotemporal context to describe molecular mechanisms by which microtubule-targeting drugs work.

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Journal Article•DOI•

Carbon nanotubes for delivery of small molecule drugs

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Bin Sheng Wong¹, Sia Lee Yoong¹, Anna Jagusiak², Tomasz Panczyk³, Han Kiat Ho¹, Wee Han Ang¹, Giorgia Pastorin¹ - Show less +3 more•Institutions (3)

National University of Singapore¹, Jagiellonian University Medical College², Polish Academy of Sciences³

01 Dec 2013-Advanced Drug Delivery Reviews

TL;DR: The delivery of small molecule drugs is expounded, with special attention paid to the current progress of in vitro and in vivo research involving CNT-based DDSs, before finally concluding with some consideration on inevitable complications that hamper successful disease intervention with CNTs.

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488 citations

Journal Article•DOI•

Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death

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Malgorzata Borowiak¹, Malgorzata Borowiak², Wallis Nahaboo², Martin Reynders¹, Katharina Nekolla¹, Pierre Jalinot², Jens Hasserodt², Markus Rehberg¹, Marie Delattre², Stefan Zahler¹, Angelika M. Vollmar¹, Dirk Trauner¹, Oliver Thorn-Seshold², Oliver Thorn-Seshold¹ - Show less +10 more•Institutions (2)

Ludwig Maximilian University of Munich¹, École normale supérieure de Lyon²

16 Jul 2015-Cell

TL;DR: The photostatins are introduced, inhibitors that can be switched on and off in vivo by visible light, to optically control microtubule dynamics and are promising as a new class of precision chemotherapeutics whose toxicity may be spatiotemporally constrained using light.

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292 citations

Cites background from "Drugs that target dynamic microtubu..."

...…such as cardiotoxicity and neurotoxicity (Ghinet et al., 2013; Hooper et al., 2013; Tozer et al., 2002; Tron et al., 2006), which limit the doses at which chemotherapeutics can be applied, thus impairing their therapeutic value (Dumontet and Jordan, 2010; Gill et al., 2014; Stanton et al., 2011)....
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..., 2006), which limit the doses at which chemotherapeutics can be applied, thus impairing their therapeutic value (Dumontet and Jordan, 2010; Gill et al., 2014; Stanton et al., 2011)....
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Journal Article•DOI•

Plant-derived Immunomodulators: An Insight on Their Preclinical Evaluation and Clinical Trials

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Ibrahim Jantan¹, Waqas Ahmad¹, Syed Nasir Abbas Bukhari¹•Institutions (1)

National University of Malaysia¹

25 Aug 2015-Frontiers in Plant Science

TL;DR: The present review will give an overview of widely investigated plant-derived compounds which have exhibited potent effects on cellular and humoral immune functions in pre-clinical investigations and will highlight their clinical potential.

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Abstract: The phagocyte-microbe interactions in the immune system is a defense mechanism but when excessively or inappropriately deployed can harm host tissues and participate in the development of different non-immune and immune chronic inflammatory diseases such as autoimmune problems, allergies, some rheumatoid disorders, cancers and others. Immunodrugs include organic synthetics, biological agents such as cytokines and antibodies acting on single targets or pathways have been used to treat immune-related diseases but with limited success. Most of immunostimulants and immunosuppressants in clinical use are the cytotoxic drugs which possess serious side effects. There is a growing interest to use herbal medicines as multi-component agents to modulate the complex immune system in the prevention of infections rather than treating the immune-related diseases. Many therapeutic effects of plant extracts have been suggested to be due to their wide array of immunomodulatory effects and influence on the immune system of the human body. Phytochemicals such as flavonoids, polysaccharides, lactones, alkaloids, diterpenoids and glycosides, present in several plants, have been reported to be responsible for the plants immunomodulating properties. Thus the search for natural products of plant origin as new leads for development of potent and safe immunosuppressant and immunostimulant agents is gaining much major research interest. The present review will give an overview of widely investigated plant-derived compounds (curcumin, resveratrol, epigallocatechol-3-gallate, quercetin, colchicine, capsaicin, andrographolide, and genistein) which have exhibited potent effects on cellular and humoral immune functions in pre-clinical investigations and will highlight their clinical potential.

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268 citations

Cites background from "Drugs that target dynamic microtubu..."

...…studied: the molecular target was recognized, the binding spot was accurately characterized, and the biological consequences of damaging microtubule dynamics were examined; complete reviews summarizing these results are available (Bhattacharyya et al., 2008; Nuki, 2008; Stanton et al., 2011)....
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Journal Article•DOI•

Medicinal Plants: A Source of Anti-Parasitic Secondary Metabolites

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Michael Wink¹•Institutions (1)

Heidelberg University¹

31 Oct 2012-Molecules

TL;DR: The identified plants and compounds offer a chance to develop new drugs against parasitic diseases and need to be tested in more detail, especially in animal models and if successful, in clinical trials.

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Abstract: This review summarizes human infections caused by endoparasites, including protozoa, nematodes, trematodes, and cestodes, which affect more than 30% of the human population, and medicinal plants of potential use in their treatment. Because vaccinations do not work in most instances and the parasites have sometimes become resistant to the available synthetic therapeutics, it is important to search for alternative sources of anti-parasitic drugs. Plants produce a high diversity of secondary metabolites with interesting biological activities, such as cytotoxic, anti-parasitic and anti-microbial properties. These drugs often interfere with central targets in parasites, such as DNA (intercalation, alkylation), membrane integrity, microtubules and neuronal signal transduction. Plant extracts and isolated secondary metabolites which can inhibit protozoan parasites, such as Plasmodium, Trypanosoma, Leishmania, Trichomonas and intestinal worms are discussed. The identified plants and compounds offer a chance to develop new drugs against parasitic diseases. Most of them need to be tested in more detail, especially in animal models and if successful, in clinical trials.

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260 citations

Cites background from "Drugs that target dynamic microtubu..."

...Some of these natural products are presently used in the chemotherapy of cancer [8,12,14]....
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...Sanguinarine is also an inhibitor of microtubule formation [14]....
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Journal Article•DOI•

Plant-Derived Anti-Inflammatory Compounds: Hopes and Disappointments regarding the Translation of Preclinical Knowledge into Clinical Progress

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Robert Fürst¹, Ilse Zündorf¹•Institutions (1)

Goethe University Frankfurt¹

29 May 2014-Mediators of Inflammation

TL;DR: This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG), and quercetin, and sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound.

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Abstract: Many diseases have been described to be associated with inflammatory processes. The currently available anti-inflammatory drug therapy is often not successful or causes intolerable side effects. Thus, new anti-inflammatory substances are still urgently needed. Plants were the first source of remedies in the history of mankind. Since their chemical characterization in the 19th century, herbal bioactive compounds have fueled drug development. Also, nowadays, new plant-derived agents continuously enrich our drug arsenal (e.g., vincristine, galantamine, and artemisinin). The number of new, pharmacologically active herbal ingredients, in particular that of anti-inflammatory compounds, rises continuously. The major obstacle in this field is the translation of preclinical knowledge into evidence-based clinical progress. Human trials of good quality are often missing or, when available, are frequently not suitable to really prove a therapeutical value. This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG), and quercetin. We will highlight their clinical potential and/or pinpoint an overestimation. Moreover, we will sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound.

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196 citations

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References

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Journal Article•DOI•

Microtubules as a target for anticancer drugs.

[...]

Mary Ann Jordan¹, Leslie Wilson¹•Institutions (1)

University of California, Santa Barbara¹

01 Apr 2004-Nature Reviews Cancer

TL;DR: Highly dynamic mitotic-spindle microtubules are among the most successful targets for anticancer therapy, and it is now known that at lower concentrations, microtubule-targeted drugs can suppress micro Tubule dynamics without changingmicrotubule mass; this action leads to mitotic block and apoptosis.

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Abstract: Highly dynamic mitotic-spindle microtubules are among the most successful targets for anticancer therapy. Microtubule-targeted drugs, including paclitaxel and Vinca alkaloids, were previously considered to work primarily by increasing or decreasing the cellular microtubule mass. Although these effects might have a role in their chemotherapeutic actions, we now know that at lower concentrations, microtubule-targeted drugs can suppress microtubule dynamics without changing microtubule mass; this action leads to mitotic block and apoptosis. In addition to the expanding array of chemically diverse antimitotic agents, some microtubule-targeted drugs can act as vascular-targeting agents, rapidly depolymerizing microtubules of newly formed vasculature to shut down the blood supply to tumours.

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4,007 citations

"Drugs that target dynamic microtubu..." refers background in this paper

...However, it is becoming appreciated that all microtubule-active drugs at low nanomolar concentrations attenuate microtubule dynamicity rather than altering net polymer mass.(4,92,93) Based on this notion, barriers between the two classes seem to be disintegrating and these drugs should be referred to instead as ‘‘suppressors of dynamic instability....
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...No wonder drugs belonging to this class continue to be among the most commonly prescribed agents in cancer chemotherapy.(4,91) Although most microtubule-interfering agents either stabilize or destabilize tubulin via binding on known tubulin-binding sites, there do exist some compounds that bind to tubulin on undefined sites or target microtubules indirectly by altering their posttranslational modification....
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...This blocks dividing cells in mitosis, eventually leading to apoptosis.(4)...
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...Formation of a short polymerization nucleus precedes elongation or polymer growth at each end by the reversible, noncovalent addition of tubulin subunits.(4) For net polymer elongation, the association of tubulin heterodimers into the growing microtubule is faster than microtubule depolymerization....
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Journal Article•DOI•

Dynamic instability of microtubule growth

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Timothy J. Mitchison¹, Marc W. Kirschner¹•Institutions (1)

University of California, San Francisco¹

15 Nov 1984-Nature

TL;DR: It is reported here that microtubules in vitro coexist in growing and shrinking populations which interconvert rather infrequently and this dynamic instability is a general property of micro Tubules and may be fundamental in explaining cellular microtubule organization.

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Abstract: We report here that microtubules in vitro coexist in growing and shrinking populations which interconvert rather infrequently. This dynamic instability is a general property of microtubules and may be fundamental in explaining cellular microtubule organization.

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3,108 citations

Journal Article•DOI•

Microtubule polymerization dynamics

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Arshad Desai¹, Timothy J. Mitchison¹•Institutions (1)

University of California, San Francisco¹

01 Jan 1997-Annual Review of Cell and Developmental Biology

TL;DR: This review describes progress toward understanding the mechanism of dynamic instability of pure tubulin and discusses the function and regulation of microtubule dynamic instability in living cells.

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Abstract: The polymerization dynamics of microtubules are central to their biological functions. Polymerization dynamics allow microtubules to adopt spatial arrangements that can change rapidly in response to cellular needs and, in some cases, to perform mechanical work. Microtubules utilize the energy of GTP hydrolysis to fuel a unique polymerization mechanism termed dynamic instability. In this review, we first describe progress toward understanding the mechanism of dynamic instability of pure tubulin and then discuss the function and regulation of microtubule dynamic instability in living cells.

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2,484 citations

"Drugs that target dynamic microtubu..." refers background in this paper

...MAPs bind in a nucleotide-insensitive manner to the microtubule lattice.(21) Most MAPs identified to date are posttranslationally regulated by phosphorylation, with the more phosphorylated forms attenuated in their capacity to stabilize microtubules....
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...Assembly of GTP-tubulin and disassembly of GDP-tubulin are both thermodynamically favorable in the cytoplasm and can thus perform mechanical work.(21) The rapid dynamics of spindle microtubules is necessary for the capture of chromosomes during prometaphase, as the spindle fibers have to ‘‘explore’’ the cytoplasmic space to find and make productive attachments to the kinetochores....
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Journal Article•DOI•

Kinesin and Dynein Superfamily Proteins and the Mechanism of Organelle Transport

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Nobutaka Hirokawa¹•Institutions (1)

University of Tokyo¹

23 Jan 1998-Science

TL;DR: This review focuses on the molecular mechanism of organelle transport in cells and describes kinesin and dynein superfamily proteins.

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Abstract: Cells transport and sort proteins and lipids, after their synthesis, to various destinations at appropriate velocities in membranous organelles and protein complexes. Intracellular transport is thus fundamental to cellular morphogenesis and functioning. Microtubules serve as a rail on which motor proteins, such as kinesin and dynein superfamily proteins, convey their cargoes. This review focuses on the molecular mechanism of organelle transport in cells and describes kinesin and dynein superfamily proteins.

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1,632 citations

Journal Article•DOI•

Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain

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Raimond B. G. Ravelli¹, Benoît Gigant², Patrick A. Curmi³, Isabelle Jourdain³, Sylvie Lachkar³, André Sobel³, Marcel Knossow² - Show less +3 more•Institutions (3)

European Bioinformatics Institute¹, Centre national de la recherche scientifique², French Institute of Health and Medical Research³

11 Mar 2004-Nature

TL;DR: Changes in the subunits of tubulin as it switches from its straight conformation to a curved one correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability.

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Abstract: Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions. Their dynamic instability is controlled by numerous compounds and proteins, including colchicine and stathmin family proteins. The way in which microtubule instability is regulated at the molecular level has remained elusive, mainly because of the lack of appropriate structural data. Here, we present the structure, at 3.5 A resolution, of tubulin in complex with colchicine and with the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with two tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments shows changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, the tubulin-colchicine complex sheds light on the mechanism of colchicine's activity: we show that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.

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1,418 citations

"Drugs that target dynamic microtubu..." refers background or methods in this paper

...The orange vector showing the directionality of an RB3/stathmin-like protein and two tubulin complexes are shown superimposed on growing end of microtubule as a reference, as this structure has been used to determine the binding domain of several depolymerizing drugs.(86,87,223) [Color figure canbe viewed in the online issue, which is available at wileyonlinelibrary....
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...Additionally, the stathmin-like protein RB3 has been used to stabilize tubulin in a bent conformation for crystallographic studies to determine the binding sites of several depolymerizing drugs.(86,87)...
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...14), contiguous to the GTP-binding domain of the a-tubulin subunit.(86,118,164,165) It is known to bind to the unpolymerized tubulin subunits in a two-step reaction process that begins with the formation of an initial pre-equilibrium complex, which is reversible and bound with low affinity....
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...Depolymerizing drug, Colchicine is shown as a space-filling model (magenta, highlighted with arrow) at the intradimer interface at the start of the peeling protofilament as determined by Ravelli et al.(86) As in previous figures, the green axis shows direction of growth of a straight protofilament while the cyan axis connects nucleotides of a peeling protofilament....
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