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Microtubule-Targeting Agents

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 October 2017) | Viewed by 74223

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Prof. Dr. John H. Miller

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Guest Editor

School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
Interests: peloruside; zampanolide, hamigeran G, natural products, anticancer, neurodegeneration, drug discovery, drug synergy

Prof. Susan L. Mooberry

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Guest Editor

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Interests: drug discovery; breast cancer; natural; products; microtubule targeting agents; pediatric cancers

Special Issue Information

Dear Colleagues,

The microtubule is a prime target for anticancer drugs and, more recently, for drugs to treat neurodegeneration. Drugs that stabilize or destabilize microtubules reduce their ability to dynamically shorten or grow, respectively, and have been a mainstay in the effective treatment of cancer for decades. The efficacy of newer cancer therapeutics that target specific receptor-signaling pathways in the cell are often compromised through up-regulation of compensatory pathways. However, there is no back-up system when microtubule function is compromised, which has led to the continued development of new agents that disrupt these critical structures both as single agents and in combination with targeted therapeutics. Clinical trials are also in progress to explore the ability of these drugs to inhibit the progression or reverse defects in neuronal fast axonal transport in neurodegenerative diseases, such as Alzheimer's disease. This Special Issue will concentrate on the use of microtubule-targeting agents (MTAs), including both microtubule stabilizers (MSAs) and destabilizers (MDAs), to treat disease.

The MDA colchicine, from the autumn crocus, was used in its plant form to treat rheumatism and swelling as far back as 1500 BC. At the turn of the 19th century, the antimitotic activities of colchicine were described, and it was critical in the identification of tubulin as the main microtubule component in the 1960s. While colchicine itself is too toxic for effective cancer treatment, there are a large number of compounds that bind within the colchicine site on tubulin that are currently undergoing preclinical and clinical evaluations. The Vinca alkaloids were first discovered in the 1950s and this class of MDAs continues to be a mainstay in the treatment of many cancers. The most recent MDA to enter the clinical treatment of cancer is Halaven^® (eribulin), which binds near the Vinca site but has distinct biological consequences and patient efficacy profiles. Susan Horwitz was the first to describe an MSA (paclitaxel, Taxol^®) in 1979. Following this discovery, research on MSAs has expanded exponentially with many new stabilizing compounds being discovered and clinically developed. Although several MSAs are currently used in the clinic, including Taxol^®(paclitaxel), Taxotere^® (docetaxel), Ixempra^®(ixabepilone), Abraxane ^®(nanoparticle albumin-bound paclitaxel), and Jetvana^® (cabazitaxel), each of these drugs bind within the same taxane site on the microtubule. There are numerous areas of active research on MTAs that are of interest, including critical insights into the mechanisms of action of these effective agents that extend far beyond their antimitotic effects. This Special Issue is seeking research papers and reviews to highlight the current state of knowledge in this rapidly expanding field. Areas of particular interest include:

New natural products, their congeners and synthetic analogs, as well as novel small molecule stabilizers and destabilizers with good potency and potential for translation to the clinic.
Design and synthesis of MTA analogs. For example, chemical scaffolds are being reconstructed based on in silico modeling and structure-activity relationships to simplify chemical structures and produce easier-to-synthesize MTAs that still retain potent anti-microtubule activity. Modification may also improve MTA solubility and perhaps enhance access to the brain. For example, the MSA epothilone D more readily crosses the blood–brain barrier than paclitaxel and may prove more effective than paclitaxel for treatment of brain tumors/metastasis or neuronal degenerative diseases.
The molecular mechanisms of stabilization and destabilization and their relation to binding sites on tubulin. Allosteric changes in tubulin following the binding of an MTA and the effect of MTAs on the dynamicity of mitotic spindles and interphase microtubules are also areas of interest.
The structure of the tubulin-MTA complex. Recent research has expanded on the initial structural studies from the 1990s using electron crystallography of zinc-induced sheets of antiparallel protofilaments to new approaches involving X-ray crystallography of MTAs bound to tubulin heterodimers and cryo-electron microscopy of MTA-bound microtubules.
The interactions between microtubules and endogenous microtubule-associated proteins (MAPs) that act as stabilizing or destabilizing agents, such as tau protein. The interactions of plus and minus end targeting agents on microtubule function is a developing area of investigation.
The interplay between MTAs and motor proteins. This is a major topic that has important connotations for microtubule function in the interphase cell.
The effects of microtubule disruption by MTAs on cellular signaling pathways that inform on their anticancer efficacy and potential biomarkers of response to specific drugs of this class.

Reviews or research papers on any of the above topics would be suitable for inclusion in the Special Issue, and we welcome submissions on or around these topics.

Prof. John H. Miller
Prof. Susan Mooberry
Guest Editors

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Keywords

microtubule
microtubule-stabilizing agents
x-ray crystallography
Cryo-electron microscopy
anticancer drug
Alzheimer's Disease
microtubule-associated proteins

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Published Papers (11 papers)

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4101 KiB

Open AccessArticle

Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin

by Ivana Spasevska, Ahmed T. Ayoub, Philip Winter, Jordane Preto, Gane K.-S. Wong, Charles Dumontet and Jack A. Tuszynski

Int. J. Mol. Sci. 2017, 18(8), 1676; https://doi.org/10.3390/ijms18081676 - 2 Aug 2017

Cited by 18 | Viewed by 7392

Abstract

Tubulin is the target for many small-molecule natural compounds, which alter microtubules dynamics, and lead to cell cycle arrest and apoptosis. One of these compounds is colchicine, a plant alkaloid produced by Colchicum autumnale. While C. autumnale produces a potent cytotoxin, colchicine, and expresses its target protein, it is immune to colchicine’s cytotoxic action and the mechanism of this resistance is hitherto unknown. In the present paper, the molecular mechanisms responsible for colchicine resistance in C. autumnale are investigated and compared to human tubulin. To this end, homology models for C. autumnale α-β tubulin heterodimer are created and molecular dynamics (MD) simulations together with molecular mechanics Poisson–Boltzmann calculations (MM/PBSA) are performed to determine colchicine’s binding affinity for tubulin. Using our molecular approach, it is shown that the colchicine-binding site in C. autumnale tubulin contains a small number of amino acid substitutions compared to human tubulin. However, these substitutions induce significant reduction in the binding affinity for tubulin, and subsequently fewer conformational changes in its structure result. It is suggested that such small conformational changes are insufficient to profoundly disrupt microtubule dynamics, which explains the high resistance to colchicine by C. autumnale. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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2832 KiB

Open AccessArticle

The Application of REDOR NMR to Understand the Conformation of Epothilone B

by Jae-Ho Lee, Moon-Su Kim, Hyo Won Lee, Ihl-Young C. Lee, Hyun Kyoung Kim, Nam Doo Kim, SangGap Lee, Hwajeong Seo and Younkee Paik

Int. J. Mol. Sci. 2017, 18(7), 1472; https://doi.org/10.3390/ijms18071472 - 9 Jul 2017

Cited by 6 | Viewed by 4987

Abstract

The structural information of small therapeutic compounds complexed in biological matrices is important for drug developments. However, structural studies on ligands bound to such a large and dynamic system as microtubules are still challenging. This article reports an application of the solid-state NMR technique to investigating the bioactive conformation of epothilone B, a microtubule stabilizing agent, whose analog ixabepilone was approved by the U.S. Food and Drug Administration (FDA) as an anticancer drug. First, an analog of epothilone B was designed and successfully synthesized with deuterium and fluorine labels while keeping the high potency of the drug; Second, a lyophilization protocol was developed to enhance the low sensitivity of solid-state NMR; Third, molecular dynamics information of microtubule-bound epothilone B was revealed by high-resolution NMR spectra in comparison to the non-bound epothilone B; Last, information for the macrolide conformation of microtubule-bound epothilone B was obtained from rotational-echo double-resonance (REDOR) NMR data, suggesting the X-ray crystal structure of the ligand in the P450epoK complex as a possible candidate for the conformation. Our results are important as the first demonstration of using REDOR for studying epothilones. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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3223 KiB

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Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin

by Ashwani Sharma, Gonzalo Sáez-Calvo, Natacha Olieric, Francisco De Asís Balaguer, Isabel Barasoain, Clemens Lamberth, J. Fernando Díaz and Michel O. Steinmetz

Int. J. Mol. Sci. 2017, 18(7), 1336; https://doi.org/10.3390/ijms18071336 - 22 Jun 2017

Cited by 11 | Viewed by 5216

Abstract

Quinolin-6-yloxyacetamides (QAs) are a chemical class of tubulin polymerization inhibitors that were initially identified as fungicides. Here, we report that QAs are potent anti-proliferative agents against human cancer cells including ones that are drug-resistant. QAs act by disrupting the microtubule cytoskeleton and by causing severe mitotic defects. We further demonstrate that QAs inhibit tubulin polymerization in vitro. The high resolution crystal structure of the tubulin-QA complex revealed that QAs bind to the colchicine site on tubulin, which is targeted by microtubule-destabilizing agents such as colchicine and nocodazole. Together, our data establish QAs as colchicine-site ligands and explain the molecular mechanism of microtubule destabilization by this class of compounds. They further extend our structural knowledge on antitubulin agents and thus should aid in the development of new strategies for the rational design of ligands against multidrug-resistant cancer cells. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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1384 KiB

Open AccessArticle

Centrosomal Protein 70 Is a Mediator of Paclitaxel Sensitivity

by Xingjuan Shi, Yujue Wang, Xiaoou Sun, Chan Wang, Peng Jiang, Yu Zhang, Qinghai Huang, Xiangdong Liu, Dengwen Li, Jun Zhou and Min Liu

Int. J. Mol. Sci. 2017, 18(6), 1267; https://doi.org/10.3390/ijms18061267 - 20 Jun 2017

Cited by 7 | Viewed by 4338

Abstract

Centrosome aberrations have been implicated in the development and progression of breast cancer. Our previous worked show that centrosomal protein 70 (Cep70) regulates breast cancer growth and metastasis. However, it remains elusive whether Cep70 is implicated in the sensitivity of the anti-microtubule drug paclitaxel in breast cancer. Here we provide evidence that Cep70 is a mediator of paclitaxel sensitivity in breast cancer. Cell proliferation assays show that Cep70 expression correlates with paclitaxel sensitivity in breast cancer cell lines. In addition, paclitaxel sensitivity varies when altering Cep70 expression level. Mechanistic studies reveal that Cep70 interacts with tubulin, and promotes the ability of paclitaxel to stimulate microtubule assembly. These data demonstrate that Cep70 mediates paclitaxel sensitivity in breast cancer. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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2261 KiB

Open AccessArticle

Zampanolide, a Microtubule-Stabilizing Agent, Is Active in Resistant Cancer Cells and Inhibits Cell Migration

by Jessica J. Field, Peter T. Northcote, Ian Paterson, Karl-Heinz Altmann, J. Fernando Díaz and John H. Miller

Int. J. Mol. Sci. 2017, 18(5), 971; https://doi.org/10.3390/ijms18050971 - 3 May 2017

Cited by 26 | Viewed by 5338

Abstract

Zampanolide, first discovered in a sponge extract in 1996 and later identified as a microtubule-stabilizing agent in 2009, is a covalent binding secondary metabolite with potent, low nanomolar activity in mammalian cells. Zampanolide was not susceptible to single amino acid mutations at the taxoid site of β-tubulin in human ovarian cancer 1A9 cells, despite evidence that it selectively binds to the taxoid site. As expected, it did not synergize with other taxoid site microtubule-stabilizing agents (paclitaxel, ixabepilone, discodermolide), but surprisingly also did not synergize in 1A9 cells with laulimalide/peloruside binding site agents either. Efforts to generate a zampanolide-resistant cell line were unsuccessful. Using a standard wound scratch assay in cell culture, it was an effective inhibitor of migration of human umbilical vein endothelial cells (HUVEC) and fibroblast cells (D551). These properties of covalent binding, the ability to inhibit cell growth in paclitaxel and epothilone resistant cells, and the ability to inhibit cell migration suggest that it would be of interest to investigate zampanolide in preclinical animal models to determine if it is effective in vivo at preventing tumor growth and metastasis. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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1072 KiB

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Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues

by Laura M. Woods, Joseph W. Arico, Jeffrey D. Frein, Dan L. Sackett and Richard E. Taylor

Int. J. Mol. Sci. 2017, 18(3), 648; https://doi.org/10.3390/ijms18030648 - 17 Mar 2017

Cited by 2 | Viewed by 4535

Abstract

The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand–target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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Review

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16 pages, 2093 KiB

Open AccessReview

Microtubule-Actin Crosslinking Factor 1 and Plakins as Therapeutic Drug Targets

by Quincy A. Quick

Int. J. Mol. Sci. 2018, 19(2), 368; https://doi.org/10.3390/ijms19020368 - 26 Jan 2018

Cited by 10 | Viewed by 5671

Abstract

Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the three major filaments that comprise the cytoskeleton. Plakins have been found to be involved in disorders and diseases of the skin, heart, nervous system, and cancer that are attributed to autoimmune responses and genetic alterations of these macromolecules. Despite their role and involvement across a spectrum of several diseases, there are no current drugs or pharmacological agents that specifically target the members of this protein family. On the contrary, microtubules have traditionally been targeted by microtubule inhibiting agents, used for the treatment of diseases such as cancer, in spite of the deleterious toxicities associated with their clinical utility. The Research Collaboratory for Structural Bioinformatics (RCSB) was used here to identify therapeutic drugs targeting the plakin proteins, particularly the spectraplakins MACF1 and BPAG1, which contain microtubule-binding domains. RCSB analysis revealed that plakin proteins had 329 ligands, of which more than 50% were MACF1 and BPAG1 ligands and 10 were documented, clinically or experimentally, to have several therapeutic applications as anticancer, anti-inflammatory, and antibiotic agents. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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767 KiB

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Microtubule Depolymerization by Kinase Inhibitors: Unexpected Findings of Dual Inhibitors

by Kenji Tanabe

Int. J. Mol. Sci. 2017, 18(12), 2508; https://doi.org/10.3390/ijms18122508 - 23 Nov 2017

Cited by 29 | Viewed by 5207

Abstract

Microtubule-targeting agents are widely used as clinical drugs in the treatment of cancer. However, some kinase inhibitors can also disrupt microtubule organization by directly binding to tubulin. These unexpected effects may result in a plethora of harmful events and/or a misinterpretation of the experimental results. Thus, further studies are needed to understand these dual inhibitors. In this review, I discuss the roles of dual inhibitors of kinase activity and microtubule function as well as describe the properties underlining their dual roles. Since both kinase and microtubule inhibitors cause cell toxicity and cell cycle arrest, it is difficult to determine which inhibitor is responsible for each phenotype. A discrimination of cell cycle arrest at G0/G1 or G2/M and/or image analyses of cellular phenotype may eventually lead to new insights on drug duality. Because of the indispensable roles of microtubules in mitosis and vesicle transport, I propose a simple and easy method to identify microtubule depolymerizing compounds. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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2134 KiB

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Taxol^®: The First Microtubule Stabilizing Agent

by Chia-Ping Huang Yang and Susan Band Horwitz

Int. J. Mol. Sci. 2017, 18(8), 1733; https://doi.org/10.3390/ijms18081733 - 9 Aug 2017

Cited by 199 | Viewed by 14445

Abstract

Taxol^®, an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action of Taxol^® emphasizes the research done in the Horwitz’ laboratory. It discusses the contribution of photoaffinity labeled analogues of Taxol^® toward our understanding of the binding site of the drug on the microtubule. The importance of hydrogen/deuterium exchange experiments to further our insights into the stabilization of microtubules by Taxol^® is addressed. The development of drug resistance, a major problem that arises in the clinic, is discussed. Studies describing differential drug binding to distinct β-tubulin isotypes are presented. Looking forward, it is suggested that the β-tubulin isotype content of a tumor may influence its responses to Taxol^®. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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636 KiB

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Potential Role of Microtubule Stabilizing Agents in Neurodevelopmental Disorders

by Sara Anna Bonini, Andrea Mastinu, Giulia Ferrari-Toninelli and Maurizio Memo

Int. J. Mol. Sci. 2017, 18(8), 1627; https://doi.org/10.3390/ijms18081627 - 26 Jul 2017

Cited by 28 | Viewed by 6613

Abstract

Neurodevelopmental disorders (NDDs) are characterized by neuroanatomical abnormalities indicative of corticogenesis disturbances. At the basis of NDDs cortical abnormalities, the principal developmental processes involved are cellular proliferation, migration and differentiation. NDDs are also considered “synaptic disorders” since accumulating evidence suggests that NDDs are developmental brain misconnection syndromes characterized by altered connectivity in local circuits and between brain regions. Microtubules and microtubule-associated proteins play a fundamental role in the regulation of basic neurodevelopmental processes, such as neuronal polarization and migration, neuronal branching and synaptogenesis. Here, the role of microtubule dynamics will be elucidated in regulating several neurodevelopmental steps. Furthermore, the correlation between abnormalities in microtubule dynamics and some NDDs will be described. Finally, we will discuss the potential use of microtubule stabilizing agents as a new pharmacological intervention for NDDs treatment. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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529 KiB

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An Emerging Role for Tubulin Isotypes in Modulating Cancer Biology and Chemotherapy Resistance

by Amelia L. Parker, Wee Siang Teo, Joshua A. McCarroll and Maria Kavallaris

Int. J. Mol. Sci. 2017, 18(7), 1434; https://doi.org/10.3390/ijms18071434 - 4 Jul 2017

Cited by 105 | Viewed by 9492

Abstract

Tubulin proteins, as components of the microtubule cytoskeleton perform critical cellular functions throughout all phases of the cell cycle. Altered tubulin isotype composition of microtubules is emerging as a feature of aggressive and treatment refractory cancers. Emerging evidence highlighting a role for tubulin isotypes in differentially influencing microtubule behaviour and broader functional networks within cells is illuminating a complex role for tubulin isotypes regulating cancer biology and chemotherapy resistance. This review focuses on the role of different tubulin isotypes in microtubule dynamics as well as in oncogenic changes that provide a survival or proliferative advantage to cancer cells within the tumour microenvironment and during metastatic processes. Consideration of the role of tubulin isotypes beyond their structural function will be essential to improving the current clinical use of tubulin-targeted chemotherapy agents and informing the development of more effective cancer therapies. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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