Abstract
Tubulin is the target of some of the most widely used and time-honored anticancer tubulin-binding agents (TBAs). The clinical usefulness of many TBAs has been held back as a result of tumor cell drug-resistance. The elucidation of the three-dimensional structure of αβ-tubulin dimer has provided an opportunity for rational drug design aimed at generating compounds that will target tubulin in therapeutically more efficacious ways compared to presently available drugs. An issue to be addressed is which one(s) of the tubulin species, their isotypes, or their posttranslationally modified forms, should be specifically targeted in cancer chemotherapy. This review offers a critical appraisal of current knowledge on tubulins in cancer and an update on new anti-neoplastic microtubule-targeted treatment strategies. Specifically, it examines, across disciplines, cellular/molecular, biochemical, clinical/pathological, and pharmacological aspects of β-tubulin isotypes, posttranslational modifications of tubulin dimers, γ-tubulin and microtubule nucleation, and microtubule regulatory proteins. Emphasis is placed on the overexpression of (i) the βIII isotype, which functions as a survival factor associated with dynamic instability of microtubules; (ii) γ-tubulin, a key microtubule nucleating protein; and (iii) the microtubule severing enzyme spastin, involved in cell motility and proliferation of glioblastoma cells. The role of βIII-tubulin in resistance of cancer cells to taxanes is examined. Attention is called to the novel concept that βIII-tubulin functions as a "gateway" for prosurvival signals in partnership with GTPases, such as GBP1. Appraisal is also offered on epothilones and the concept of hypersensitization to TBAs as promising therapeutic strategies in taxane resistant epithelial cancers and in high-grade gliomas.
Keywords: Microtubules, tubulin, cancer, solid tumors, gliomas, beta-tubulin isotypes, gamma-tubulin, spastin, tubulin binding agent(s), epothilones
Current Pharmaceutical Design
Title:Tubulins as Therapeutic Targets in Cancer: from Bench to Bedside
Volume: 18 Issue: 19
Author(s): Christos D. Katsetos and Pavel Draber
Affiliation:
Keywords: Microtubules, tubulin, cancer, solid tumors, gliomas, beta-tubulin isotypes, gamma-tubulin, spastin, tubulin binding agent(s), epothilones
Abstract: Tubulin is the target of some of the most widely used and time-honored anticancer tubulin-binding agents (TBAs). The clinical usefulness of many TBAs has been held back as a result of tumor cell drug-resistance. The elucidation of the three-dimensional structure of αβ-tubulin dimer has provided an opportunity for rational drug design aimed at generating compounds that will target tubulin in therapeutically more efficacious ways compared to presently available drugs. An issue to be addressed is which one(s) of the tubulin species, their isotypes, or their posttranslationally modified forms, should be specifically targeted in cancer chemotherapy. This review offers a critical appraisal of current knowledge on tubulins in cancer and an update on new anti-neoplastic microtubule-targeted treatment strategies. Specifically, it examines, across disciplines, cellular/molecular, biochemical, clinical/pathological, and pharmacological aspects of β-tubulin isotypes, posttranslational modifications of tubulin dimers, γ-tubulin and microtubule nucleation, and microtubule regulatory proteins. Emphasis is placed on the overexpression of (i) the βIII isotype, which functions as a survival factor associated with dynamic instability of microtubules; (ii) γ-tubulin, a key microtubule nucleating protein; and (iii) the microtubule severing enzyme spastin, involved in cell motility and proliferation of glioblastoma cells. The role of βIII-tubulin in resistance of cancer cells to taxanes is examined. Attention is called to the novel concept that βIII-tubulin functions as a "gateway" for prosurvival signals in partnership with GTPases, such as GBP1. Appraisal is also offered on epothilones and the concept of hypersensitization to TBAs as promising therapeutic strategies in taxane resistant epithelial cancers and in high-grade gliomas.
Export Options
About this article
Cite this article as:
D. Katsetos Christos and Draber Pavel, Tubulins as Therapeutic Targets in Cancer: from Bench to Bedside, Current Pharmaceutical Design 2012; 18 (19) . https://dx.doi.org/10.2174/138161212800626193
DOI https://dx.doi.org/10.2174/138161212800626193 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Delivery of Large Genomic DNA Inserts > 100 kb Using HSV-1 Amplicons
Current Gene Therapy Progress in Research of K<sub>V</sub>1.1 and K<sub>V</sub>1.3 Channels as Therapeutic Targets
Current Topics in Medicinal Chemistry Editorial
Current Medical Imaging Pharmacophores for Ligand Recognition and Activation / Inactivation of the Cannabinoid Receptors
Current Pharmaceutical Design Molecular Imaging of Therapeutic Potential of Reporter Probes
Current Drug Targets Meet Our Editorial Board Member
CNS & Neurological Disorders - Drug Targets Surface Plasmon Resonance Imaging Sensor for Cathepsin Determination Based on Immobilized Cystatin
Protein & Peptide Letters Nanosponge Carriers- An Archetype Swing in Cancer Therapy: A Comprehensive Review
Current Drug Targets Cerenkov Luminescence Imaging at a Glance
Current Molecular Imaging (Discontinued) Gold Nanoparticles - Synthesis and Applications in Cancer Management
Recent Patents on Materials Science An Insight into Drug Repositioning for the Development of Novel Anti-Cancer Drugs
Current Topics in Medicinal Chemistry Identification of AHSA1 as a Potential Therapeutic Target for Breast Cancer: Bioinformatics Analysis and <i>in vitro</i> Studies
Current Cancer Drug Targets Multi Fractal Process of Powder Particle Breakage and Aggregation
Current Nanoscience PET Imaging of the Peripheral Benzodiazepine Receptor: Monitoring Disease Progression and Therapy Response in Neurodegenerative Disorders
Current Pharmaceutical Design Current Therapeutic Paradigms in Glioblastoma
Reviews on Recent Clinical Trials Integrins as Novel Drug Targets for Overcoming Innate Drug Resistance
Current Cancer Drug Targets G-Protein Signaling, Lipid Rafts and the Possible Sites of Action for the Antidepressant Effects of n-3 Polyunsaturated Fatty Acids
CNS & Neurological Disorders - Drug Targets Clinical Impact of Gene Expression Profiling on Oncology Diagnosis, Prognosis, and Treatment
Combinatorial Chemistry & High Throughput Screening Sigma Receptors and Cocaine Abuse
Current Topics in Medicinal Chemistry Current Drug Targets for Modulating Alzheimer's Amyloid Precursor Protein: Role of Specific Micro-RNA Species
Current Medicinal Chemistry