Abstract
Microtubules are highly dynamic cellular polymers made of αβ-tubulin and associated proteins. They play a key role during mitosis, participating in the exact organization and function of the spindle, and are critical for assuring the integrity of the segregated DNA. Therefore, they represent one of the more effective targets in current cancer therapy. Paclitaxel (Taxol®) is the prototype of the taxane family of antitumor drugs, and it was the first natural product shown to stabilize microtubules. This unique mechanism of action is in contrast to other microtubule poisons, such as Vinca alkaloids, colchicine, and cryptophycines, which inhibit tubulin polymerization. Taxanes block cell cycle progression through centrosomal impairment, induction of abnormal spindles and suppression of spindle microtubule dynamics. Triggering of apoptosis by aberrant mitosis or by subsequent multinucleated G1-like state related to mitotic slippage, depends on cell type and drug schedule. The development of fluorescent derivatives of paclitaxel led us to locate spindle pole microtubules and centrosomes as main sub-cellular targets of cytotoxic taxoids in living cells. In this review we discuss these findings in the context of a cell cycle-dependent response to taxanes, based on the cellular targets, and the status of the implicated cell cycle checkpoints. We also review those events that can influence this response, like the different signal transduction pathways activated / inactivated in relation to Bcl-2 phosphorylation and induction of apoptosis, and the controversial role of the p53 status on cell sensitivity to paclitaxel. Finally, cell cycle-dependent resistance, an emerging concept in combination sequential chemotherapy, is discussed on the basis of the cell cycle-dependent mechanisms of action of taxanes.
Keywords: taxanes, centrosome targets, paclitaxel, vinca alkaloids, bcl-2
Current Cancer Drug Targets
Title: Taxanes: Microtubule and Centrosome Targets, and Cell Cycle Dependent Mechanisms of Action
Volume: 3 Issue: 3
Author(s): M. Abal, J. M. Andreu and I. Barasoain
Affiliation:
Keywords: taxanes, centrosome targets, paclitaxel, vinca alkaloids, bcl-2
Abstract: Microtubules are highly dynamic cellular polymers made of αβ-tubulin and associated proteins. They play a key role during mitosis, participating in the exact organization and function of the spindle, and are critical for assuring the integrity of the segregated DNA. Therefore, they represent one of the more effective targets in current cancer therapy. Paclitaxel (Taxol®) is the prototype of the taxane family of antitumor drugs, and it was the first natural product shown to stabilize microtubules. This unique mechanism of action is in contrast to other microtubule poisons, such as Vinca alkaloids, colchicine, and cryptophycines, which inhibit tubulin polymerization. Taxanes block cell cycle progression through centrosomal impairment, induction of abnormal spindles and suppression of spindle microtubule dynamics. Triggering of apoptosis by aberrant mitosis or by subsequent multinucleated G1-like state related to mitotic slippage, depends on cell type and drug schedule. The development of fluorescent derivatives of paclitaxel led us to locate spindle pole microtubules and centrosomes as main sub-cellular targets of cytotoxic taxoids in living cells. In this review we discuss these findings in the context of a cell cycle-dependent response to taxanes, based on the cellular targets, and the status of the implicated cell cycle checkpoints. We also review those events that can influence this response, like the different signal transduction pathways activated / inactivated in relation to Bcl-2 phosphorylation and induction of apoptosis, and the controversial role of the p53 status on cell sensitivity to paclitaxel. Finally, cell cycle-dependent resistance, an emerging concept in combination sequential chemotherapy, is discussed on the basis of the cell cycle-dependent mechanisms of action of taxanes.
Export Options
About this article
Cite this article as:
Abal M., Andreu M. J. and Barasoain I., Taxanes: Microtubule and Centrosome Targets, and Cell Cycle Dependent Mechanisms of Action, Current Cancer Drug Targets 2003; 3 (3) . https://dx.doi.org/10.2174/1568009033481967
DOI https://dx.doi.org/10.2174/1568009033481967 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...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
Related Articles
-
Allergic Asthma: A Summary from Genetic Basis, Mouse Studies, to Diagnosis and Treatment
Current Pharmaceutical Design Intersection of MicroRNA and Gene Regulatory Networks and their Implication in Cancer
Current Pharmaceutical Biotechnology Author Index To Volume 6
Anti-Cancer Agents in Medicinal Chemistry Potential Clinical Applications of Multi-functional Milk Proteins and Peptides in Cancer Management
Current Medicinal Chemistry Pathways of T Cell Activation and Terminal Differentiation in Chronic Inflammation
Current Drug Targets - Inflammation & Allergy Changing the Endocrine Dependence of Breast Cancer: Data and Hypotheses
Current Medicinal Chemistry Flavonoids, Breast Cancer Chemopreventive and/or Chemotherapeutic Agents
Current Medicinal Chemistry Flavonoids as Multi-Target Compounds: A Special Emphasis on their Potential as Chemo-adjuvants in Cancer Therapy
Current Pharmaceutical Design Paclitaxel Loaded Nanoliposomes in Thermosensitive Hydrogel: A Dual Approach for Sustained and Localized Delivery
Anti-Cancer Agents in Medicinal Chemistry Metallo-Organic G-Quadruplex Ligands in Anticancer Drug Design
Mini-Reviews in Medicinal Chemistry Diastereoselective Addition of Organometallic Reagents to Diimines Derived from (R,R)-1,2-Diaminocyclohexane and Aromatic Aldehydes
Letters in Organic Chemistry Protein Kinase C Modulates Aurora-kinase Inhibition Induced by CCT129202 in HMC-1560,816 Cell Line
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Synaptic Activity-Regulated Wnt Signaling in Synaptic Plasticity, Glial Function and Chronic Pain
CNS & Neurological Disorders - Drug Targets Meet the Editorial Board
Anti-Cancer Agents in Medicinal Chemistry Combined Anticancer Therapies: An Overview of the Latest Applications
Anti-Cancer Agents in Medicinal Chemistry Fresh Platinum Complexes with Promising Antitumor Activity
Anti-Cancer Agents in Medicinal Chemistry Recent Advances in the Chemistry and Biology of Folypoly-γ-glutamate Synthetase Substrates and Inhibitors
Current Medicinal Chemistry - Anti-Cancer Agents Re and Tc Complexes with Pyrazolyl-Containing Chelators: from Coordination Chemistry to Target-Specific Delivery of Radioactivity
Current Radiopharmaceuticals The Mevalonate Pathway and Innate Immune Hyper-Responsiveness in the Pathogenesis of COPD and Lung Cancer: Potential for Chemoprevention
Current Molecular Pharmacology The Emerging Diabetes Online Community
Current Diabetes Reviews