Taxanes: Microtubule and Centrosome Targets, and Cell Cycle Dependent Mechanisms of Action
Abstract
Microtubules are highly dynamic cellular polymers made of alphabeta-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.
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Taxanes act by stabilizing the link between individual tubulin dimers.
“Taxanes act by stabilizing the link between individual tubulin dimmers [21].”
From Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (2009) · cites this paper as [21]
In the specific case of paclitaxel, the combined effect may be attributed to their similar site of action - the spindle microtubules.
“In the specific case of Paclitaxel, one of the most commonly used treatments for late-stage human breast cancer [20], the combined effect may be attributed to their similar site of action – the spindle microtubules [1,2,21].”
From Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (2009) · cites this paper as [21]
Taxanes increase the length of tubulin filaments within the cell.
“As illustrated schematically in Figure 7A taxanes increase the length of tubulin filaments within the cell.”
From Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) (2009) · cites this paper as [21]
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- Authors
- Abal, M., Andreu, J., & Barasoain, I.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Current Cancer Drug Targets
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2003-06-01
- Volume
- 3
- Issue
- 3
- Pages
- 193-203
- ISSN
- 1568-0096 (ISSN-L)
- OpenAlex
- W2164778107
- Cited by
- 383
- References
- 0
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 21 · 2022: 22 · 2021: 22 · 2020: 14 · 2019: 19 · 2018: 22 · 2017: 21 · 2016: 23 · 2015: 11 · 2014: 22 · 2013: 14 · 2012: 16
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Cancer Drug Targets (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Fundación Científica Asociación Española Contra el Cáncer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- taxanes, paclitaxel, microtubules, centrosome, spindle microtubules, mitosis, mitotic slippage, apoptosis, Bcl-2 phosphorylation, p53, taxane resistance, cell cycle checkpoints, antimitotic agents
- MeSH terms
- Animals, Cell Cycle, Humans, Microtubules, Drug Delivery Systems, Paclitaxel, Centrosome
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