Article Figures & Data
Figures
- Figure 1.
Chemical structures of MTIs.
Tables
- Table 1.
Classes of MTIs
Compound class Approved agents Compounds in development Effect(s) on microtubules Taxanes Paclitaxel DJ-927 Polymerization and or stabilization Docetaxel Albumin-bound paclitaxel Epothilones Ixabepilone KOS-1584 Epothilone B Vinca alkaloids Vinblastine Depolymerization and or destabilization Vincristine Vinorelbine Halichondrin b Erubilin mesylate - Table 2.
Tubulin/microtubule-binding properties of MTIs
Property MTI class Vinca alkaloids Taxanes-paclitaxel epothilones-ixabepilone Mechanism of action • Direct binding to β-subunit of α/β-tubulin dimers • Direct binding to β-subunit of α/β-tubulin dimers • Direct binding to β-subunit of α/β-tubulin dimers Binding site • Binds to β-tubulin at site near exchangeable GTP-binding site • β-tubulin binding site located near inter microtubule protofilament contacts • Overlaps paclitaxel binding site on β-tubulin • Two distinct binding sites on microtubules • Does not overlap binding sites for GTP, colchicine, podophyllotoxin, or vincas • Epothilones competitively inhibit binding of paclitaxel to β-tubulin • High affinity binding at microtubule ends • Poor binding to soluble tubulin • High affinity binding to polymerized tubulin • Low affinity binding along microtubule surface • High affinity binding to polymerized tubulin • Thr274, Arg282, Glu292, and Ala231 play essential roles in epothilone binding • Phe270 and Ala364 play essential roles in taxane binding Biochemical effect(s) • Suppress microtubule dynamics • Suppress microtubule dynamics • Suppress microtubule dynamics • Suppress microtubule assembly • Enhance microtubule assembly • Enhance microtubule assembly • Induce microtubule depolymerization • Induce tubulin polymerization • Induce tubulin polymerization • Suppress microtubule treadmilling • Suppress microtubule treadmilling • Suppress microtubule treadmilling • Suppress microtubule dynamic instability • Suppress microtubule dynamic instability • Suppress microtubule dynamic instability • Induce tubulin association into coiled spiral aggregates • Induce microtubule bundling • Induce microtubule bundling • Decrease polymer mass at high concentrations • Induce formation of multipolar spindles • Induce formation of multipolar spindles • Increase polymer mass at high concentrations • Increase polymer mass at high concentrations Selectivity • No difference in β-tubulin isotype binding affinity • Selective binding and inactivation of βII-tubulin containing microtubules • Broad selectivity for microtubules containing multiple β-tubulin isotypes • Higher affinity for α/βII and α/βIII tubulin dimers in the presence of GTP observed for vincristine • Not active against βIII and βIV-tubulin containing microtubules • Active against βIII and βIV-tubulin containing microtubules • Do not stabilize microtubules in Saccharomyces cerevisiae • Stabilize microtubules in S. cerevisiae cells • Substrates for drug efflux transporters such as P-gp • Are not substrates for drug efflux transporters such as P-gp NOTE: See refs. 3, 5, 7, 8, 31, 34, 35, 42, 85, 86.
- Table 3.
Cellular effects of epothilones and taxanes
Property Epothilones-Ixabepilone Taxanes-Paclitaxel Resistance β-tubulin overexpression • Retains cytotoxic activity in cells expressing βIII-tubulin • Loss of activity in cells expressing βIII-tubulin β-tubulin mutation • Active in cells expressing β-tubulin with point mutations (Phe270 → Val and Ala364 → Thr) that confer resistance to paclitaxel • Loss of activity in cells expressing β-tubulin with point mutations (Phe270 → Val and Ala364 → Thr) that affect binding to βIII-tubulin subunit MAP-tau overexpression • Reduced activity in cells expressing high levels of MAP-tau • MAP-tau competes with paclitaxel for binding to β-tubulin • Reduced activity in cells expressing high levels of MAP-tau Cell Damage Cell cycle arrest • Selective blocking of mitotic spindle microtubule assembly and function • Selective blocking of mitotic spindle microtubule assembly and function • Override centrosomal dependent nucleation of microtubules • Override centrosomal dependent nucleation of microtubules • Induces G2-M cell cycle arrest • Induces G2/M cell cycle arrest • Block mitosis at metaphase-anaphase boundary • Block mitosis at metaphase-anaphase boundary Apoptosis • Induce phosphorylation of Bcl-2 • Induce phosphorylation of Bcl-2 • p53-dependent activation of pro-apoptotic effector Bax via transcription-dependent and -independent pathways • Activation of pro-apoptotic effectors Bax, Bad, and Apaf-1 • Cytochrome C and Smac/DIABLO accumulation in paclitaxel-resistant cells • Inactivation of the anti-apoptotic effectors Bcl-2 and BclxL • Activation of caspase-2, caspase-3, and caspase-8 • Cytochrome C accumulation • Activation of caspase-2 and caspase-9 NOTE: See refs. 8, 12, 16, 31, 32, 34, 41, 42, 49–52.
August 2009
Volume 8, Issue 8
Volume 8, Issue 8
Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance
Jump to section
- Article
- Abstract
- Introduction
- Microtubule Structure
- Microtubule Dynamics
- Microtubule-Destabilizing Agents
- Microtubule-Stabilizing Agents
- Resistance
- Novel Microtubule Inhibitors in Development
- Epothilones
- Epothilone B Analog Ixabepilone
- Epothilone B (Patupilone, EPO906)
- Epothilone D and Analogs (KOS-862 and KOS-1584)
- Vinca Alkaloids, Vinflunine
- Halichondrin B Analog Erubilin Mesylate
- Taxane Analog DJ-927
- Conclusions
- Disclosure of Potential Conflicts of Interest
- Footnotes
- References
- Figures & Data
- Info & Metrics
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