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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

Edith A. Perez
Edith A. Perez
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DOI: 10.1158/1535-7163.MCT-09-0366 Published August 2009
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    Figure 1.

    Chemical structures of MTIs.

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  • Table 1.

    Classes of MTIs

    Compound classApproved agentsCompounds in developmentEffect(s) on microtubules
    TaxanesPaclitaxelDJ-927Polymerization and or stabilization
    Docetaxel
    Albumin-bound paclitaxel
    EpothilonesIxabepiloneKOS-1584
    Epothilone B
    Vinca alkaloidsVinblastineDepolymerization and or destabilization
    Vincristine
    Vinorelbine
    Halichondrin bErubilin mesylate
  • Table 2.

    Tubulin/microtubule-binding properties of MTIs

    PropertyMTI class
    Vinca alkaloidsTaxanes-paclitaxelepothilones-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

    PropertyEpothilones-IxabepiloneTaxanes-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.

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Molecular Cancer Therapeutics: 8 (8)
August 2009
Volume 8, Issue 8
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Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance
Edith A. Perez
Mol Cancer Ther August 1 2009 (8) (8) 2086-2095; DOI: 10.1158/1535-7163.MCT-09-0366

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Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance
Edith A. Perez
Mol Cancer Ther August 1 2009 (8) (8) 2086-2095; DOI: 10.1158/1535-7163.MCT-09-0366
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  • 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
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