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.