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.