Eribulin exerts its pharmacologic effects by binding to the plus ends of microtubules and suppressing microtubule growth, without affecting microtubule shortening, and by inducing the formation of nonproductive tubulin aggregates (Figure 1). This pattern of effects on microtubule stabilization is distinct from that of other clinically important tubulin-targeting agents, which include taxanes, epothilones, and vinca alkaloids. Vinca alkaloids (e.g., vincristine, vinblastine) bind to the plus ends and the sides of the microtubule, thereby reducing the concentration of tubulin aggregates and shrinking of the microtubules. Taxanes (e.g., paclitaxel, docetaxel) promote microtubule polymerization and maintain the microtubule structure, leading to the inhibition of mitotic spindle. Epothilones (e.g., ixabepilone) induce microtubule polymerization through a mechanism that appears to be similar to that of paclitaxel, as epothilones compete with paclitaxel for binding to microtubules and suppress microtubule dynamics.
Mechanism of action of eribulin. The polymerization of microtubules occurs when heterodimers of α-tubulin and β-tubulin assemble to form a cylinder that is composed of tubulin heterodimers in a head-to-tail structure (A). Tubulin polymerizes in an end-to-end fashion with the α subunit of one tubulin dimer binding to the β subunit of the next. Therefore, one end will have the α subunit exposed while the other end will have the β subunit exposed. These ends are designated the minus (−) and plus (+) ends, respectively. The (−) end is capped so elongation of the microtubule occurs from the (+) direction. (B) Eribulin binds to the centromeric cap of the microtubule. A few molecules of vinblastine bound to high-affinity sites at the microtubule (+) end suffice to suppress microtubule cycling. A microtubule cutaway reveals the interior surface of the structure. Paclitaxel binds along the interior surface of the microtubule. Ixabepilone is known to share a common binding site with paclitaxel and has a high binding affinity for beta-III microtubulin. Despite the fact that epothilones bind close to or at the paclitaxel binding site on tubulin, the binding of epothilones to tubulin and the subsequent microtubule formation may be distinct from those of paclitaxel and require further research to elucidate all of the potential binding sites. (Adapted, with permission, from references 12–16).
Eribulin binds to a single site on soluble tubulin with low affinity and to a small number of sites at the microtubule ends with high affinity. This binding at the microtubule ends leads to the blockade of tubulin dimers from adding to the growing end of the microtubules. Eribulin binds at or near the tubulin vinca domain, a region located at the interface to two tubulin heterodimers. It appears to exert its activity by inhibiting microtubule growth. Unlike the antimitotic agents, paclitaxel and vinblastine, eribulin does not affect microtubule shortening.[10,19]
In vitro data have shown that eribulin inhibits cancer cell proliferation via the induction of irreversible cell-cycle blocks at G2-M, disruption of mitotic spindles, and initiation of apoptosis.[18,20] Although eribulin is a substrate for the P-glycoprotein drug efflux pump, it retains full in vitro activity against cancer cells that are taxane resistant due to β-tubulin mutations.
Am J Health Syst Pharm. 2012;69(9):745-755. © 2012 American Society of Health-System Pharmacists
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