Peloruside A Does Not Bind to the Taxoid Site on β-Tubulin and Retains Its Activity in Multidrug-Resistant Cell Lines

Abstract

Peloruside A (peloruside), a microtubule-stabilizing agent from a marine sponge, is less susceptible than paclitaxel to multidrug resistance arising from overexpression of the P-glycoprotein efflux pump and is not affected by mutations that affect the taxoid binding site of ␤-tubulin. In vitro studies with purified tubulin indicate that peloruside directly induces tubulin polymerization in the absence of microtubule-associated proteins. Competition for binding between peloruside, paclitaxel, and laulimalide revealed that peloruside binds to a different site on tubulin to paclitaxel. Moreover, laulimalide was able to displace peloruside, indicating that peloruside and laulimalide may compete for the same or overlapping binding sites. It was concluded that peloruside and laulimalide have binding properties that are distinct from other microtubule-stabilizing compounds currently under investigation.

Macromolecular Accessibility of Fluorescent Taxoids Bound at a Paclitaxel Binding Site in the Microtubule Surface

“…The compounds whose activity has been confirmed can be divided into two different groups, those that bind to the paclitaxel site (paclitaxel and its analogs, epothilones, eleuterobins, sarcodyctins, discodermolide, 3,17-diacetoxy2ethoxy-6oxo-B-homo-estra-1,3,5 (10)-triene) (49, 50, 56 -58), and those that share the laulimalide site (laulimalide and peloruside) (49,59).…”

Docking and molecular dynamics studies of the binding between Peloruside A and tubulin

“…That is to say, when there is not another competitive taxane site drug with stronger affinity force, PLA will preferentially bind to the taxane site, otherwise it will favorably bind to the alternative site. The result theoretically resolved the priority of binding sites for PLA, and it can be used to reasonably explain the interesting experimental fact that PLA does not compete with taxane-site drugs for binding to microtubules 8 , but it can synergize with them 10 , because PLA will occupy the alternative site while the preferential drugs occupy the taxane site. The components of binding free energy show that, in each binding mode, the van der Waals energy (DG vdw ) and the electrostatic energy (DG ele ) make major contributions to the binding free energy, and the nonpolar solvation free energy (DG nonpolar ) is also favorable for the binding, whereas the polar solvation free energy (DG polar ) is unfavorable.…”

“…These results demonstrate the great potential to develop PLA as a promising drug for cancer therapy. Previous experimental studies discovered that PLA did not compete with taxane site drugs for binding to microtubules 8 , instead, it could synergize with them 10 . The initial studies through molecular docking and TR-NOESY nuclear magnetic resonance (NMR) proposed that the binding site of PLA was on a-tubulin 11,12 .…”

“…PLA was further found to be a microtubule-stabilizing agent and to have potent antimitotic activity, making cells block in G2/M phase and apoptosis 6,7 . Interestingly, PLA was likely to overcome the P-gpmultiplemediated multiple drug resistance 8 , and it did not show any obvious toxicity in animal tests 9 . These results demonstrate the great potential to develop PLA as a promising drug for cancer therapy.…”

Developmental Biology of Neoplastic Growth

“…13) isolated from a New Zealand marine sponge Mycale sp. (West et al 2000), stabilizes microtubules by binding at a different site from that of taxoids, but it shares the binding site with laulimalide (Hood et al 2002;Gaitanos et al 2004). …”