Peloruside A inhibits microtubule dynamics in a breast cancer cell line MCF7.
Peloruside A (PelA), a novel microtubule-stabilizing agent and potential anti-cancer drug, isolated from the marine sponge Mycale hentscheli, binds to a distinct, non-taxoid binding site on tubulin. Using live-cell confocal microscopy, the effects of PelA on microtubule dynamics were quantified in a human breast adenocarcinoma cell line (MCF7) stably expressing GFP-α-tubulin. Changes in microtubule length were tracked over time in cells treated with PelA concentrations ranging from 3.8-100 nM. As with other microtubule-targeting drugs like paclitaxel and epothilone B, microtubule dynamics were suppressed in a concentration-dependent manner. At the PelA IC₅₀ concentrations for cell proliferation (3.8 nM) and G₂/M block (25 nM), PelA inhibited dynamicity by 23% and 45%, respectively. At 25 nM PelA, effects included a 24% and 41% reduction in average growth rate and growth length, respectively. Additionally, the total time spent in pause increased by 53% and coincided with a 36% reduction in the average amount of time spent growing. Rescue and catastrophe frequencies were not significantly affected by PelA, except for length-based catastrophe (67% increase). The results provide further insight into PelA's unique mode of stabilization and contribute to our understanding of how microtubule-targeting agents exert their anti-mitotic effects.
Chan
Ariane
A
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
Andreae
Peter M
PM
Northcote
Peter T
PT
Miller
John H
JH
D001943:Breast Neoplasms / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D034261:Epothilones / Q000494:pharmacology; D005260:Female; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors
D019086:Bridged Bicyclo Compounds, Heterocyclic; D034261:Epothilones; D007783:Lactones; C414085:peloruside A; C093788:epothilone B