School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
Invest New Drugs. 2011 Aug;29(4):615-26. doi: 10.1007/s10637-010-9398-2. Epub 2010 Feb 20.
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.
佩拉罗昔德 A（PelA）是一种新型微管稳定剂和潜在的抗癌药物，从海洋海绵 Mycale hentscheli 中分离得到，它与微管蛋白上的一个独特的、非紫杉烷结合位点结合。使用活细胞共聚焦显微镜，在稳定表达 GFP-α-微管蛋白的人乳腺癌腺癌细胞系（MCF7）中定量研究了 PelA 对微管动力学的影响。用 PelA 处理浓度范围为 3.8-100 nM 的细胞，跟踪微管长度随时间的变化。与其他微管靶向药物如紫杉醇和埃坡霉素 B 一样，微管动力学呈浓度依赖性抑制。在 PelA 对细胞增殖的 IC₅₀浓度（3.8 nM）和 G₂/M 阻断的 IC₅₀浓度（25 nM）下，PelA 分别抑制了 23%和 45%的动态性。在 25 nM PelA 下，平均增长率和生长长度分别降低了 24%和 41%。此外，暂停时间增加了 53%，而平均生长时间减少了 36%。除了基于长度的灾难（增加 67%）外，PelA 对灾难和拯救频率没有显著影响。这些结果进一步深入了解了 PelA 的独特稳定模式，并有助于我们理解微管靶向剂如何发挥其抗有丝分裂作用。
