Ganguly Anutosh, Cabral Fernando, Yang Hailing, Patel Kamala D
Department of Microbiology Immunology and Infectious Diseases, University of Calgary.
Department of Integrative Biology and Pharmacology, University of Texas Medical School.
Oncoscience. 2015 Jun 12;2(6):585-95. doi: 10.18632/oncoscience.169. eCollection 2015.
Peloruside A is a novel antimitotic drug originally isolated from the marine sponge Mycale hentschieli. Previous studies showed that peloruside A stabilizes microtubules by binding to a site on tubulin distinct from paclitaxel, another microtubule stabilizing drug. Peloruside A blocks mitosis, but little is known about the effects on other cellular activities. Here we report that peloruside A is the most potent microtubule inhibitor yet tested for its ability to block endothelial cell migration. Quantitative analysis indicated that it inhibits microtubule dynamics and endothelial cell migration at 1/200(th) of the concentration needed to inhibit cell division (the cytotoxic concentration), indicating that it could potentially have a large margin of safety when used to specifically target angiogenesis. By comparison, paclitaxel, a well-known cancer therapeutic drug, suppresses cell migration at 1/13(th) of its cytotoxic concentration; and vinblastine suppresses cell migration at just slightly below its cytotoxic antimitotic concentration. Thus, different microtubule targeted drugs have varying relative potencies for inhibition of cell migration versus cell division. The results suggest that peloruside A may be an especially useful agent for anti-angiogenesis therapy and point to the likelihood that other antimitotic drugs might be found with an even larger potential margin of safety.
Peloruside A是一种新型抗有丝分裂药物，最初从海洋海绵Mycale hentschieli中分离出来。先前的研究表明，Peloruside A通过与微管蛋白上一个不同于紫杉醇（另一种微管稳定药物）的位点结合来稳定微管。Peloruside A可阻断有丝分裂，但对其对其他细胞活动的影响知之甚少。在此我们报告，Peloruside A是迄今为止测试过的阻断内皮细胞迁移能力最强的微管抑制剂。定量分析表明，它抑制微管动力学和内皮细胞迁移的浓度仅为抑制细胞分裂所需浓度（细胞毒性浓度）的1/200，这表明在用于特异性靶向血管生成时，它可能具有很大的安全边际。相比之下，著名的癌症治疗药物紫杉醇抑制细胞迁移的浓度为其细胞毒性浓度的1/13；长春碱抑制细胞迁移的浓度略低于其细胞毒性抗有丝分裂浓度。因此，不同的微管靶向药物在抑制细胞迁移与细胞分裂方面具有不同的相对效力。结果表明，Peloruside A可能是抗血管生成治疗的一种特别有用的药物，并指出有可能发现其他具有更大潜在安全边际的抗有丝分裂药物。
