Chan Ariane, Singh A Jonathan, Northcote Peter T, Miller John H
Centre for Biodiscovery and Schools of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.
Invest New Drugs. 2015 Jun;33(3):564-74. doi: 10.1007/s10637-015-0232-8. Epub 2015 Mar 31.
Peloruside A is a microtubule-stabilizing agent that is currently under investigation as a potential anticancer agent. Peloruside A binds to a site on β-tubulin that is distinct to that of the taxanes (paclitaxel and docetaxel) and the epothilones. An attractive clinical quality of microtubule-stabilizing agents is their ability to target multiple mechanisms of tumour growth. In addition to inducing tumour cell apoptosis by arresting cells in mitosis, microtubule-stabilizing agents also inhibit angiogenesis, a process needed by tumor cells for growth and metastasis. In this study, the effects of peloruside A on endothelial cell processes important for angiogenesis were assessed in comparison to docetaxel. Both peloruside A and docetaxel potently inhibited the proliferation of human umbilical vein endothelial cells, with IC50 values of 1.4 and 1.7 nM, respectively. Peloruside also potently blocked endothelial cell migration during wound closure and the three-dimensional organization of the endothelial cells into capillary-like tubes. In the wound scratch assay, peloruside A inhibited wound recovery with an IC50 of 6.3 nM after 18 h. Docetaxel was approximately 3-fold more potent than peloruside A. The number of capillary-like tubes that formed after 16 h culture in Matrigel™ was also inhibited in a dose-dependent manner with an IC50 of 4.5 nM. Docetaxel was about 2-fold more potent than peloruside A in preventing tube formation. This inhibition of endothelial cell function occurred at relatively non-cytotoxic concentrations over the 16-18 h incubations for both stabilizing agents, suggesting that anti-angiogenic effects are likely to occur before therapeutically relevant doses begin to inhibit tumor growth or adverse side effects develop.
Peloruside A是一种微管稳定剂，目前正作为一种潜在的抗癌药物进行研究。Peloruside A与β-微管蛋白上的一个位点结合，该位点与紫杉烷类（紫杉醇和多西他赛）及埃坡霉素的结合位点不同。微管稳定剂具有吸引力的临床特性是它们能够靶向肿瘤生长的多种机制。除了通过使细胞停滞在有丝分裂期来诱导肿瘤细胞凋亡外，微管稳定剂还能抑制血管生成，而血管生成是肿瘤细胞生长和转移所必需的过程。在本研究中，与多西他赛相比，评估了Peloruside A对血管生成重要的内皮细胞过程的影响。Peloruside A和多西他赛均能有效抑制人脐静脉内皮细胞的增殖，IC50值分别为1.4 nM和1.7 nM。Peloruside还能有效阻断伤口愈合过程中内皮细胞的迁移以及内皮细胞向毛细血管样管的三维组织化。在伤口划痕试验中，Peloruside A在18小时后以6.3 nM的IC50抑制伤口愈合。多西他赛的效力比Peloruside A高约3倍。在Matrigel™中培养16小时后形成的毛细血管样管的数量也呈剂量依赖性受到抑制，IC50为4.5 nM。在防止管形成方面，多西他赛的效力比Peloruside A高约2倍。在16 - 18小时的孵育过程中，两种稳定剂在相对无细胞毒性的浓度下就发生了对内皮细胞功能的抑制，这表明抗血管生成作用可能在具有治疗相关性的剂量开始抑制肿瘤生长或出现不良副作用之前就已发生。
