Kamath Kathy, Smiyun Greg, Wilson Leslie, Jordan Mary Ann
Department of Molecular, Cellular, and Developmental Biology, The Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California.
Cytoskeleton (Hoboken). 2014 Jan;71(1):46-60. doi: 10.1002/cm.21153. Epub 2013 Nov 8.
Several antiangiogenic mechanisms have been proposed for the widely-used cancer chemotherapeutic drugs taxotere (docetaxel) and taxol (paclitaxel), but none has been definitively identified. We analyzed their effects at a range of concentrations on migration and mitosis of human umbilical vein endothelial cells (HUVECs) on microtubule and focal adhesion morphology and microtubule dynamic instability during migration. Both taxanes inhibited migration by inhibiting both maintenance of the forward direction of the cell and by slowing migration over the entire contorted path length. At low (but not all) taxane concentrations that inhibit HUVEC migration, the shortening rates and shortening lengths of microtubules at the leading edge were strongly inhibited; peripheral microtubules were reduced in number and fewer targeted focal adhesions; focal adhesions doubled in length and became ring-shaped, elongate, and reduced in number; and an increase in stabilized microtubules occurred centrally. HUVEC migration was 13-19-fold more sensitive to taxanes than was mitosis confirming that taxanes exhibit significant effects in addition to mitotic arrest that may contribute to their overall antitumor effects. No relationship was detected between centrosome position and migration characteristics. The data suggest that taxanes inhibit migration, at least in part, by inhibiting the dynamic instability of microtubules that possibly interact with guanine nucleotide exchange factors and thus with the focal adhesion-associated G-proteins that then lead to disruption of the regulated formation and turnover of focal adhesions. A mechanism is presented by which subcytotoxic concentrations of taxanes might stabilize dynamic instability of a few microtubules and thereby inhibit migration and angiogenesis.
对于广泛使用的癌症化疗药物多西他赛（泰索帝）和紫杉醇，已经提出了几种抗血管生成机制，但尚未明确确定任何一种机制。我们分析了它们在一系列浓度下对人脐静脉内皮细胞（HUVEC）迁移和有丝分裂的影响，以及对微管和粘着斑形态的影响，以及迁移过程中微管动态不稳定性的影响。两种紫杉烷都通过抑制细胞向前方向的维持以及减缓在整个扭曲路径长度上的迁移来抑制迁移。在抑制HUVEC迁移的低（但不是所有）紫杉烷浓度下，前沿微管的缩短速率和缩短长度受到强烈抑制；外周微管数量减少，靶向粘着斑减少；粘着斑长度加倍，变成环形、伸长且数量减少；并且在中心出现稳定微管增加。HUVEC迁移对紫杉烷的敏感性比对有丝分裂高13 - 19倍，这证实了紫杉烷除了有丝分裂停滞外还表现出显著作用，这可能有助于它们的整体抗肿瘤作用。未检测到中心体位置与迁移特征之间的关系。数据表明，紫杉烷至少部分地通过抑制微管的动态不稳定性来抑制迁移，微管的动态不稳定性可能与鸟嘌呤核苷酸交换因子相互作用，从而与粘着斑相关的G蛋白相互作用，进而导致粘着斑的调节形成和周转受到破坏。本文提出了一种机制，通过该机制，亚细胞毒性浓度的紫杉烷可能稳定少数微管的动态不稳定性，从而抑制迁移和血管生成。
