Antiangiogen concentrations of vinflunine increase the interphase microtubule dynamics and decrease the motility of endothelial cells
Antiangiogen concentrations of vinflunine increase the interphase microtubule dynamics and decrease the motility of endothelial cells
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DOI：
10.1158/0008-5472.can-05-3885
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发表时间：
2006-03-15
期刊：
影响因子：
11.2
通讯作者：
Braguer, D
中科院分区：
文献类型：
--
作者：
Pourroy, B;Honoré, S;Braguer, D
血管生成是肿瘤进展和转移的关键事件。这一复杂的过程构成了癌症治疗的有效靶标，但可被极低浓度的微管靶向药物 (MTD) 抑制。然而，MTD 抗血管生成活性的内在机制仍不清楚。最近，我们发现低抗血管生成和非细胞毒性浓度的紫杉醇可诱导内皮细胞微管动力学意外增加。在这项研究中，我们发现，最新的长春花生物碱长春氟宁在低浓度（0.1 和 2 nmol/L 时为 29% 和 54%）孵育 4 小时后，增加了人内皮细胞的微管动态不稳定性。正如之前在紫杉醇中观察到的那样，生长率和缩短率增加，暂停时间百分比和平均暂停持续时间减少。与紫杉醇相反，长春氟宁不会显着干扰过渡频率。此外，低浓度的长春氟宁不影响有丝分裂指数和后期/中期比率。有趣的是，这些低浓度的长春氟宁增加了微管动力学，通过抑制形态发生和随机运动表现出抗血管生成作用。 Matrigel 上的毛细管形成减少达 44%。细胞速度和随机运动系数降低（0.1 和 2 nmol/L 时分别为 13% 和 19% 和 13% 和 33%），持续时间统计上增加。总而言之，我们的结果证实微管动力学的增加与 MTD 抗血管生成活性有关，并强调了间期微管动力学在血管生成中的关键作用。
Angiogenesis is a key event in tumor progression and metastasis. This complex process, which constitutes a potent target for cancer therapy, is inhibited by very low concentrations of microtubule-targeting drugs (MTD). However, the intimate mechanisms of the antiangiogenic activity of MTDs remain unclear. Recently, we have shown that low antiangiogenic and noncytotoxic concentrations of paclitaxel induced an unexpected increase in microtubule dynamics in endothelial cells. In this study, we showed that vinflunine, the newest Vinca alkaloid, increased microtubule dynamic instability in human endothelial cells after 4-hour incubation at low concentrations (29% and 54% at 0.1 and 2 nmol/L). The growth and shortening rates were increased, and the percentage of time spent in pause and the mean duration of pauses were decreased, as previously observed with paclitaxel. As opposed to paclitaxel, the transition frequencies were not significantly disturbed by vinflunine. Moreover, low concentrations of vinflunine did not affect mitotic index and anaphase/metaphase ratio. Interestingly, these low vinflunine concentrations that increased microtubule dynamics exhibited an antiangiogenic effect through the inhibition of both morphogenesis and random motility. Capillary tube formation on Matrigel was decreased up to 44%. The cell speed and the random motility coefficient were decreased (13% and 19% and 13% and 33% at 0.1 and 2 nmol/L, respectively) and the persistent time was statistically increased. Altogether, our results confirm that the increase in microtubule dynamics is involved in MTD antiangiogenic activity and highlight the crucial role of interphase microtubule dynamics in angiogenesis.