Abstract
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.
Highlights
Microtubules, key components of the cytoskeleton, are dynamic polymers of tubulin that form a well-organized network of polarized tube filaments
To determine whether this observation may be extended to other Microtubule-targeting drugs (MTD), we investigated the effect of the newest Vinca alkaloid, vinflunine, on microtubule dynamics in living human dermal microvascular endothelial cells (HMEC-1) and their involvement on cellular processes that are required for angiogenesis
HMEC-1 cells were transiently transfected by electroporation with green fluorescent protein-a tubulin and the dynamic properties of their microtubules were analyzed by time-lapse fluorescence microscopy following a 4-hour vinflunine incubation
Summary
Microtubules, key components of the cytoskeleton, are dynamic polymers of tubulin that form a well-organized network of polarized tube filaments. Microtubule dynamics are highly regulated both spatially and temporally and this regulation is crucial for mitosis, cell migration, cell signaling, and trafficking [1]. Microtubule-targeting drugs (MTD), e.g., Vinca alkaloids and taxanes, are major cancer chemotherapeutic drugs largely used in many human tumoral diseases. Similar to other MTDs, vinflunine suppresses microtubule dynamics both in vitro [4, 5] and in living cancer cells [4, 6]. It classically slows down the metaphase-to-anaphase transition, blocks cancer cells in mitosis, and induces apoptosis [6,7,8,9]
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