Mechanisms of inhibition of endothelial cell migration by taxanes

Abstract

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.

Effect of Ephedra foeminea active compounds on cell viability and actin structures in cancer cell lines

“…Identified compounds (Kamath et al, 2014). However, despite the effect on actin, and actin's involment in cell migration (Yamaguchi and Condeelis, 2007), there was no significant effect on cell migration by any of the E. foeminea extracts or fruit juice.…”

Mechanism of action of ixabepilone and its interactions with the βIII-tubulin isotype

“…Drug binding and suppression of microtubule dynamic instability also impair many interphase functions of microtubules including migration, intracellular trafficking, and cell secretion [11][12][13]. Several studies have briefly reported some of ixabepilone's properties in cells [14,15] and in vitro [7][8][9], but there has been no full elucidation of its mechanism of action including its response to altered tubulin isotype expression.…”

Erucin, the Major Isothiocyanate in Arugula (Eruca sativa), Inhibits Proliferation of MCF7 Tumor Cells by Suppressing Microtubule Dynamics

“…Microtubules are dynamic tube shaped protein polymers (25 nm in diameter) that play important roles in determining cell shape, polarity, cellular migration, signaling, and mitosis [31]–[33]. Microtubules can undergo two unusual non-equilibrium dynamic behaviors, dynamic instability, the switching between growth and shortening at microtubule plus ends [34], [35], and treadmilling, the net plus end assembly and minus end disassembly (reviewed in [31]).…”

“…Microtubule dynamics are rapid during mitosis and are critical for the accurate and time-sensitive attachment of chromosomes to the mitotic spindle, movement of the chromosomes to form the metaphase plate, and production of proper tension at the kinetochores, all of which are essential for the passage through the metaphase/anaphase spindle checkpoint [36], [37]. Microtubule dynamics are also important in cell polarity, cell migration and metastasis [33].…”