Cellular responses to the interaction of the anti-tumor drug taxol with the microtubles

Abstract

Taxol, an anti-cancer compound discovered in the rare Pacific yew tree Taxus Brevifolia, binds to the microtubules and stabilizes them. It effects cells primarily in G2 or M phase, both of which require highly active microtubules. By interfering with the microtubules needed for the mitotic spindle, taxol alters/blocks mitosis, which decreases cell proliferation. High concentrations of taxol induce microtubule polymerization, which creates bundles in the cells. Concentrations too low to enhance polymerization still stabilize microtubule dynamics, a necessary behavior (particularly during mitosis) that involves alternating periods of rapid shrinkage, pause, and rapid growth. Increased polymerization and stabilization stems from taxol’s ability to strengthen lateral interactions between the protofilaments that comprise the microtubule. The binding site for taxol on the tubulin subunit is located adjacent to a structural component termed the M-loop, which is highly involved in lateral interactions. In binding to this area, taxol decreases the flexibility of the M-loop (by changing its shape and by creating density in a previously empty area) so that lateral interactions between adjacent tubulin subunits are strengthened. The cumulative effect is to strengthen lateral connections between protofilaments, and in this way the microtubule becomes more stable. Mitotic spindles that have lost their dynamics or have accumulated into bundles will have difficulty carrying out mitosis. Unfortunately, cells have numerous ways of becoming resistant to taxol treatment.