Taxol suppresses dynamics of individual microtubules in living human tumorcells

Microtubules are intrinsically dynamic polymers; and their dynamics play a crucial role in mitotic spindle assembly, the mitotic checkpoint, and chrom osome movement. We hypothesized that, in living cells, suppression of micro tubule dynamics is responsible for the ability of taxol to inhibit mitotic progression and cell proliferation. Using quantitative fluorescence video m icroscopy, we examined the effects of taxol (30-100 nM) on the dynamics of individual microtubules in two living human tumor cell Lines: Caov-3 ovaria n adenocarcinoma cells and A-498 kidney carcinoma cells. Taxol accumulated more in Caov-3 cells than in A-498 cells. At equivalent intracellular taxol concentrations, dynamic instability was inhibited similarly in the two cel l lines. Microtubule shortening rates were inhibited in Caov-3 cells and in A-498 cells by 32 and 26%, growing rates were inhibited by 24 and 18%, and dynamicity was inhibited by 31 and 63%, respectively. All mitotic spindles were abnormal, and many interphase cells became multinucleate (Caov-3, 30% ; A-498, 58%). Taxol blocked cell cycle progress at the metaphase/anaphase transition and inhibited cell proliferation. The results indicate that supp ression of microtubule dynamics by taxol deleteriously affects the ability of cancer cells to properly assemble a mitotic spindle, pass the metaphase/ anaphase checkpoint, and produce progeny.