Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics

Microtubule dynamics are crucial for mitotic spindle assembly and chromosom e movement. Suppression of dynamics by Taxol appears responsible for the dr ug's potent ability to inhibit mitosis and cell proliferation. Although Tax ol is an important chemotherapeutic agent, development of resistance limits its efficacy. To examine the role of microtubule dynamics in Taxol resista nce, we measured the dynamic instability of individual rhodamine-labeled mi crotubules in Taxol-sensitive and -resistant living human cancer cells. Tax ol-resistant A549-T12 and -T24 cell lines were selected from a human lung c arcinoma cell line, A549. They are, respectively, 9- and 17-fold resistant to Taxol and require low concentrations of Taxol for proliferation. We foun d that microtubule dynamic instability was significantly increased in the T axol-resistant cells. For example, with A549-T12 cells in the absence of ad ded Taxol, microtubule dynamicity increased 57% as compared with A549 cells . The length and rate of shortening excursions increased 75 and 59%, respec tively. These parameters were further increased in A549-T24 cells, with ove rall dynamicity increasing by 167% compared with parental cells. Thus, the decreased Taxol-sensitivity of these cells can be explained by their increa sed microtubule dynamics. When grown without Taxol, A549-T12 cells were blo cked at the metaphase/anaphase transition and displayed abnormal mitotic sp indles with uncongressed chromosomes. In the presence of 2-12 nM Taxol, the cells grew normally, suggesting that mitotic block resulted from excessive microtubule dynamics. These results indicate that microtubule dynamics pla y an important role in Taxol resistance, and that both excessively rapid dy namics and suppressed dynamics impair mitotic spindle function and inhibit proliferation.