Mechanism of cytotoxic effects of taxotere in the K562 human premyelocytic leukemia line

Background Taxotere, a semisynthetic derivative of Taxol, is known to possess cytotoxic effects on various animal cells. Methods To better understand the precise mechanism of this drug action, the human promyelocytic leukemia cell line, K562, and its adriamycin and vincristine resistant sublines, respectively termed K562/ADM and K562/VCR, were used as targets. Results The IC₅₀ for taxotere was almost equal to that for VCR. Due to cross-resistance in the K562/ADM cells, the IC₅₀ value was 42.3 times greater with taxotere, although it was still lower than with ADM and VCR. A much lower cross-resistance was noted with the K562/VCR cells. Assessment of MDR-1 mRNA indicated that expression of the multidrug resistance gene product p-glycoprotein in the cell membrane was partly responsible for the resistance. K562 cells treated with taxotere accumulated in G₂M of the cell cycle, and morphologically, cells in metaphase were found to be remarkably increased. This indicates inhibition of mitosis. Unlike vincristine or vinblastine, taxotere enhanced the assembly of tubulin into microtubules in the absence of guanosine triphosphate (GTP). Moreover, microtubule disassembly was inhibited even in the presence of calcium ions. Conclusion These results suggest that the tubulin equilibrium was shifted towards formation and away from degradation of microtubules that lead to metaphase arrest and eventual cell death. Syntheses of DNA, RNA and protein were not inhibited, and topoisomerases I and II were unaffected. Thus taxotere is an analogue of Taxol, showing a similar mechanism of cytotoxic effect to Taxol on the human K562 leukemia cell line as well as on rodent tumor cell lines.