Taxol-induced cell cycle arrest and apoptosis: dose-response relationship in lung cancer cells of different wild-type p53 status and under isogenic condition

The effective dose, schedule, molecular basis of the cytotoxicity of taxol and their dependence on the genetic background in tumor cells are still not well understood. Here, we examined how the dose-response relationship for taxol varies in lung cancer cells with different p53 status and under isoge nic conditions. DNA content analyses in A 549 (p53, +/+) and H 1299 (p53, - /-) cells, showed that taxol progressively induced G2/M arrest in both cell lines in a concentration-dependent manner, which was accompanied by a para llel decrease in the G1 population. G2/M arrest, however, occurred at a low er concentration in A 549 cell lines than in H 1299 cells. The S-phase popu lation in A 549 cells was not significantly changed up to 0.025 muM, but dr opped by six-fold at 1.0 muM taxol, in contrast to that in H 1299 cells. A sub-G1 apoptotic population was present at 24 h, even at 0.002 IJ M taxol, when G2/M arrest was not appreciably detected. In both cell lines, the maxi mum apoptosis of about 28% was achieved at 0.025 muM taxol, implicating tha t wild-type p53 does not modulate the level of taxol-induced apoptosis. Whe n we examined the role of the wild-type p53 in isogenic cell lines develope d in a H 1299 background, the maximum level of apoptosis was in the range o f 28-34% at a drug concentration around 0.03 muM, not significantly differe nt from that observed in parental H 1299 cells. We conclude that taxol is e ffective in inducing apoptosis at very low doses (0.020-0.035 muM), and tha t the presence or absence of the wild-type p53 does not make a statisticall y significant difference in the level of apoptotic cell death in these lung cancer cell lines, but the maximum is attained at a lower drug concentrati on in the presence of p53. (C) 2001 Elsevier Science Ireland Ltd. All right s reserved.