Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent cytotoxicity

The present study was performed to gain insight into the role of p53 on the cytotoxicity of tubulin-binding agents (TBA) on cancer cells. Drug sensiti vity, cell cycle distribution and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma. MCF-7: the MN-1 cell line c ontaining wild-type p53 (wt-p53) and the MDD2 line, containing a dominant n egative variant of the p53 protein (mut-p53). The MDD2 cell line was signif icantly more resistant to the cytotoxic effects of vinblastine and paciltax el than the MN1 cell line. MN1 cells, but not MDD2 cells, displayed wt-p53 protein accumulation as well as p21/WAF1 and cyclin G1 induction after expo sure to TBA. Both cell lines arrested at G(2)/M after drug treatment. Howev er exposure of MN1 cells to TBA resulted in a stronger variation in mitocho ndrial membrane potential, associated with cleavage of PARP. and more apopt osis, as measured by annexin V expression. After exposure to vinblastine, R af 1 kinase activity was reduced in MDD2 cells but not in MN1 cells. Additi on of flavopiridol to vinblastine- and paclitaxel-treated cells reversed th e MDD2-resistant phenotype by inducing G, cell cycle arrest and inhibiting endoreduplication. We conclude that the p53 status of cancer cells influenc es their sensitivity to TBA cytotoxicity. This effect is likely to involve differences in the apoptotic cascade. (C) 2001 Cancer Research Campaign.