title: Disruption of p53 function in immortalized human cells does not affect survival or apoptosis after taxol or vincristine treatment.
abstract: In the present study, we report our findings on the impact of p53 disruption on the sensitivity of human cell lines to the antimitotic agents Taxol and vincristine. Comparisons of cell survival and apoptosis were made with y-irradiation and, in some cases, several other DNA-damaging chemotherapeutic agents. Studies in eight Burkitt's lymphoma and lymphoblastoid cell lines (four wild-type p53 and four mutant p53 cell lines) revealed that the DNA-damaging agents assayed tended to exhibit less growth inhibition in the mutant p53 cell lines compared to the wild-type p53 cell lines. In contrast, no significant correlation was apparent between p53 gene status and the growth-inhibitory potency of Taxol or vincristine in these eight cell lines. We also found that contrary to gamma-irradiation, Taxol and vincristine could induce apoptosis in lymphoma cell lines harboring p53 mutations. These observations were explored further in lymphoblastoid VDSO cells (wild-type p53) from a normal individual and stably transfected VDSO derivatives lacking p53 function due to expression of the human papillomavirus type-16 E6 gene. We found that p53 disruption in VDSO/E6 cells blocked y-ray-induced apoptosis and afforded a survival advantage to VDSO/E6 cells compared to control-transfected cells. In contrast, p53 disruption did not affect Taxol- or vincristine-induced apoptosis or survival in VDSO cells. The effect of p53 disruption on Taxol sensitivity was explored further in the breast carcinoma MCF-7 and colon carcinoma HCT-116 cell lines that had been stably transfected with either the human papillomavirus type-16 E6 gene or a dominant-negative mutant p53 gene. Again, in these cell model systems, we found that p53 disruption did not affect the growth-inhibitory potency of Taxol. Taken together, our results suggest that p53 status is not a dominant factor in the mechanism by which antimitotic agents induce apoptosis and reduce survival in immortalized human cell lines.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Fan
authors.forename: B
authors.initials: B
authors.lastname: Cherney
authors.forename: W
authors.initials: W
authors.lastname: Reinhold
authors.forename: K
authors.initials: K
authors.lastname: Rucker
authors.forename: P M
authors.initials: PM
authors.lastname: O'Connor
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016158:Genes, p53 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008223:Lymphoma / Q000378:metabolism; D009154:Mutation; D017239:Paclitaxel / Q000494:pharmacology*; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D017239:Paclitaxel