[Roles of p53 in chemotherapy of glioblastoma].
LN382, a glioblastoma cell line, has a temperature-sensitive mutant p53. At the permissive temperature (34 degrees C), arrest of cell growth at the G1 phase occurred with recovered p53's transcriptional activity, and restored p53 protein turnover. In order to understand the influence of the functional status of p53 on the sensitivity to anticancer agents in glioblastoma cells, I analyzed responses of LN382 cells and U251MG cells with a mutant p53 as a control at 34 degrees C and 37 degrees C to etoposide, paclitaxel, and cisplatin, and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). Restoration of p53 protein function in LN382 cells at 34 degrees C reduced the cytotoxicity of etoposide and paclitaxel, whereas that of cisplatin and ACNU was not affected. In contrast, the temperature shift to 34 degrees C did not alter the cytotoxicity of etoposide, paclitaxel, cisplatin, or ACNU in U251MG cells. Transduction of wild-type p53 in LN382 cells also reduced the sensitivity of the cells to etoposide. Cell cycle analysis using flow cytometry revealed that this decrease in sensitivity was associated with an impaired transition to the G2M phase subsequent to the addition of etoposide or paclitaxel. These results indicate that cell cycle arrest induced by wild-type p53 function may abrogate the cytotoxic effects of etoposide and paclitaxel, which are dependent on G2M-associated apoptosis.
Ikeda
J
J
Department of Neurological Disorder, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy*; D015376:Nimustine / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D013696:Temperature; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D015376:Nimustine; D005047:Etoposide; D017239:Paclitaxel; D002945:Cisplatin