Decreased cytotoxic effects of doxorubicin in a human ovarian cancer-cell line expressing wild-type p53 and WAF1/CIP1 genes.
The cytotoxicity of Doxorubicin and cis-dichloro-diammine-platinum (DDP) was evaluated in clones, obtained from a human ovarian cancer cell line transfected with a temperature-sensitive p53 mutant, which express mutant p53 at 37 degrees C and wild-type-like p53 at 32 degrees C. DDP was equally active in cells not expressing p53 (SKN) or cells expressing a mutated form of p53 (SK23a kept at 37 degrees C) or a wild-type-like form of p53 (SK23a cells kept at 32 degrees C). In contrast, Doxorubicin was less cytotoxic in cells expressing wild-type p53 than in cells expressing no p53 or mutated p53. This reduction was not due to a decreased intracellular accumulation or to a faster efflux of Doxorubicin. Topoisomerase II was found to be present in the same amount in all the systems utilized and to be functionally active, thus not accounting for the observed effect of Doxorubicin. A clear induction of WAF1/CIP1 and GADD45 genes in cells expressing wild-type p53 after Doxorubicin treatment was found. DDP, which was equally active in the cells utilized, caused an increase in the transcription only of GADD45 gene but not of WAF1/CIP1 gene. Doxorubicin was also able to induce the transcription of WAF1/CIP1 gene in SKN cells (not expressing p53) or in SK23a cells at 37 degrees C (expressing mutated p53), indicating that the expression of this gene also, in some tumor-cell lines, is not necessarily or uniquely induced by wild-type p53.
Vikhanskaya
F
F
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
D'Incalci
M
M
Broggini
M
M
D015152:Blotting, Northern; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000633:toxicity*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010051:Ovarian Neoplasms; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors; D011506:Proteins; D012334:RNA, Neoplasm / Q000032:analysis / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D002945:Cisplatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004250:DNA Topoisomerases, Type II; D004317:Doxorubicin; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011506:Proteins; D012334:RNA, Neoplasm; D000097642:GADD45 Proteins; C493956:CDKN1A protein, human