Role of wild-type p53 in the enhancement of camptothecin cytotoxicity against human prostate tumor cells.
The role of wild-type human p53 protein in enhancing camptothecin cytotoxicity was examined by infecting human prostate PC3 cells with adenovirus expressing human wild-type p53 gene (Adwtp53). The prostate PC3 cells are null for p53 gene. Infection induced the synthesis of both wtp53, and WAF1 (p21) proteins, resulting in growth arrest of PC3 cells. In the presence of camptothecin, an inhibitor of topoisomerase 1, significant increases in both p53 and p21 proteins were detected in Adwtp53-infected PC3 cells. While Adwtp53 and camptothecin, as single agents, caused apoptosis and cell death, combinations of camptothecin and Adwtp53 were better in inducing apoptosis and cell death in PC3 cells. In contrast, cisplatin neither stabilized p53 and p21 proteins nor enhanced DNA fragmentation when combined with Adwtp53 in PC3 cells, indicating specificity for camptothecin. These observations suggest that introduction of wild-type p53 gene with topoisomerase I inhibitors may offer a clinical advantage for the treatment of prostate tumors containing mut53 or null for p53 gene.
Arah
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Department of Developmental Therapeutics, National Cancer Institute, NIH, Bethesda, Maryland 20982, USA.
Song
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Seth
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Cowan
K H
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Sinha
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BK
D000256:Adenoviridae; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D005822:Genetic Vectors; D006801:Humans; D007700:Kinetics; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin; D002166:Camptothecin