Abstract
The aminothiol WR-1065 (the active form of amifostine) protects normal tissues from the toxic effects of certain cancer drugs, while leaving their antitumor effects unchanged. The present data address the mechanism of action of this dichotomous effect. (35)S-Labeled WR-1065 bound directly to the transcription factors nuclear factor-kappaB, activator protein-1, and p53, resulting in enhanced binding of these proteins to target regulatory DNA sequences and subsequent transactivation of a number of downstream genes. Since other small molecular thiols could mimic WR-1065, the redox potential of the sulfhydryl is an important determinant of its activity. In nontransformed cells, WR-1065 protected cells from the cytotoxic effects of paclitaxel in a p53-dependent manner. However, in a transformed human tumor cell line, there was no cytoprotectivity by WR-1065, consistent with the premise that p53-dependent growth arrest is the basis for the protective effect of this compound, and that this pathway is abrogated in human tumors. The combined data support the principle that the cellular effects of the aminothiol WR-1065 are mediated through an impact on transcriptional regulation and are not only a consequence of radical scavenging.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / metabolism*
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Antineoplastic Agents / pharmacology
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Cell Line
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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Cytoprotection / drug effects*
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Electrophoresis, Polyacrylamide Gel
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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HeLa Cells / cytology
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HeLa Cells / drug effects
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HeLa Cells / metabolism
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Humans
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Melanoma / genetics
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Melanoma / metabolism
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Mercaptoethylamines / metabolism*
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Mercaptoethylamines / pharmacology
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Mice
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NF-kappa B / metabolism
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NF-kappa B p50 Subunit
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Nuclear Proteins*
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Paclitaxel / metabolism*
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Paclitaxel / pharmacology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-jun / metabolism
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Proto-Oncogene Proteins c-mdm2
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism*
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Transcriptional Activation / drug effects
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Mercaptoethylamines
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NF-kappa B
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NF-kappa B p50 Subunit
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-jun
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Transcription Factor AP-1
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Transcription Factors
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Tumor Suppressor Protein p53
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N-(2-mercaptoethyl)-1,3-diaminopropane
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Paclitaxel