PT  - JOURNAL ARTICLE
AU  - Hongxie Shen
AU  - Zhijian J. Chen
AU  - Jack T. Zilfou
AU  - Elizabeth Hopper
AU  - Maureen Murphy
AU  - Kenneth D. Tew
TI  - Binding of the Aminothiol WR-1065 to Transcription Factors Influences Cellular Response to Anticancer Drugs
DP  - 2001 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1067--1073
VI  - 297
IP  - 3
4099  - http://jpet.aspetjournals.org/content/297/3/1067.short
4100  - http://jpet.aspetjournals.org/content/297/3/1067.full
SO  - J Pharmacol Exp Ther2001 Jun 01; 297
AB  - 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. 35S-Labeled WR-1065 bound directly to the transcription factors nuclear factor-κB, 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. The American Society for Pharmacology and Experimental Therapeutics