The cytoprotective aminothiol WR1065 activates p21waf-1 and down regulates cell cycle progression through a p53-dependent pathway.
The phosphoaminothiol WR1065, the active metabolite of the pro-drug amifostine (WR2721), protects cultured cells and tissues against cytotoxic exposure to radiation or chemotherapeutic agents. We show here that WR1065 and the pro-drug WR2721 activate the p53 tumor suppressor protein and induce the expression of the cyclin-dependent kinase inhibitor p21waf-1 in the breast cancer cell line MCF-7, and in the mouse fibroblast cell line balb/c 3T3. Using two MCF-7 derived cell lines, MN1 and MDD2, we show that induction of p21waf-1 is detectable in MN1 (expressing a functional p53) but not in MDD2 (p53 disabled). These effects are observed at concentrations of WR1065 (0.5 to 1 mM) identical to those required to protect against cytotoxicity by hydrogen peroxide. Induction of p53 is not prevented by addition of aminoguanidine, an inhibitor of Cu-dependent amine-oxidases which blocks the extra-cellular degradation of WR1065 into toxic metabolites. Moreover, spermidine, a natural polyamine structurally related to amifostine, does not activate p53. Induction of p53 by WR1065 results in a delay in the G1/S transition in MCF-7 and MN-1 cells, but not in the p53 disabled cells MDD2. These data indicate that WR1065, a polyamine analog with thiol anti-oxidant properties, activates a cell cycle check-point involving p53.
North
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S
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon, France.
El-Ghissassi
F
F
Pluquet
O
O
Verhaegh
G
G
Hainaut
P
P
D016475:3T3 Cells / Q000187:drug effects / Q000528:radiation effects; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D005720:Gamma Rays; D006801:Humans; D008624:Mercaptoethylamines / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013095:Spermidine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004247:DNA; D013095:Spermidine