dicumarol and Kidney-Neoplasms

In the study, we investigated the effect of dicoumarol, an anti-coagulant agent with the inhibitory activity of NAD(P)H quinone oxidoreductase 1 (NQO1), on TRAIL-induced apoptosis in renal cancer cell. Combined treatment with dicoumarol and TRAIL significantly induced apoptosis in various human renal carcinoma cells including Caki, ACHN, and A498, but not in normal human skin fibroblasts (HSF) and mouse kidney cells (TMCK-1). When we elucidated the relevance of NQO1 in dicoumarol plus TRAIL-mediated apoptosis, both ES936 (a NQO1 inhibitor) and knockdown of NQO1 with siRNA had no effect on TRAIL-mediated apoptosis, suggesting that the stimulating effect of dicoumarol on TRAIL-mediated apoptosis is independent of NQO1 activity. We found that dicoumarol transcriptionally down-regulated Bcl-2 expression via inhibition of NF-κB and CREB activity, whereas it down-regulated Mcl-1 and c-FLIP expression at the post-translational level. Overexpression of Bcl-2, Mcl-1, or c-FLIP overcame the dicoumarol plus TRAIL-induced apoptosis, indicating that down-regualtion of these anti-apoptotic proteins may critically contribute to the sensitizing effect of dicoumarol on TRAIL-mediated apoptosis.

Topics: Animals; Apoptosis; Carcinoma, Renal Cell; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; CREB-Binding Protein; Dicumarol; Down-Regulation; Enzyme Inhibitors; Humans; Indolequinones; Kidney Neoplasms; Mice; Myeloid Cell Leukemia Sequence 1 Protein; NAD(P)H Dehydrogenase (Quinone); NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP; Transcription, Genetic

Quinone metabolites of catechol estrogens have been postulated to mediate estradiol-induced carcinogenesis. In this study, this postulate was examined by investigating the effect of modulators of quinone metabolism on estradiol-induced tumor incidence in male Syrian hamsters. 2(3)-t-Butyl-4-hydroxyanisol (BHA) and dicumarol which are known to stimulate or inhibit respectively, the activity of quinone reductase, lowered tumor incidence by 33 and 42% respectively (3/9 and 5/12 tumor-free animals/total respectively), from 100% (13/13) observed with 17 beta-estradiol (E2) treatment only. Ebselen, a substance with glutathione peroxidase-like activity, and sodium 2-mercaptoethanesulfonate (Mesna), a cytoprotective thiol-containing agent, were only marginally effective in decreasing the estradiol-induced kidney tumor incidence (3/11 and 4/19 tumor-free animals/total respectively). The lowering of tumor incidence by BHA and dicumarol correlated well with a 40-45% decrease in renal peroxidatic activity of cytochrome P450 in hamsters treated with these substances plus estradiol for 1 month. In addition, these compounds also inhibited the oxidation of diethylstilbestrol to its corresponding quinone in vitro. An influence on quinone reductase or other detoxifying enzymes in chronically treated male Syrian hamsters could not be detected. These data support a mediation of estradiol-induced carcinogenesis by quinones formed by metabolic oxidation of catechol estrogens.

Topics: Animals; Antioxidants; Azoles; Butylated Hydroxyanisole; Cricetinae; Dicumarol; Estradiol; Glutathione Peroxidase; Isoindoles; Kidney Neoplasms; Male; Mercaptoethanol; Mesna; Mesocricetus; NADPH-Ferrihemoprotein Reductase; Organoselenium Compounds; Quinone Reductases; Quinones; Selenium