dicumarol and Body-Weight

A novel series of 4-substituted-3,4-dihydrobenzo[h]quinoline-2,5,6(1H)-triones as NQO1-directed antitumor agents were designed, synthesized, biologically evaluated. Compounds 3n, 3o and 3j proved to be good NQO1 substrates that showed increased metabolic rates relative to that of β-lapachone. In addition, 3n, 3o and 3j potently inhibited the growth of NQO1-rich breast cancer MCF-7 cell, liver hepatocellular HepG2 cell, and lung cancer A549 cell. In cellular mechanistic studies, the representative compound 3o triggered ROS generation depending on the NQO1 dose, and induce HepG2 cell apoptosis by the generated oxidative stress. In HepG2 xenografts mouse model, at the dose of 20 mg/kg, 3o remarkably suppressed the tumor growth without affecting the animal weights.

Topics: Animals; Antineoplastic Agents; Apoptosis; Body Weight; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Heterografts; Humans; Mice; Models, Molecular; Molecular Targeted Therapy; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms, Experimental; Oxidative Stress; Quinolines; Reactive Oxygen Species; Structure-Activity Relationship

Inducibility of oxidative stress in rat liver in vivo by menadione-associated redox cycling activation under redox enzyme modulating conditions was examined by monitoring hepatocyte injury and 8-hydroxydeoxyguanosine (8-OHdG) levels of liver DNA. In addition, the treatment-associated liver tumor initiating activity was assessed in terms of development of gamma-glutamyl-transpeptidase (GGT)- and glutathione S-transferase placental form (GST-P)-positive foci and hyperplastic nodules. With or without following menadione treatment (50 mg/kg, i.g.), redox enzyme modulations of increased cytochrome P450 reductase activity induced by phenobarbital (PB)-Na (100 mg/kg, i.p. for 5 days), inhibition of DT-diaphorase by dicumarol (25 mg/kg, i.p.) and depletion of glutathione by phorone (200 mg/kg, i.p.), with or without further supplement of iron EDTA-Na-Fe(III) (70 mg/kg, i.p.), caused both substantial hepatocyte necrosis and 8-OHdG production in Fischer 344 male rats. Subsequent feeding with a 0.05% PB diet for 64 weeks resulted in slightly increased development of GGT-positive foci but not GST-P positive lesions or hyperplastic nodules, suggesting a lack of tumor-initiating activity of the oxidative DNA damage associated with redox enzyme modulations with or without menadione.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Body Weight; Cytochrome Reductases; Deoxyguanosine; Dicumarol; DNA; DNA Damage; gamma-Glutamyltransferase; Glutathione; Iron; Ketones; Liver; Liver Neoplasms, Experimental; Male; NAD(P)H Dehydrogenase (Quinone); Necrosis; Neoplasms, Experimental; Organ Size; Oxidation-Reduction; Phenobarbital; Quinone Reductases; Rats; Rats, Inbred F344; Time Factors; Vitamin K

Topics: Animals; Blood Coagulation; Body Weight; Castration; Chickens; Cholesterol; Comb and Wattles; Dicumarol; Male; Mortality; Physiology, Comparative; Prothrombin Time; Rats; Testosterone

Topics: Administration, Oral; Animals; Body Weight; Depression, Chemical; Dicumarol; Hemorrhage; Male; Mice; Vitamin K

Topics: Acyltransferases; Animals; Benzene Derivatives; Body Weight; Chemical and Drug Induced Liver Injury; Chlorine; Chromatography, Gas; Chromatography, Thin Layer; Dicumarol; Enzyme Induction; Female; Hexobarbital; Hydrocarbons, Halogenated; Levulinic Acids; Liver; Organ Size; Phenols; Porphyrias; Porphyrins; Rats; Sleep; Succinates