ABSTRACT
The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS, Salirasib) interferes with Ras membrane interactions that are crucial for Ras-dependent transformation. It remains unknown whether modifications of the carboxyl group of FTS can affect its activity. Here we show that specific modifications of the FTS carboxyl group by esterification or amidation yield compounds with improved growth inhibitory activity, compared to FTS, as shown in Panc-1 and U87 cells. The most potent compounds were FTS-methoxymethyl ester and FTS-amide. However, selectivity toward active Ras-GTP, as known for FTS, was apparent with the amide derivatives of FTS. FTS-amide exhibited the overall highest efficacy in inhibition of Ras-GTP and cell growth. This new compound significantly inhibited growth of both Panc-1 tumors and U87 brain tumors. Thus amide derivatives of the FTS carboxyl group provide potent cell-growth inhibitors without loss of selectivity toward the active Ras protein and may serve as new candidates in cancer therapy.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Farnesol/analogs & derivatives , Neoplasms/drug therapy , Neoplasms/pathology , Salicylates/chemical synthesis , Salicylates/therapeutic use , Amides/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cyclic AMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Disease Progression , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Farnesol/chemical synthesis , Farnesol/chemistry , Farnesol/pharmacokinetics , Farnesol/therapeutic use , Humans , MAP Kinase Signaling System/drug effects , Mice , Mice, Nude , Molecular Structure , Neoplasms/enzymology , Oncogene Protein p21(ras)/metabolism , Salicylates/chemistry , Salicylates/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Because hyperglycemia-induced oxidative stress may be a cause of retinopathy, this study examined the hypothesis that administration of exogenous antioxidants, stobadine (ST) and vitamin E (vitE), can restore retinal abnormalities in experimental diabetes. METHODS: Normal and streptozotocin (STZ)-induced male Wistar rats received daily intraoral doses of ST (24.7 mg/kg) and vitE (alpha-dl-tocopherol acetate, 400-500 IU/kg) individually or in combinations for 8 months. The biochemical parameters including aldose reductase enzyme (AR) activity and lipid peroxidation (MDA), and histopathological changes such as retinal capillary basement membrane thickness (RCBMT) and vascular endothelial growth factor (VEGF) expression were evaluated. RESULTS: A 37.99% increase in RCBMT was observed in rats after 8 months diabetes duration. The increase in RCBMT was 12.34% in diabetic rats treated with ST and 23.07% in diabetic rats treated with vitE. In diabetic rats treated with antioxidant combination, just a 4.38% increase was observed in RCBMT. The excess VEGF immunoreactivity and increased MDA and AR activity determined in diabetic retina were significantly attenuated by individual antioxidant treatments. Although both antioxidants decreased blood glucose, HbA1c, fructosamine and triglyceride levels in diabetic rats, poor glycemic control was maintained in all experimental groups during the treatment period. However, the antioxidant combination led to almost complete amelioration in retinal MDA and RCBMT in diabetic rats. CONCLUSIONS: The ability of antioxidant combination to arrest retinal abnormalities and lipid peroxidation even in the presence of poor glycemic control might advocate the key role of direct oxidative damage and the protective action of antioxidants in retinal alterations associated with diabetic retinopathy.
