ABSTRACT
BACKGROUND: We previously reported on the design and synthesis of novel azatyrosinamide derivatives selective for ras-transformed NIH3T3 cells and with improved toxicity over azatyrosine. This study was aimed at investigating the mechanism of action and the antitumour activity of these compounds in ras-transformed cells. MATERIALS AND METHODS: Nine azatyrosinamides were previously screened for anticancer activity in both wild-type and ras-transformed NIH3T3 cells; the most active compounds were further tested in vitro and in vivo. RESULTS: HPW98-1 and HPW98-2 induced formation of apoptotic bodies in ras-transformed NIH3T3 cells in vitro and inhibited anchorage-independent growth. Excess tyrosine reduced the cytotoxic effect of azatyrosine, but not of HPW98-1 and HPW98-2. HPW98-1 reduced vascular endothelial growth factor-mediated angiogenesis in a Matrigel plug assay and attenuated growth of a ras-transformed NIH3T3 xenograft and a human SW620 xenograft. CONCLUSION: Our results support the continued study of HPW98-1 for its potential use in the treatment of RAS-related cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms, Experimental/drug therapy , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacology , Animals , Genes, ras/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mice, SCID , NIH 3T3 Cells , Xenograft Model Antitumor AssaysABSTRACT
In this study we selected a rat model of Parkinson's disease (PD) by using intrastriatal infusion of the 1-methyl-4-phenyl-pyridinium ion (MPP+) to investigate the neuroprotective action of melatonin and its inhibitory activity on MPP+-impaired glutathione (GSH) system in the nigrostriatal system. Results show that MPP+ caused not only a severe neuronal injury in the striatum and in the ipsilateral substantia nigra (SN), but it also induced a significant decrease in GSH levels and an increase in the GSSG/GSH ratio 3 days after intrastriatal MPP+ infusion. Intraperitoneal co-administration of melatonin (10 mg/kg, five times) significantly attenuated MPP+-induced nigrostriatal neurotoxicity and GSH impairment. Depletion of cytosolic GSH by L-buthionine sulfoximine (BSO) did not cause neuronal damage by itself. It, however, when co-administrated with MPP+, potentiated the GSH reduction in the striatum, without aggravating nigrostriatal neurodegeneration induced by MPP+. Moreover, the MPP+-caused neuronal damage was positively correlated with a rising ratio of GSSG/GSH, but not with a drop of GSH. These results suggest that the MPP+-triggered oxidative stress may play a more important role than the loss of the antioxidant GSH in determining neuronal injury. Interestingly, the neuronal damage and oxidative stress elicited by co-treatment of BSO with MPP+ were effectively reduced by melatonin. Our results hence provide direct evidence showing that melatonin attenuates MPP+-induced nigrostriatal dopaminergic injury by its ability to impede the increase of GSSG/GSH ratio; therefore melatonin may have therapeutic implications in PD.
