Sodium valproate effect on chloride metabolism in rats: a new approach to its possible anticancer mechanism

摘要

Aim: Sodium valproate (NaVP) defines a novel class of histone deacetylases (HDAC) inhibitors inducing differentiation of transformed cells by their antitumor properties. Earlier we have showed that single doses of NaVP havse natriuretic, kaliuretic and chlori-duretic effects in rats. The chloriduretic effect of repeated NaVP doses has not previously been investigated. The aim of the present study was to define the peculiarities of 24 h urinary chloride (Cl~) excretion in young adult Wistar rats and to evaluate the related effects of single and repeated NaVP doses in a 10-day treatment. Materials and methods: 24 h urinary Cl~, creatinine and pH levels were measured in 14 control intact Wistar male rats and 13 Wistar male rats after a single per os administration of 300 mg/kg NaVP (VP rats), 5 Wistar male rats after 10 days of the daily intragastric administration of 300 mg/kg NaVP (VP-10 rats) and 5 matched control male rats. 24 h urine was collected keeping a rat alone in a special diuresis cage (Tecniplast, Italy) for 24 h with free access to tap water, without food, in the same temperature and light conditions. 24 h urinary Cl~-, Na~+ levels were analyzed with an EML-105 electrolyte analyzer (Radiometer, Denmark). Urinary pH levels were measured with a pH/mV/ion meter (ION Meter pH 340/ION, Germany). Results: After a single dose and after 10 days of NaVP administration, 24 h total diuresis and 24 h diuresis per 100 g of body weight were significantly higher in VP and VP-10 rats as compared with the respective control. 24 h urine Cl~ excretion was significantly higher in VP and VP-10 rats than in matched controls. The study data shows that repeated NaVP doses enhance C1~- excretion with urine. Authors discuss the possible new mechanism of NaVP anticancer effects related to intracel-lular Or level changes. Conclusion: The understanding of the hypothesized NaVP mechanism may lead to the recognition of Cl~- as animportant mediator in tumor development and as a novel therapeutic target for cancer.