A Novel Anti-Hepatitis C Virus and Antiproliferative Agent Alters Metabolic Networks in HepG2 and Hep3B Cells

摘要: A series of novel diflunisal hydrazide-hydrazones has been reported together with their anti-hepatitis C virus and antiproliferative activities in a number human hepatoma cell lines. However, the mechanisms underlying efficacy these agents remain unclear. It was chosen to investigate lead hydrazide-hydrazone, 2',4'-difluoro-4-hydroxy-N'- [(pyridin-2-yl)methylidene]biphenyl-3-carbohydrazide (compound 3b), two cultured lines-HepG2 Hep3B-using metabolomic protocol aimed at uncovering any effects this agent on cellular metabolism. One sub-therapeutic concentration (2.5 μM) one close IC50 for antimitotic effect (10 μM), after 72 h culture, were both compound 3b its inactive parent diflusinal as control. GCMS-based investigation performed lysates culture 24 h. The intracellular levels total 42 metabolites found be statistically significantly altered either HepG2 or Hep3B cells, only eight which affected concluded that following pathways-purine pyrimidine catabolism, glutathione cycle, energy metabolism through glycolysis pentose phosphate pathway. Although findings occurred significant cytotoxicity cells 10 μM not occur until culture. These observations show metabolomics can provide mechanistic insights into drug candidates prior appearance pharmacological effect.