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

Keogh, Adrian; Şenkardeş, Sevil; Idle, Jeffrey; Küçükgüzel, Ş Güniz; Beyoglu, Diren (2017). A Novel Anti-Hepatitis C Virus and Antiproliferative Agent Alters Metabolic Networks in HepG2 and Hep3B Cells. Metabolites, 7(2) MDPI 10.3390/metabo7020023

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

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery

UniBE Contributor:

Keogh, Adrian; Idle, Jeffrey and Beyoglu, Diren

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2218-1989

Publisher:

MDPI

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

05 Mar 2018 12:59

Last Modified:

05 Mar 2018 12:59

Publisher DOI:

10.3390/metabo7020023

PubMed ID:

28574427

Uncontrolled Keywords:

antihepatitis C virus antiproliferative diflunisal hydrazone metabolic networks metabolomics

BORIS DOI:

10.7892/boris.109063

URI:

https://boris.unibe.ch/id/eprint/109063

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