Metabolic effects of the cytotoxic guanidino-containing drug CHS 828 in human U-937 lymphoma cells.
N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N''-4-pyridylguanidine, CHS 828, is a new anti-neoplastic agent with promising anti-tumor activity both in vitro and in vivo. To characterize the metabolic events over time, the lymphoma cell line U-937 GTB was exposed to CHS 828 and the structurally related mitochondrial inhibitor meta-iodobenzylguanidine (MIBG). There was an instant stimulation of the extracellular acidification rate in response to CHS 828 as measured by the Cytosensor microphysiometer. MIBG shared this metabolic feature. During the first 24 hours of CHS 828 exposure, the consumption of glucose was not significantly affected, but was thereafter shut off. CHS 828 exposure induced a slight increase in lactate production, with 114% of control after 8 hours and 126% for MIBG. Only limited cytotoxicity from CHS 828 exposure was observed after 24 hours and ATP levels remained at 65% of control. Thereafter, the ATP level decreased rapidly and subsequently cell death appeared. Thus, the CHS 828-induced increase in metabolic activity was associated with increased lactate production, probably from increased glycolytic activity. However, CHS 828 also appears to induce a late inhibition of glucolysis leading to energy depletion and subsequent cell death.
Ekelund
Sara
S
Department of Medical Sciences, University Hospital, Uppsala, Sweden. Sara.Ekelund@medsci.uu.se
Larsson
Rolf
R
Nygren
Peter
P
D019797:3-Iodobenzylguanidine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D003486:Cyanides / Q000633:toxicity*; D006146:Guanidines / Q000633:toxicity*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D019797:3-Iodobenzylguanidine