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.