Early stimulation of acidification rate by novel cytotoxic pyridyl cyanoguanidines in human tumor cells: comparison with m-iodobenzylguanidine.
CHS 828, a newly recognized pyridyl cyanoguanidine, has shown promising antitumor activity both in vitro and in vivo and is presently in early phase I clinical trial in collaboration with EORTC. In this study, the effects of CHS 828 and a series of analogues on extracellular acidification and cytotoxicity were compared with those of m-iodobenzylguanidine (MIBG) in human tumor cells. The extracellular acidification rate was measured using the Cytosensor microphysiometer, and determination of cytotoxicity and proliferation was [(14)C] performed by the fluorometric microculture cytotoxicity assay (FMCA) and measurement of [(14)C]thymidine and leucine uptake. CHS 828 significantly increased the acidification rate during the first 15-24 hr in a concentration-dependent manner. This effect was abolished by removal of glucose from the medium, substituted with 10 mM of pyruvate, indicating stimulated glycolysis as the source of the increased acidification rate. However, CHS 828 induced cytotoxicity at concentrations well below those that affected the rate of acidification; when a series of closely related pyridylguanidine analogues were tested and compared, no apparent relationship between cytotoxicity and acidification could be discerned. Furthermore, comparable increases in the acidification rate were evident in one subline with high-grade resistance to the cytotoxic actions of CHS 828. The results indicate that CHS 828 may share the inhibitory actions of MIBG on mitochondrial respiration with a subsequent increase in glycolysis and acidification rate. However, this mechanism of action appears neither necessary nor sufficient to fully explain the cytotoxic actions of CHS 828 in human tumor cells, actions which remain to be mechanistically clarified.
Division of Clinical Pharmacology, Akademiska Hospital, Uppsala, Sweden. Sara.Ekelund@medsci.uu.se
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Ekelund
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Liminga
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Björkling
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Ottosen
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Schou
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Binderup
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Larsson
D019797:3-Iodobenzylguanidine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003486:Cyanides / Q000737:chemistry / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D005470:Fluorometry; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003486:Cyanides; D004273:DNA, Neoplasm; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D009363:Neoplasm Proteins; D019797:3-Iodobenzylguanidine