CHS 828 kill tumour cells by inhibiting the nuclear factor-kappaB translocation but unlikely through down-regulation of proteasome.
CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine) has shown promising activity in many preclinical systems and in phase I/II clinical trials. The nuclear transcription factor kappa B (NF-kappaB) has been identified as a target for CHS 828. The aim of this study was to confirm the inhibitory effect of CHS 828 on NF-kappaB translocation and to explore its possible effect on the proteasome using 7 cell lines. Translocation of NF-kappaB from the cytoplasm to the nucleus was analysed using a quantitative cytometric system, ArrayScan. The activity of the proteasome was assayed by monitoring the hydrolysis of a fluorogenic substrate. In parallel, the in vitro cytotoxic effect of CHS 828 was analyzed using a 72-h microtiter plate-based cytotoxicity assay (FMCA). CHS 828 inhibited NF-kappaB translocation in the cell lines where it was able to inhibit the tumour cell growth. However, the results did not prove any effect of CHS 828 on proteasome activity when compared to a proteasome inhibitor activity.
Hassan
Saadia B
SB
Division of Clinical Pharmacology, Department of Medical Sciences, University Hospital, 751 85 Uppsala, Sweden. sadia.hassan@medsci.uu.se
Lövborg
Henrik
H
Lindhagen
Elin
E
Karlsson
Mats O
MO
Larsson
Rolf
R
D002470:Cell Survival; D003486:Cyanides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021381:Protein Transport
D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex