Cell death with atypical features induced by the novel antitumoral drug CHS 828, in human U-937 GTB cells.
N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N"-4-pyridylguanidine (CHS 828), with promising antitumoral effects in vitro and in vivo, is currently in clinical Phase I and II studies. Its exact mechanism of action is unclear, but previous studies indicate that CHS 828 induces a controlled, delayed mode of cell death. The characteristics of the cell death process were investigated in vitro in the apoptosis-prone cell line U-937 GTB. Mitochondria showed hyperpolarization at 24 to 32 h and a subsequent late disruption of mitochondria membrane potential (Deltapsi(m)). Between 44 and 72 h of CHS 828 exposure, there was an increasing frequency of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) positive cells indicative of apoptosis, but caspase-3 was only modestly increased and caspases-8 and -9 showed no activation upon CHS 828 exposure. Furthermore, the morphology of exposed cells did not conform to classical apoptosis, and viability and morphology were unaffected by inhibition of caspases. Thus, CHS 828 induces several unexpected features in this system, suggesting a potentially novel mechanism of action.
Martinsson
P
P
Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala University, SE-751 85 Uppsala, Sweden. petra.martinsson@medsci.uu.se
de la Torre
M
M
Binderup
L
L
Nygren
P
P
Larsson
R
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003486:Cyanides / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020298:U937 Cells
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D020169:Caspases