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-pyridlguanidine (CHS 828), w ith promising antitumoral effects in vitro and in vivo, is currently in cli nical 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 investiga ted in vitro in the apoptosis-prone cell line U-937 GTB. Mitochondria showe d hyperpolarization at 24 to 32 h and a subsequent late disruption of mitoc hondria membrane potential (Delta psi (m)). Between 44 and 72 h of CHS 828 exposure, there was an increasing frequency of terminal deoxynucleotidyl tr ansferase (TdT)-mediated dUTP nick end labeling (TUNEL) positive cells indi cative of apoptosis, but caspase-3 was only modestly increased and caspases -8 and -9 showed no activation upon CHS 828 exposure. Furthermore, the morp hology of exposed cells did not conform to classical apoptosis, and viabili ty and morphology mere unaffected by inhibition of caspases. Thus: CHS 828 induces several unexpected features in this system, suggesting a potentiall y novel mechanism of action. (C) 2001 Elsevier Science B.V. All rights rese rved.