Induction of apoptosis and cell cycle arrest by imexon in human pancreatic cancer cell lines.
Imexon is an aziridine-containing small molecule currently in Phase I clinical trials. This agent has been shown to bind to thiols and increase intracellular oxidants, inducing apoptosis in hematologic cancer cells. Pancreatic cancers are known to be sensitive to oxidation, suggesting this disease may be an appropriate target for this agent. The current report examines the activity of imexon in pancreatic cells. Imexon induced concentration-dependent and time-dependent apoptosis in a panel of six human pancreatic carcinoma cell (PCC) lines. The mean IC50 (SD) for growth inhibition by the SRB assay was 200 (101) microM for a 48 h exposure with a range of 64-358 microM. Cell killing was schedule-dependent, favoring exposure times > or =48 h. Imexon-treated MiaPaCa-2 cells underwent non-lethal growth arrest following exposure to concentrations < or =200 microM for 48 h. When concentrations were increased to 300 microM for > or =48 h, the MiaPaCa-2 cells arrested in G2 phase and activated caspases 3, 8, and 9 were detected. After a 72 h exposure to the IC80 concentration of imexon, cells exhibited a loss of mitochondrial membrane potential detected by CMXRos staining. However, there was no loss of reduced cellular thiols unless very high concentrations of > or =400 microM were used. In contrast, reactive oxygen species (ROS) were elevated in a dose-dependent fashion, starting at very low imexon concentrations. Imexon also significantly inhibited MiaPaCa-2 tumor growth in SCID mice at 100 mg/kg/d for 9 d. The tumor growth inhibition (% T/C) was 27% of control, and the tumor growth delay was 21 d, indicating an active agent by NCI standards. The levels of imexon that are cytotoxic in human PCC's are achievable based on the preliminary results of the ongoing Phase I trial. Imexon appears to be active against PCCs in vitro and has an entirely novel mechanism of action involving G2 arrest, accumulation of ROS, and the induction of apoptosis.
Dorr
Robert T
RT
The University of Arizona, College of Medicine, Department of Pharmacology, 1515 N Campbell Avenue, Tucson, Arizona 85724, USA. bdorr@azcc.arizona.edu
Raymond
Mary Ann
MA
Landowski
Terry H
TH
Roman
Nicholas O
NO
Fukushima
Shoji
S
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006588:Hexanones / Q000494:pharmacology*; D006801:Humans; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms / Q000473:pathology*; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured
D006588:Hexanones; D017382:Reactive Oxygen Species; C014919:4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one