Modulation of pyridyl cyanoguanidine (CHS 828) induced cytotoxicity by 3-aminobenzamide in U-937 GTB cells.
The role of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and the ADP-ribosylation inhibitor 3-aminobenzamide (3-ABA) in the cytotoxicity induced by the novel antitumoral cyanoguanidine CHS 828 was investigated in the human lymphoma cell line U-937 GTB. Exposing cells to CHS 828 and 3-ABA in combination resulted in a 100-fold higher IC(50) compared to exposure to CHS 828 alone. CHS 828 did not activate PARP, measured as PARP-activity and formation of poly(ADP-ribose). The ATP-levels and levels of extracellular acidification rate of cells exposed to CHS 828 in combination with 3-ABA were maintained for a longer period than for cells exposed to CHS 828 alone. To characterize the mode of cell death, caspase-3 activity and gross morphology were assessed. 3-ABA increased and delayed the caspase-3 activity in cells exposed to CHS 828. Cells exposed to high concentrations of CHS 828 showed a necrotic morphology, while high concentrations of CHS 828 in combination with 3-ABA switched the mode of cell death, generating an apoptotic morphology. The results indicate that the cytotoxicity and morphology induced by CHS 828 is not due to PARP activation but can be modulated by the ADP-ribosylation inhibitor 3-ABA.
Lövborg
Henrik
H
Division of Clinical Pharmacology, University Hospital, Uppsala University, S-751 85 Uppsala, Sweden. henrik.lovborg@medsci.uu.se
Martinsson
Petra
P
Gullbo
Joachim
J
Ekelund
Sara
S
Nygren
Peter
P
Larsson
Rolf
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003486:Cyanides / Q000494:pharmacology*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000378:metabolism; D020298:U937 Cells / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D003486:Cyanides; D004791:Enzyme Inhibitors; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D011506:Proteins; D011064:Poly Adenosine Diphosphate Ribose; C025160:3-aminobenzamide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases