Induction of apoptosis by spermine-metabolites in primary human blood cells and various tumor cell lines.
Polyamines are involved in the regulation of cellular growth and survival by interacting with processes like translation, transcription or ion transport. The aim of our study was to analyze whether polyamines induce apoptosis in hematopoetic cells and to investigate the molecular mechanisms involved. We found an induction of apoptosis by spermine in primary human cells and malignant tumor cell lines. Spermine-treatment resulted in an intracellular increase of reactive oxygen species. Apoptosis was mediated by a collapse of mitochondrial membrane potential, a decrease in Bcl-2 expression and a release of apoptosis mediating molecules from mitochondrial intermembrane space (cytochrome C, Smac/DIABLO). Spermine-mediated apoptosis was caspase-dependent. To test whether spermine mediates apoptosis through metabolites we analyzed the effects of several molecules that interfere with its catabolism. Aminoguanidine, an inhibitor of serum amine oxidase, aldehyde-dehydrogenase, which degrades aldehydes to less reactive molecules or N-acetyl-cysteine, a glutathion precursor, significantly inhibited spermine-mediated apoptosis. From these data we conclude that spermine-derived aldehydes and intracellular accumulation of reactive oxygen species result in mitochondria mediated apoptosis.
Schiller
M
M
Department of Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. martin.schiller@med.uni-heidelberg.de
Blank
N
N
Heyder
P
P
Herrmann
M
M
Gaipl
U S
US
Kalden
J R
JR
Lorenz
H M
HM
D000111:Acetylcysteine / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000097:blood; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D008232:Lymphoproliferative Disorders / Q000097:blood; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011700:Putrescine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013095:Spermidine / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics
D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011073:Polyamines; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D013096:Spermine; D003907:Dexamethasone; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D006631:Amine Oxidase (Copper-Containing); D013095:Spermidine; D011700:Putrescine; D000111:Acetylcysteine