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Induction of apoptosis by polyamine metabolites in immunocompetent cells and different tumor cell lines

Polyamines (PAs) are involved in regulation of cell growth and cellular survival by interacting with processes like translation, transcription or ion transport. It is described that polyamines can induce apoptosis in mesenchymal cell lines. The aim of our study was to analyze whether the physiological PAs (putrescine, spermidine or spermine) or the PA-derivate deoxyspergualin (DSG), a novel immunosuppressant, induce apoptosis in immunocompetent cells. Furthermore, we wanted to investigate which molecular mechanisms are involved in the execution of the cell death program. By means of flow cytometric analysis we found an induction of apoptosis by spermine (Spm) and DSG in quiescent and activated PBMCs, PHA generated lymphoblasts, and various tumor cell lines (Jurkat, SKW-3, U937). Moreover, DSG and Spm triggered apoptosis in human Fas-deficient cells and in cell lines MV4.11. and RS4.11., which are described to be resistant to apoptosis induction by many conventional chemotherapeutic agents. Apoptosis induction after Spm or DSG treatment was dependent on caspase activity and associated with a decrease in mitochondrial membrane potential and Bcl-2 expression. In order to test whether PAs mediate their proapoptotic effects through metabolites resulting from PA catabolism, we tested different antagonists of PA degrading enzymes or PA metabolites. We show that aminoguanidine (inhibition of PA oxidase), aldehyd-dehydrogenase (degradation of PA-aldehydes) or N-acetyl-cystein (prevention of PA-induced glutathion depletion) prevented PA-mediated apoptosis. Acrolein, and PA-related aldehyde, could induce programmed cell death in our system. We conclude that PA aldehydes and PA-triggered glutathion depletion cause apoptosis in immunocompetent cells and apoptosis-resistant tumor cell lines.

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Lorenz, HM., Schiller, M., Gabler, C. et al. Induction of apoptosis by polyamine metabolites in immunocompetent cells and different tumor cell lines. Arthritis Res Ther 4 (Suppl 1), 53 (2002).

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