Sensitization of tnf-induced apoptosis with polyamine synthesis inhibitors in different human and murine tumour cell lines.
Rat/mouse T cell hybridoma-derived PC60 R55/R75 cells were used as a model to study tumour necrosis factor (TNF)-induced apoptosis. The role of ornithine decarboxylase (ODC) activity and polyamines in this process was investigated. In PC60 R55/R75 cells, TNF-induced ODC activity was completely suppressed by externally added spermine (Spm). TNF decreased the intracellular levels of the three polyamines Spm, spermidine (Spd) and putrescine (Put). A reduction of the intracellular [Spm] with methylglyoxal bis(quanyl hydrasone) (MGBG), CGP48644a, or bis(ethyl)norspermine (BENSpm), clearly sensitized the cells towards the apoptotic effect of TNF. Conversely, an increase in intracellular [Spm] with DFMO or externally added Spm reduced cellular sensitivity. Similar results were obtained after TNF treatment of the human cell lines Kym 39A6 (rhabdomyosarcoma), HeLaH21 (cervix carcinoma) and U937 (histocytoma) and after alphaFas treatment of HeLaH21, U937 and CEM-CM3 (human T cell line). These results suggest that a decrease of intracellular Spm levels rather then ODC activity per se is involved in the sensitization towards apoptosis induced by TNF or alphaFas.
Penning
L C
LC
Laboratory of Molecular Biology, University of Gent, Flemish Interuniversity Institute of Biotechnology, K.L. Ledeganckstraat 35, B-9000 Gent, Belgium. lopen@sci.kun.nl
Schipper
R G
RG
Vercammen
D
D
Verhofstad
A A
AA
Denecker
T
T
Beyaert
R
R
Vandenabeele
P
P
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007189:Indans / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008935:Mitoguazone / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011700:Putrescine / Q000494:pharmacology; D013095:Spermidine / Q000494:pharmacology; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D000578:Amidines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D007189:Indans; D008562:Membrane Glycoproteins; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D014409:Tumor Necrosis Factor-alpha; C059685:N(1),N(11)-diethylnorspermine; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D013096:Spermine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009955:Ornithine Decarboxylase; D008935:Mitoguazone; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine