Inhibition of polyamine oxidase enhances the cytotoxicity of polyamine oxidase substrates. A model study with N1-(n-octanesulfonyl)spermine and human colon cancer cells.
N(1)-(n-octanesulfonyl)spermine (N(1) OSSpm) is a substrate of polyamine oxidase. It shares several properties with spermine, such as antagonism of NMDA-type glutamate receptors, calmodulin antagonism, and cytotoxicity, but it is more potent by orders of magnitude in these regards than spermine. The human colon carcinoma-derived cell line CaCo-2 was used as a model to study the toxicity of N(1) OSSpm as a function of polyamine oxidase (PAO) activity and differentiation. If the formation of hydrogen peroxide and aminoaldehyde by the PAO-catalysed reactions was prevented by selective inactivation of the enzyme with MDL 72527, cytotoxicity of N(1)OSSpm was not diminished, but on the contrary, enhanced. Exponentially growing CaCo-2 cells were considerably more sensitive to N(1)OSSpm than differentiating cells. The results suggest that cytotoxic substrates of PAO exhibit enhanced cytotoxicity in cells, if PAO activity is inhibited. Since tumour cells are known to have lower polyamine oxidase activities than their normal counterparts, it will be interesting to explore whether cytotoxic substrates of polyamine oxidase, for which N(1)OSSpm is an example, are suited to preferentially kill tumour cells.
Seiler
N
N
ULP/CJF INSERM 95-09, France. Nikolaus.Seiler@ircad.U-Strasbg.fr
Duranton
B
B
Vincent
F
F
Gossé
F
F
Renault
J
J
Raul
F
F
D017209:Apoptosis; D018938:Caco-2 Cells; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology*; D003603:Cytotoxins / Q000378:metabolism* / Q000633:toxicity; D053938:DNA Fragmentation; D006801:Humans; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000097667:Polyamine Oxidase
D020169:Caspases; D003603:Cytotoxins; D009955:Ornithine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D013096:Spermine; D013449:Sulfonamides; D000097667:Polyamine Oxidase; C105933:N(1)-(n-octanesulfonyl)spermine