Effect of the polyamine oxidase inactivator MDL 72527 on N(1)-(n-octanesulfonyl)spermine toxicity.
N(1)-(n-octanesulfonyl)spermine (N(1)OSSpm) is a potent calmodulin antagonist. In the present work, its toxicity to DHD/K12/TRb and CaCo-2 cells, two colon carcinoma-derived cell lines, was studied with the aim to identify those properties of the cells, which determine their sensitivity to N(1)OSSpm and related structures. Exposure of the cells to MDL 72527, a compound considered to be a selective inactivator of polyamine oxidase (PAO) increased the cytotoxicity of N(1)OSSpm to both cell lines. In contrast, toxicity of trifluoperazine, a calmodulin antagonist with a polyamine-unrelated structure, was not enhanced by MDL 72527. Combined exposure of cells to 2-(difluoromethyl)ornithine (DFMO) (a selective inactivator of ornithine decarboxylase), MDL 72527 and N(1)OSSpm produced a synergistic cytotoxic effect. Neither the intrinsic PAO activity of the cells (as determined with N(1), N(12)-diacetylspermine as substrate), nor their ability to accumulate the drug was a determinant of the cytotoxic effect of N(1)OSSpm. These data suggest that MDL 72527 has a target unrelated to PAO, which is responsible for the enhancement of N(1)OSSpm (and spermine) toxicity. Identification of this target may be of use if the therapeutic potentials of MDL 72527 are to be exploited.
Seiler
N
N
CJF INSERM 95-09, Institut de Recherche Contre les, Cancers de l'Appareil Digestif (IRCAD), 1 place de l'hôpital, B.P. 426, 67091, Strasbourg, Cedex, France. nikolaus.seiler@ircad.u-strasbg.fr
Badolo
L
L
Duranton
B
B
Vincent
F
F
Schneider
Y
Y
Gossé
F
F
Raul
F
F
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004357:Drug Synergism; D000518:Eflornithine / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011073:Polyamines / Q000032:analysis / Q000378:metabolism; D011700:Putrescine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013096:Spermine / Q000031:analogs & derivatives* / Q000633:toxicity; D013449:Sulfonamides / Q000633:toxicity*; D014268:Trifluoperazine / Q000633:toxicity; D014407:Tumor Cells, Cultured; D000097667:Polyamine Oxidase
D006631:Amine Oxidase (Copper-Containing); D002147:Calmodulin; D000518:Eflornithine; D006146:Guanidines; D009955:Ornithine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D011700:Putrescine; D013096:Spermine; D013449:Sulfonamides; D014268:Trifluoperazine; D000097667:Polyamine Oxidase; C105933:N(1)-(n-octanesulfonyl)spermine; C044445:MDL 72527; C004479:pimagedine