Effect of the polyamine oxidase inactivator MDL 72527 on N1-(n-octanesulfonyl)spermine toxicity

Abstract

N 1-(n-octanesulfonyl)spermine ( N 1OSSpm) 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 1OSSpm 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 1OSSpm 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 1OSSpm 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 1OSSpm. These data suggest that MDL 72527 has a target unrelated to PAO, which is responsible for the enhancement of N 1OSSpm (and spermine) toxicity. Identification of this target may be of use if the therapeutic potentials of MDL 72527 are to be exploited.