Regulation of polyamine biosynthesis in rat hepatoma (HTC) cells by a bisbenzyl polyamine analogue

Abstract

A bisbenzyl polyamine analogue, MDL 27695, rapidly repressed ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (AdoMet DC) activity and depleted polyamines in rat hepatoma (HTC) cells. The suppression of ODC and AdoMet DC activity was temporally related to metabolism of MDL 27695 by intracellular polyamine oxidase to a free-amine analogue, MDL 26752, which, when added directly to HTC cells, suppressed ODC activity and polyamine biosynthesis more rapidly and to a greater extent than did the bisbenzyl analogue. The ODC suppression caused by MDL 27695 was completely blocked by the addition of a polyamine oxidase inhibitor to the HTC-cell cultures along with MDL 27695. These data suggested that MDL 27695 acted as a prodrug, with metabolism to an active analogue being necessary for ODC repression to occur. MDL 27695 and MDL 26752 completely abolished division of HTC cells when added to cultures at 1 microM. This established them as being among the most potent antiproliferative polyamine analogues yet described. MDL 27695 has also been shown to possess significant antimalarial effects both in vitro and in vivo, and it is possible that the marked suppression of polyamine biosynthesis described herein may contribute to its anti-malarial effects as well as its antiproliferative effects in mammalian cells.