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Effects of Inhibitors of Polyamine Biosynthesis on the Growth and Melanogenesis of Murine Melanoma Cells¹

Department of Biochemistry, University of Helsinki, SF-00170 Helsinki, Finland

Both 2-difluoromethylornithine (DFMO), an irreversible inhibitor of omithine decarboxylase (EC 4.1.1.17), and methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase (EC 4.1.1.50), strikingly stimulated melanotic expression of murine Cloudman S91 melanoma cells. The stimulation of tyrosinase (EC 1.10.3.1) activity and melanin formation by DFMO was closely associated with intracellular depletion of putrescine and spermidine developed in response to the drug. However, little or no evidence was obtained indicating that enhanced melanogenesis in response to MGBG was mediated through an inhibition of polyamine biosynthesis. Indirect inhibitors of omithine decarboxylase, such as 1,3-diaminopropane and 1,3-diaminopropan-2-ol, but not putrescine, likewise inhibited the growth of the melanoma cells and stimulated their melanin production. The stimulation of melanogenesis by polyamine antimetabolites was not mediated by cyclic adenosine 3':5'-monophosphate, in contrast to the effect elicited by -melanotropin. It is also unlikely that MGBG or the diamines acted as lysosomotropic agents capable of stimulating tyrosinase activity in situ, since the enzyme activity was stimulated by the drugs irrespective of whether assayed in cultured cells or using cell-free homogenates. None of the agents stimulated tyrosinase activity in vitro. The effect of DFMO and MGBG on melanoma cell proliferation was reversible, but the restoration of normal growth and melanin formation, especially in cells exposed to DFMO, was remarkably slow. The present results represent a further experimental model, in which the inhibition of polyamine accumulation is accompanied by signs of terminal differentiation.

¹ This investigation was financially supported by a grant from the University of Helsinki, by the Research Council for Natural Sciences (Academy of Finland), and by the Sigrid Juselius Foundation.

² To whom requests for reprints should be addressed, at Department of Biochemistry, University of Helsinki, Unioninkatu 35, SF-00170 Helsinki 17, Finland.

Received 4/30/84. Revised 8/24/84. Revised 9/11/84. Accepted 12/ 7/84.

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