Methylglyoxal bis(guanylhydrazone) stimulates the cellular transport system of the polyamines
FEBS Letters(1982)
Abstract
1. INTRODUCTION Methylglyoxal bis(guanylhydrazone) (MGBG), an inhibitor of polyamine biosynthesis [l], is ap- parently transported into the interior of the cell (by virtue of its structural resemblance to spermidine) via an inducible transport system used by the natu- ral polyamines spermidine and spermine [2-51. Cellular uptake of polyamines, and hence also of MGBG, is strikingly enhanced under conditions of intracellular putrescine and spermidine depletion, as a result of the use of inhibitors of ornithine de- carboxylase (EC 4.1.1.17) [5]. Even though the lat- ter phenomenon is obviously aimed at normalizing the reduced intracellular polyamine pools, it also offers a means of enhancing the cellular accumula- tion of the antiproliferatively acting MGBG when profound growth inhibition is desired [6]. Although intracellular polyamine depletion trig- gers a variety of compensatory mechanisms, such as induction and stabilization of ornithine and ad- enosylmethionine (EC 4.1.150) decarboxylases (for ref. see [7]), the greatly enhanced transport of extracellular polyamines can apparently alone abolish the antiproliferative effects of polyamine antimetabolites (inhibitors of polyamine bio- synthesis) in the presence of only trace amounts of exogenous polyamines. This fact may be prac- tically important since polyamine antimetabolites [MGBG and 2-difluoromethylornithine (DFMO)] have already been used alone (for ref. see [6]) or in combination [8] in the treatment of human malig- nancies. We will show here that when cultured Ehrlich ascites carcinoma cells were exposed to MGBG for not longer than a few hours, the uptake of poly- amines, especially that of diamines, was greatly en- hanced. Exposure to MGBG likewise stimulated the uptake of polyamines by tumor cells that have been brought to the state of severe polyamine de- privation with DFMO, a condition characterized by strikingly increased uptake of polyamines (51. The enhanced uptake of polyamines induced by the antimetabolites was apparently responsible for the appearance of substantial amounts of cadaver- ine (and putrescine) in L1210 leukemia cells har- vested from mice treated with MGBG alone or in combination with DFMO. 2. MATERIALS AND METHODS 2.1.
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Key words
Polyamine antimetabolites,Ehrlich ascites carcinoma,L1210 leukemia
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