Recent Advances in the Understanding of Mammalian Polyamine Catabolism

The Regulation and Potential Role of Polyamine Catabolism in Drug Response and Disease Processes

Robert A. Casero, Jr., Alison V. Fraser, Tracy Murray-Stewart, Amy Hacker, Naveen Babbar, Jennifer Fleischer, and Yanlin Wang

1. Introduction

As more data emerge, the significance of polyamine catabolism in polyamine homeostasis, drug response, and disease etiology is expanding. Importantly, the regulation and function of the polyamine catabolic pathway has emerged as a rational target for drug intervention in both chemotherapeutic and chemopreventive strategies. Mammalian intracellular polyamine catabolism had long been thought to be a two-step process primarily regulated by a rate-limiting acetyltransferase, spermidine/spermine ^-acetyltransferase (SSAT), followed by the activity of a constitutively expressed acetylpolyamine oxidase (PAO). However, as recent reports have clearly demonstrated, mammalian polyamine catabolism also includes the activity of a previously unrecognized spermine oxidase (SMO/PAOhl). The production of reactive oxygen species (ROS) and other toxic products by these various polyamine catabolic enzymes can result in both useful and potentially dangerous consequences. This chapter will examine some of the most recent findings related to polyamine catabolism and will address the cloning and characterization of mammalian polyamine oxidases, including the newly discovered SMO/PAOhl. Additio nally, further characterization of the highly regulated SS AT, as facilitated by many recent advances with transgenic models, will be discussed with respect to the potential role that it and the oxidases play in determining response to various drugs and stimuli. Although the polyamine catabolic pathway is well described and being studied in multiple organisms, this work will focus primarily on results directly related to mammalian systems, with special emphasis given to the relationship between polyamine catabolism and human disease. Specifically, data indicating that the induction of polyamine catabolism by specific antitumor polyamine analogs plays a

From: Polyamine Cell Signaling: Physiology, Pharmacology, and Cancer Research Edited by: J.-Y. Wang and R. A. Casero, Jr. © Humana Press Inc., Totowa, NJ

Polyamine Pathway
Fig. 1. The polyamine metabolic pathway. AdoMetDC, S-adenosylmethionine decarboxylase; DFMO, 2-difluoromethylornithine; ODC, ornithine decarboxylase; PAO, N1-acetyl polyami ne oxidase; SMO/PAOh1, spermine oxidase; SSAT, spermidine/spermine N1-acetyltransferase.

direct role in determining drug response will be discussed. Also to be examined is the recent recognition that the oxidation of polyamines contributes to disease processes, and the potential targeting of polyamine catabolism as a strategy for chemoprevention.

2. Overview of Polyamine Metabolism

The mammalian polyamines—putrescine, spermidine, and spermine—are naturally occurring polycationic alkylamines. The polyamine metabolic pathway has been considered a target for antiproliferative drug development since it was discovered that polyamines are absolutely essential for cell proliferation. Effective inhibitors now exist for virtually all of the biosynthetic enzymes of the polyamine pathway (Fig. 1). Much of the work in the last 30 yr or more has focused on inhibiting the biosynthetic enzymes that control polyamine production, particularly the rate-limiting enzymes of biosynthesis, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC). The most widely studied inhibitor of polyamine biosynthesis is 2-difluromethylornithine (DFMO), an enzyme-activated inhibitor of ODC (1,2). Though DFMO was not effective as a single agent for cancer, it has seen considerable success

Polyamine Cell Proliferation Odc
Fig. 2. Select polyamine analogs. BENSpm, N1,N11-b «(ethyl)norspermine; CPENSpm, N1- et hy l -N11-(cyclopropyl)methyl-4,8,diazaundecane; CHENSpm, N1- ethyl -Nn-(cy cl ohepty l )methy l -4,8,diazaundecane; IPENSpm, (S)-N1- (2 - methy l -1 - b uty l ) -N11- ethyl -4 ,8,di azaunde cane.

as an antitrypanosomal drug targeting the organism responsible for African sleeping sickness and is being clinically evaluated as a chemopreventive agent (3).

Although the efficacy of polyamine biosynthetic inhibitors has been limited in can-c er treatment, their study has provided a wealth of data demonstrating that targeting polyamine metabolism is a rational approach for antineoplastic therapy. Recently, an alternative approach to specifically inhibiting polyamine biosynthetic enzymes has e m e rgsd. The development of agents that mimic the autoregulatory function of the polyamines but are unable to functionally substitute in the growth-promoting roles has proceeded. Several classes of polyamine analogs have been synthesized and evaluated in multiple in vitro and in vivo model systems, and in some cases, clinical trials (4-12). Most polyamine analogs have the ability to downregulate the biosynthetic enzymes ODC and AdoMetDC, compete with the natural polyamines for uptake into cells, and many also upregulate polyamine catabolism.

In early studies of the polyamine analogs (Fig. 2), including N1, N11-b /Xethy 1) no rsper-mine (BENSpm) that was synthesized by Bergeron and colleagues, we observed that

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