Molecular mechanisms of polyamine analogs in cancer cells

Abstract

The natural polyamines are aliphatic cations with multiple functions and are essential for cell growth. Soon after the critical requirement of polyamines for cell proliferation was recognized, the metabolism of polyamines was pursued as a target for antineoplastic therapy. Initially, much attention was focused on the development of inhibitors of polyamine biosynthesis as a means to inhibit tumor growth. The best-characterized inhibitor is alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. While compensatory mechanisms in polyamine metabolism reduce the effectiveness of DFMO as a single chemotherapeutic agent, it is currently undergoing extensive testing and clinical trials for chemoprevention and other diseases. There has been increasing interest over the last two decades in the cytotoxic response to agents that target the regulation of polyamine metabolism rather than directly inhibiting the metabolic enzymes in tumor cells. This interest resulted in the development of a number of polyamine analogs that exhibit effective cytotoxicity against tumor growth in preclinical models. The analogs enter cells through a selective polyamine transport system and can be either polyamine antimetabolites that deplete the intracellular polyamines or polyamine mimetics that displace the natural polyamines from binding sites, but do not substitute in terms of growth-promoting function. Synthesis of the first generation of symmetrically substituted bis(alkyl)polyamine analogs in the mid-1980s was based on the theory that polyamines may utilize feedback mechanisms to auto-regulate their synthesis. In the 1990s, unsymmetrically substituted bis(alkyl) polyamine analogs were developed. These compounds display structure-dependent and cell type-specific cellular effects and regulation on polyamine metabolism. More recently, a novel class of analogs has been synthesized, which include conformationally restricted, cyclic and long-chain oligoamine analogs. The development and use of these analogs have provided valuable information for understanding the molecular mechanisms of targeting the polyamine pathway as a means of cancer therapy.

Role of p53/p21Waf1/Cip1 in the regulation of polyamine analogue-induced growth inhibition and cell death in human breast cancer cells

“…4,5 Polyamine analogues have been synthesized as metabolic modulators that deplete natural intracellular polyamine pools, or polyamine mimetics that displace the natural polyamines from binding sites, but do not substitute for their growth promoting function. 2,6 Symmetrically substituted bis(alkyl)polyamine analogues represent the first generation of these analogues, some of which downregulate polyamine biosynthesis and increase SSAT activity in certain tumor cell types like non-small cell lung cancer cells, melanoma and human breast cancer cells. [7][8][9] A second generation of polyamine analogues are unsymmetrically substituted compounds that display structure-dependent and cell type-specific effects on regulation of polyamine metabolism.…”

“…Some of these novel analogues have shown significant activity against multiple human tumors both in vitro and in vivo. 6,12,13 Although it is clear that polyamine analogues can induce cell death, the mechanisms remain elusive. Interaction with DNA, displacement of natural polyamines from their binding sites, induction of polyamine catabolic enzyme activity and depletion of mitochondrial DNA have all been proposed as possible mechanisms underlying the anti-tumor action of polyamine analogues.…”

Spermine Oxidase SMO(PAOh1), Not N1-Acetylpolyamine Oxidase PAO, Is the Primary Source of Cytotoxic H2O2 in Polyamine Analogue-treated Human Breast Cancer Cell Lines

“…The natural polyamines, spermine, spermidine, and putrescine, are ubiquitous polycationic alkylamines that are required for normal eukaryotic cell growth and differentiation (1,2). Neither mammalian cells lacking polyamine biosynthetic enzymes nor cells depleted of polyamines are able to replicate (3).…”

“…Until recently, mammalian intracellular polyamine catabolism was considered to be a consequence of two enzymes, the rate-limiting and inducible cytosolic spermidine/ spermine N 1 -acetyltransferase (SSAT) 3 and a relatively constitutively expressed, peroxisomal N 1 -acetylpolyamine oxidase (PAO) (1,2). The products of SSAT/PAO activities on spermine and spermidine are the reactive oxygen species, H 2 O 2 , spermidine, and putrescine, respectively (depending on the starting substrate), and 3-acetoaminopropanol.…”

Polyamine Analogues as Novel Anti-HER Family Agents in Human Breast Cancer

“…Treatment of human breast cancer cell lines with polyamine analogues has been shown to inhibit cell growth and in some cases induce apoptosis (6)(7)(8). One subset of polyamine analogues are conformationally restricted and long chain analogues named oligoamines (9). Our laboratory has focused on the oligoamine, CGC-11144, because of its effects in human breast cancer cells.…”