Polyamines are small organic cations that are essential for normal cell growth and development in eukaryotes. Under normal physiological conditions, intracellular polyamine concentrations are tightly regulated through a dynamic network of biosynthetic and catabolic enzymes and a poorly characterized transport system. This precise regulation ensures that the intracellular concentration of polyamines is maintained within strictly controlled limits. It has frequently been observed that the metabolism of, and the requirement for, polyamines in tumours is frequently dysregulated. Elevated levels of polyamines have been associated with breast, colon, lung, prostate, and skin cancers, and altered levels of the rate limiting enzymes in both biosynthesis and catabolism have been observed. Based on these observations and the absolute requirement for polyamines in tumour growth, the polyamine pathway is a rational target for chemoprevention and chemotherapeutics. Here we describe the recent advances made in the polyamine field and focus on the roles of polyamines and polyamine metabolism in neoplasia through a discussion of the current animal models for the polyamine pathway, chemotherapeutic strategies that target the polyamine pathway, chemotherapeutic clinical trials for polyamine pathway specific drugs, and ongoing clinical trials targeting polyamine biosynthesis.

Ornithine decarboxylase (ODC) is the first and usually ratelimiting enzyme in the polyamine biosynthetic pathway. Under normal physiological conditions, polyamine content and ODC enzyme activity are highly regulated. However, the induction of ODC activity is an early step in neoplastic transformation. The studies described here use normal mouse keratinocytes (C5N cells), and spindle carcinoma cells (A5 cells) to explore the regulation of ODC in nonmelanoma skin cancer development. Previous results have shown that induction of ODC activity is both necessary and sufficient for the promotion of skin tumors. We see a marked increase in ODC enzyme activity in A5 cells compared with C5N keratinocytes, which correlates with a 4-fold stabilization of ODC mRNA. These data suggest that ODC is post-transcriptionally regulated in skin tumor development. Thus, we sought to investigate whether the ODC transcript interacts with the RNA-binding protein HuR, which is known to bind to and stabilize its target mRNAs. We show that HuR is able to bind to the ODC 3-UTR in A5 cells but not in C5N cells. Immunofluorescence results reveal that HuR is present in both the nucleus and cytoplasm of A5 cells, whereas C5N cells exhibit strictly nuclear localization of HuR. Knockdown experiments in A5 cells showed that when HuR is depleted, ODC RNA becomes less stable, and ODC enzyme activity decreases. Together, these data support the hypothesis that HuR plays a causative role in ODC up-regulation during nonmelanoma skin cancer development by binding to and stabilizing the ODC transcript. Ornithine decarboxylase (ODC)2 catalyzes the conversion of the amino acid ornithine to the diamine putrescine, which is subsequently converted to the higher polyamines spermidine and spermine (1, 2). Polyamines are small, ubiquitous polycations and are necessary for normal cell growth and development. Thus, the ablation of ODC is lethal in utero (3). Because of their charge, polyamines are able to bind to RNA, DNA, and proteins and thereby influence gene expression (4). Both polyamine content and ODC enzyme activity are tightly regulated in cells, and ODC is induced in response to a variety of proliferative stimuli by alterations in its transcription, translation, and protein degradation (5-10). A link between neoplastic transformation and increased ODC enzyme activity, as well as increases in intracellular putrescine and spermidine, have been well documented in animal models of skin carcinogenesis and other epithelial tumors (11-17). Moreover, a link between human nonmelanoma skin cancer (NMSC), the most prevalent cancer in the United States, and elevated ODC enzyme activity levels has been described (18). The induction of ODC activity during tumor development has been attributed to both increased Odc gene transcription and translation of the ODC mRNA (9, 19).Interestingly, changes in intracellular polyamine pools have also been shown to affect the localization of RNA-binding proteins (RBPs), which influence the stability of their target mRNA transcripts (2...

The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 dysregulation is thought to contribute to the development of cancer. We reported that (bis)guanidines, (bis)biguanides and their urea- and thiourea isosteres are potent inhibitors of LSD1, and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of small molecule amidoximes that are moderate inhibitors of recombinant LSD1, but that produce dramatic changes in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related protein (SFRP) 2, H-cadherin (HCAD) and transcription factor GATA4. These compounds represent leads for an important new series of drug-like epigenetic modulators with the potential for use as antitumor agents.