Polyamines and cancer: implications for chemotherapy and chemoprevention

Abstract

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.

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

“…Interestingly, several studies targeting the polyamine pathways in conjunction with other drugs are currently in clinical trials. 40 However, the direct role of PAOX in tumor formation in vivo and its effects on the levels of the different polyamines warrants further investigation in the future.…”

Chemoprevention of Prostate Cancer with the Polyamine Synthesis Inhibitor Difluoromethylornithine

“…Polyamines are small cationic molecules that have diverse roles in the cellular management of normal and malignant cells (Nowotarski et al 2013). The biochemical pathways which intersect with polyamine metabolism are complex and a simplified version is shown in Fig.…”

Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans?

“…The net cytosolic spermidine content further depends on its catabolism, which is mainly driven by acetylation and subsequent oxidation [29–31], but also on its uptake from the extracellular space and its excretion by the cell. This may be mediated by membrane transporters such as the ones operating in yeast and bacteria [32], but could also involve endocytosis/exocytosis processes. Still, polyamine transport in mammals remains not well understood and needs further examination.…”