Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications

Polyamines are aliphatic cations with multiple functions and are essential for life. Cellular polyamine levels are regulated by multiple pathways such as synthesis from amino acid precursors, cellular uptake mechanisms that s alvage polyamines from diet and intestinal microorganisms, as well as stepw ise degradation and efflux. Investigations using polyamine biosynthetic inh ibitors indicate that alterations in cellular polyamine levels modulate nor mal and cancer cell growth. Studies using transgenic mice overexpressing po lyamine biosynthetic enzymes support a role of polyamines in carcinogenesis . Many, if not all, signal transduction pathways intersect with polyamine b iosynthetic pathways and the regulation of intracellular polyamine levels. Direct binding of polyamines to DNA and their ability to modulate DNA-prote in interactions appear to be important in the molecular mechanisms of polya mine action in cell proliferation. Consistent with the role of polyamines a s facilitators of cell growth, several studies have shown their ability to protect cells from apoptosis. However, polyamines also have a role in facil itating cell death. The basis of these diverse cellular responses is curren tly not known. Cell death response might be partly mediated by the producti on of hydrogen peroxide during polyamine catabolism. In addition, the abili ty of polyamines to alter DNA-protein and protein-protein interactions migh t be disruptive to cellular functions, when abnormally high levels are accu mulated due to defects in polyamine catabolic or efflux pathways. A large b ody of data indicates that polyamine pathway can be a molecular target for therapeutic intervention in several types cancers. Inhibitors of biosynthes is, polyamine analogues as well as oligonucleotide/polyamine analogue combi nations are promising drug candidates for chemoprevention and/or treatment of cancel.