Targeting polyamines and inflammation for cancer prevention

Abstract

Increased polyamine synthesis and inflammation have long been associated with intraepithelial neoplasia, which are risk factors for cancer development in humans. Targeting polyamine metabolism (by use of polyamine synthesis inhibitors or polyamine catabolism activators) and inflammation (by use of nonsteroidal anti-inflammatory drugs) has been studied for many cancers, including colon, prostate, and skin. Genetic epidemiology results indicate that a genetic variant associated with the expression of a polyamine biosynthetic gene is associated with risk of colon and prostate cancers. A clinical trial of difluoromethylornithine (DFMO), a selective inhibitor of polyamine synthesis, showed that the 1 year treatment duration reduced prostate volume and serum prostate-specific antigen doubling time in men with a family history of prostate cancer. A second, clinical trial of DFMO in combination with sulindac, a NSAID in patients with prior colon polyps found that the 3-year treatment was associated with a 70% reduction of all, and over a 90% reduction of advanced and/or multiple metachronous colon adenomas. In this chapter, we discuss that similar combination prevention strategies of targeting polyamines and inflammation can be effective in reducing risk factors associated with the development of human cancers.

Fig. 4.1

Polyamine Metabolism, Inflammation and Carcinogenesis. The processes of polyamine metabolism and inflammation are coupled, in part, by the solute carrier transporter SLC3A2, which imports the amino acid arginine using diamines as the antiport molecule (Uemura et al. 2008). SLC3A2 is physically associated with the spermidine/spermine N¹-acetyltransferase (SAT1), which acetylates spermidine and spermine and target them for export by this transporter. As shown in this figure, the activity of the surface transporter to import aiginine can be enhanced by increasing polyamine synthesis and/or export, as occurs in human prostate carcinogenesis (Bettuzzi et al. 2000). Inhibition of polyamine synthesis, by agents such as DFMO and activation of polyamine catabolism and export by drugs such as the NSAIDS, reduce cell and tissue polyamines and subsequently arginine transport. The consequence of arginine pool size reduction is to reduce the levels of the pro-inflammatory molecule NO. Reduced NO, along with reduced polyamines, is associated with reduced carcinogenesis. Spermine can be oxidized to spermidine with the generation of H₂O₂ in the process, which can in turn lead to DNA damage which is pro-carcinogenic (Babbar and Casero 2006). Increased catabolism/export by NSAIDs leads to a decrease in spermine, thereby leading to decreased production of the DNA damaging H₂O₂