Iron regulation by Sirtuins 1 & 2 and their therapeutic modulation by Sirtinol
Sirtuins 1 & 2 (SIRTs 1 & 2) are deacetylases that are overexpressed in several types of cancer, thereby contributing to various hallmarks of cancer, such as increased proliferation and chemoresistance. Therefore, these enzymes represent potential therapeutic targets. Sirtinol is a small-molecule pharmacological inhibitor of SIRT1 and SIRT2 that shows promise as an anti-tumor drug in several types of cancer. Treatment with Sirtinol reduces tumor proliferation and invasiveness and enhances the cytotoxic effects of other targeted therapies. In addition to its enzyme-inhibitory activity, sirtinol has iron-chelating properties that may contribute to its cytotoxicity in tumor cells by disrupting iron metabolism and inducing oxidative stress. However, the detailed mechanism(s) by which Sirtinol may cause iron-induced oxidative stress to kill tumor cells remain unknown. Furthermore, Sirtinol’s anti-cancer activities and the mechanism(s) by which it induces cytotoxicity have not been extensively evaluated. This review focuses on the following topics: 1) the role of SIRTs 1 & 2 as tumor promoters, providing a rationale for developing inhibitors like sirtinol for these enzymes; 2) examine the connection between SIRTs 1 and 2 and iron metabolism; 3) we examine sirtinol’s anti-tumor properties in relation to its ability to function as a tridentate iron chelator.