SIRT1 siRNA-loaded lipid nanoparticles enhanced doxorubicin-induced cell death in prostate cancer cell lines

Abstract

Most chemotherapeutics induce apoptosis by creating DNA damage in tumor cells. However, high expression of Sirtuin 1 (SIRT1), which is a histone deacetylase activates DNA repair mechanisms leading to the repair of chemotherapeutic-induced DNA damage and subsequently prevention of apoptosis. Therefore, inhibition of SIRT1 is a useful strategy in cancer therapy to achieve a more efficient eradication of tumor cells.In this study, novel lipoplexes composed of 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) containing lipid nanoparticles and SIRT1 siRNA have been formulated by the freeze-drying method. SIRT1 silencing effect has been demonstrated by a 2.5- to 4- fold decrease in mRNA and protein expression levels. The efficiency of the lipoplexes to enhance the activity of doxorubicin, a DNA damage-inducing chemotherapeutic agent, has been studied on prostate cancer cell lines with different p53 expression patterns, namely LNCaP, DU145, and PC3. SIRT1 silencing by lipoplexes enhanced DNA damage recognition and increased the activity of doxorubicin on cancer cell death. These results have shown that SIRT1 siRNA-loaded lipid nanoparticles can enhance the efficiency of doxorubicin on prostate cancer cell lines.