Assessment of SIRT2 inhibitors in mouse models of cancer

Abstract

New therapeutics directed against established and novel molecular targets are urgently needed to intervene against cancer. Recently, it was reported that several members of the sirtuin family (SIRT1–7), the mammalian orthologs of the silent information regulator 2 (Sir2) protein in Saccharomyces cerevisiae, play important roles in carcinogenesis. Although SIRT2 has been attributed both tumor-promoting and tumor-suppressing activities in different contexts, selective SIRT2 inhibition with a small molecule mechanism-based inhibitor known as Thiomyristoyl lysine (TM) repressed the growth of breast cancer cell lines. In light of the anticancer effect of SIRT2 inhibition in cell culture, it was critical to assess the efficacy of TM as a potential anticancer therapy in vivo. This was accomplished by testing the SIRT2 inhibitor in genetically engineered and xenotransplantation mouse models of breast cancer, using the procedures detailed in this chapter.