Antitumor Activity of a Small-Molecule Inhibitor of Human Silent Information Regulator 2 Enzymes

Abstract

SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein. Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2. Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest. Treatment of BCL6-expressing Burkitt lymphoma cells with cambinol as a single agent induced apoptosis, which was accompanied by hyperacetylation of BCL6 and p53. Because acetylation inactivates BCL6 and has the opposite effect on the function of p53 and other checkpoint pathways, the antitumor activity of cambinol in Burkitt lymphoma cells may be accomplished through a combined effect of BCL6 inactivation and checkpoint activation. Cambinol was well tolerated in mice and inhibited growth of Burkitt lymphoma xenografts. Inhibitors of NADdependent deacetylases may constitute novel anticancer agents. (Cancer Res 2006; 66(8): 4368-77)

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

“…The acetyl-lysine target site is, however, a viable option for the design of sirtuin inhibitors, particularly since the acetyl-lysine binding site shows significant differences with the acetyl-lysine binding site of the class I/II HDACs. Consistent with targeting the acetyl-lysine site of the sirtuin proteins for inhibition, a recent report describes the identification of the sirtuin inhibitor cambinol that shows competitive binding with acetyl-lysine (Heltweg et al, 2006). The targeting of the nicotinamide inhibitory, D-pocket, may also represent a fruitful avenue of investigation.…”

Sirtuins: critical regulators at the crossroads between cancer and aging

“…In mouse xenograft models, cambinol alone was effective specifically against tumors expressing BCL6 (Heltweg et al, 2006). DNA damage does not promote BCL6 acetylation (Bereshchenko et al, 2002), but inhibition of SIRT1 with cambinol sensitizes cells to DNA-damage-induced apoptosis independently of p53 (Heltweg et al, 2006). Cambinol also induced p53, FOXO3a and Ku70 acetylation (Heltweg et al, 2006), indicating that multiple targets of SIRT1 may control the response to DNA damage.…”

“…BCL6 is regulated by several post-translational modifications, including phosphorylation, which targets BCL6 for proteasome-mediated degradation (Niu et al, 1998), and acetylation by p300, which inactivates BCL6 repression of targets through disruption of the interaction with HDACs (Bereshchenko et al, 2002). Like nuclear factor-kB (NF-kB), p53 and Ku70, BCL6 is deacetylated by both HDACs and SIRT1 (Bereshchenko et al, 2002;Heltweg et al, 2006). BCL6 repressor activity is controlled by competing HATs and HDACs/SIRT1, and acetylation impairs the oncogeneic properties and transforming capabilities of BCL6 (Bereshchenko et al, 2002).…”

“…BCL6 repressor activity is controlled by competing HATs and HDACs/SIRT1, and acetylation impairs the oncogeneic properties and transforming capabilities of BCL6 (Bereshchenko et al, 2002). Cambinol, a SIRT1 inhibitor, inactivates BCL6 in Burkitt's lymphoma cells by promoting its acetylation, and leads to apoptosis induction (Heltweg et al, 2006). In mouse xenograft models, cambinol alone was effective specifically against tumors expressing BCL6 (Heltweg et al, 2006).…”

Sirtuins and inflammation: Friends or foes?

“…Sirtuin inhibitors have also been extensively studied, mostly in the setting of cancer therapy, as shown by [72]. It is noteworthy however that nicotinamide, the prototypic sirtuin inhibitor, 18 displays anti-inflammatory properties both in vitro and in vivo [49], [73].…”