Heltweg Birgit, Gatbonton Tonibelle, Schuler Aaron D, Posakony Jeff, Li Hongzhe, Goehle Sondra, Kollipara Ramya, Depinho Ronald A, Gu Yansong, Simon Julian A, Bedalov Antonio
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Cancer Res. 2006 Apr 15;66(8):4368-77. doi: 10.1158/0008-5472.CAN-05-3617.
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 NAD-dependent deacetylases may constitute novel anticancer agents.
SIRT1和其他依赖烟酰胺腺嘌呤二核苷酸（NAD）的去乙酰化酶通过对包括p53和BCL6癌蛋白在内的重要调节蛋白进行去乙酰化，参与了细胞对应激的反应调控以及肿瘤发生过程。在此，我们描述了一种名为坎比诺尔（cambinol）的化合物的鉴定，它能抑制人SIRT1和SIRT2的依赖NAD的去乙酰化酶活性。与SIRT1在应激期间促进细胞存活的作用一致，在基因毒性应激期间用坎比诺尔抑制SIRT1活性会导致关键应激反应蛋白的过度乙酰化，并促进细胞周期停滞。用坎比诺尔单独处理表达BCL6的伯基特淋巴瘤细胞可诱导细胞凋亡，同时伴随着BCL6和p53的过度乙酰化。由于乙酰化会使BCL6失活，且对p53和其他检查点通路的功能有相反作用，坎比诺尔在伯基特淋巴瘤细胞中的抗肿瘤活性可能是通过BCL6失活和检查点激活的联合作用来实现的。坎比诺尔在小鼠中耐受性良好，并能抑制伯基特淋巴瘤异种移植瘤的生长。依赖NAD的去乙酰化酶抑制剂可能构成新型抗癌药物。
