Tenovin-6

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Background

Tenovin-6 is an analog of tenovin-1 with more water-soluble and it inhibits the protein deacetylase activities of SIRT1, SIRT2 and SIRT3 with IC50 value of 21 μM, 10 μM, and 67 μM, respectively [1].It has been identified that　the cytotoxic effects of　tenovin-6 may occur through the dysregulation of autophagy rather　than induction of apoptosis in chronic lymphocytic leukemia cells. Sir2p homologs could be targets　for tenovin-6 in mammalian cells.Tenovin-6 decreases purified human SirT1 peptide deacetylase activity in vitro with an IC50 of 21 mM and human SirT2 activity with an IC50 of 10 mM. Inhibition of SirT3 by tenovin-6 in this assay was significantly lower with an IC50 of 67 mM. And the activity of HDAC8 is poorly inhibited by tenovin-6 with an IC50 above the highest concentration of 90 mM. In xenograft models, tenovins induce apoptosis in malignant cell lines, containing those derived from lympho-reticular neoplasia and decrease human tumor growth. Anti-leukaemic properties of Sirtuin inhibitors have also been demonstrated in recent pre-clinical studies on Tenovin in chronic myeloid leukaemia and Nicotinamide in CLL15 associated with increased p53-pathway function [1, 2].Tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Interestingly, tenovin-6 induced apoptosis in the cell lines, those with wild-type TP53, mutant-type and null versions, which were accompanied by up regulation of death receptor 5. In the KatoIII cell line ( TP53-null), death receptor 5 silencing markedly attenuated tenovin-6-induced apoptosis, indicating that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Tenovin-6 combined with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells [3].

[1]. Lain S, Hollick JJ, Campbell J, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell, 2008, 13(5): 454-463.
[2]. MacCallum SF, Groves MJ, James J, et al. Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6. Scientific Reports, 2013, 3: 1275.
[3]. Hirai S, Endo S, Saito R, et al. Antitumor Effects Of A Sirtuin Inhibitor, Tenovin-6, Against Gastric Cancer Cells Via Death Receptor 5 Up-Regulation. PLoS ONE, 2014, 9(7): e102831.