The SirT1 Inhibitor Tenovin-6 Induces Monocytic Differentiation in APL Cells

Abstract 1542

Tenovin-6, an inhibitor for nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase Sirtuins, shows cytotoxicity to cancerous cells and thus recognized as a potential therapeutic compound for cancer treatment (Lain S., et al. (2008) Cancer Cell. 13,454–63). Since there is limited information for the cytotoxic property of this compound for hematopetic malignancies, we treated an APL (acute promyelocytic leukemia) cell line NB4 with Tenovin-6. As expected, Annexin V assay revealed that Tenovin-6 induced apoptosis in NB4 cells. However, to our surprise, at modest concentration, Tenovin did not induce cell death, rather inhibited NB4 cell proliferation and altered cell morphology. The fluorescence-activated cell sorting (FACS) analysis revealed that tenovin-6-treated NB4 cells are positive for CD11b and CD36 with decreased level of CD13 and CD33. Moreover, tenovin-6-treated NB4 cells presented nitroblue tetrazolium reduction capacity, suggesting that tenovin-6 induced monocytic differentiation in NB4 cells.

To assess how Tenovin-6 induces cellular differentiation in NB4 cells, we investigated downstream target of Sirtuins. Although Tenovin-6 reportedly promotes acetylation of p53 by inhibiting SirT1, a founder of Sirtuin family proteins, the acetylation status of p53 is unchanged at the concentration where we observed differentiation. This suggests that Tenovin-6 induces NB4 differentiation through inhibiting other Sirtuin family proteins. These findings demonstrate a potential of Tenovin-6 as a differentiation-inducing reagent in APL cells.