Identification of a small molecule SIRT2 inhibitor with selective tumor cytotoxicity

Zhang, Yingjia; Au, Qingyan; Zhang, Menghua; Barber, James David; Ng, Shi Chung; Zhang, Bin

doi:10.1016/j.bbrc.2009.06.113

Cited by 71 publications

(60 citation statements)

References 28 publications

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“…Moreover, we found 2-and 3-fold reductions in the proportion of BrdU + proliferating NB4 and HL60 cells, respectively, after treatment with AC93253, as compared to control DMSO treated cells ( Figure 3B). In line with previously published reports, 33,34 we found that neither NAMPT nor SIRT2 inhibitors diminished the proliferation ( Figure 2D …”

Section: Inhibition Of Nampt (By Fk866) or Sirt2 (By Ac93253) In Acutsupporting

confidence: 93%

“…33 Inhibition of SIRT2 by the specific inhibitor AC93253 induces cell death in a variety of solid cancer cell lines. 34 We compared the effects of NAMPT inhibition with FK866 and SIRT2 inhibition with AC93253 on the proliferation and apoptosis of the leukemia cell lines (NB4 and HL60) and primary AML blasts (AML M2) (n = 3). To validate the specific effects of these inhibitors, we first measured SIRT2 activity in HL-60 cells treated with SIRT2 or NAMPT inhibitors and indeed found diminished SIRT2 activity after exposure to FK866 or AC93253 compared to the activity in control cells treated with DMSO (Figure 2A,B).…”

Section: Inhibition Of Nampt (By Fk866) or Sirt2 (By Ac93253) In Acutmentioning

confidence: 99%

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The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

Liu¹,

Klimenkova²,

Klimiankou³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundInhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear. Design and MethodsHere, we evaluated whether nicotinamide phosphoribosyltransferase's effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process. ResultsWe identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 β via diminished phosphorylation and, ultimately, inactivation of β-catenin by phosphorylation. ConclusionsOur results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 β/β-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation.

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Section: Inhibition Of Nampt (By Fk866) or Sirt2 (By Ac93253) In Acutsupporting

confidence: 93%

Section: Inhibition Of Nampt (By Fk866) or Sirt2 (By Ac93253) In Acutmentioning

confidence: 99%

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

Liu¹,

Klimenkova²,

Klimiankou³

et al. 2011

Haematologica

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“…Cell cycle analyses revealed that SIRT2 siRNAs consistently reduced the percentage of cells at S phase, but did not consistently increase the percentage of cells at pre-G1 phase (Supplementary Figure S2, Supplementary Tables S1 and S2), indicating that repression of SIRT2 decreased cell proliferation but did not result in cell death. To exclude potential off-target effects of the siRNAs, we treated BE(2)-C and MiaPaca-2 cells with AC-93253, a small molecule SIRT2-selective deacetylation inhibitor, 20 or the SIRT1/SIRT2 inhibitor Salermide, which inhibits SIRT2 but not SIRT1 at 25-50 mM. 21 Figure S1A).…”

Section: Resultsmentioning

confidence: 99%

“…39 Importantly, small molecule SIRT2 inhibitors have unanimously shown anticancer effects. For example, the SIRT2-selective inhibitor AC-93253 induces apoptosis in cancer cells originating from various organs, 20 and a number of 1,2-dihydrobenzochromen-derived SIRT2-selective inhibitors cause apoptosis and/or differentiation in leukemic cells. 19 Additionally, the pan-SIRT inhibitor nicotinamide suppresses growth of carcinogen-induced mouse and human bladder cancer by reducing the deacetylation activity of SIRT2.…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies. The Myc family of oncoproteins are commonly upregulated in human cancer. MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression occur in 20-25% of neuroblastoma and correlate with a poor patient outcome. 1-3 MYC oncogene amplification occurs in 54% of human pancreatic cancer cell lines 4 and 33% of human primary pancreatic tumors, 5 and significant c-Myc oncoprotein overexpression is seen in B50% of human primary pancreatic tumors. 6 Stabilization and degradation of Myc oncoproteins are controlled by ordered phosphorylation at serine 62 (S62) and threonine 58 (T58) and consequent ubiquitinproteasome pathway-mediated proteolysis. 7-9 Aurora A interacts with both N-Myc and ubiquitin, and blocks ubiquitin-regulated N-Myc protein degradation. 8 Myc oncoproteins induce malignant transformation by binding to cognate DNA sequences and consequently modulating gene transcription 10-13 as well as by enhancing ribosome biogenesis and consequently upregulating protein expression, 14,15 leading to cell proliferation.Recruitment of histone deacetylase (HDACs) to gene promoters induces histone hypoacetylation and transcriptional repression, particularly of tumor suppressor genes. 16 In a comprehensive panel of normal cells, cancer cell lines, normal tissues, and primary tumors, global loss of monoacetylation of histone H4 at lysine 16 (H4K16) is seen only in cancer cells and is associated with early stages of tumorigenesis. 17 One of the HDACs that cause H4K16 deacetylation is the class III HDAC SIRT2, which shows a strong preference for acetylated H4K16. 18 Mo...

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“…Enfin, nous avons déjà mentionné que la déacétylation de p53 a un effet oncogénique. Inversement, le traitement de différentes lignées cancéreuses avec un inhibiteur spécifique de SIRT2, tel que l'AC-93253, stimule l'acétylation de p53 et induit une cytotoxicité cellulaire [27,28]. Nos données [7] ajoutent la notion de dépendance au contexte cellulaire.…”

Section: Sirt2 Dans Le Cancer : Deux Faces D'une Même Pièceunclassified