Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRT1.

Napper, Andrew D.; Hixon, Jeffrey; McDonagh, Thomas; Keavey, Kenneth; Pons, Jean-Francois; Barker, Jonathan; Yau, Wei Tsung; Amouzegh, Patricia; Flegg, Adam; Hamelin, Estelle; Thomas, Russell J.; Kates, Michael; Jones, Stephen E.; Navia, Manuel A.; Saunders, Jeffrey O.; DiStefano, Peter S.; Curtis, Rory

doi:10.1021/jm061430o

Cited by 108 publications

(181 citation statements)

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“…EX527 showed the higher SIRT1 inhibitory activity (IC 50 = 0.38 μmol/L) and SIRT2 inhibitory activity (IC 50 = 32.6 μmol/L) compared with Sirtinol and Salermide, whereas nicotinamide had relatively low potency against SIRT1 with an IC 50 of 85.1 but potently inhibited SIRT2 (IC 50 = 1.16 μmol/L). These in vitro SIRT1/2 inhibition results are generally in consensus with the previously published data on the efficacy of some of these SIRT inhibitors on SIRT1 and SIRT2 (26,27,36). However, these in vitro data could not completely explain for the failure of EX527 to induce cell death, as EX527 has higher SIRT2 inhibitory activity than Sirtinol and higher SIRT1 inhibitory activity compared with Sirtinol and Salermide yet does not induce cell death.…”

Section: Sirt Inhibitors Display Potent In Vitro Sirt1/2 Inhibitory Asupporting

confidence: 86%

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

Peck

Chen

et al. 2010

Molecular Cancer Therapeutics

390

332

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SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 μmol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G 1 at comparable concentrations. In vitro SIRT assays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermideinduced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844-55. ©2010 AACR.

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Section: Sirt Inhibitors Display Potent In Vitro Sirt1/2 Inhibitory Asupporting

confidence: 86%

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

Peck

Chen

et al. 2010

Molecular Cancer Therapeutics

390

332

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“…Importantly however, SIRT1 silencing resulted in a significant increase in VP16-induced cell death. Similar results regarding sensitization and H4K16 acetylation were obtained using EX-527, a selective inhibitor of SIRT1 that does not inhibit HDAC or other sirtuin deacetylase family members (Napper et al, 2005;Figures 5d and e). These data indicate that inhibition of SIRT1 activity resulted in the sensitization to cell death induced by topoisomerase II inhibitor, and that this effect was associated with an increase in total H4K16 acetylation.…”

Section: Sirt1 Inhibition Mediates Increase In H4k16 Acetylation and supporting

confidence: 76%

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

Wallenborg

Vlachos

et al. 2010

Oncogene

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Various inhibitors of histone deacetylase (HDAC) activity can sensitize drug resistant cancer cells to chemotherapeutic agents. However, the mechanisms underlying such effects of distinct HDAC inhibitors (HDACi) remain poorly understood. Here we show that both the HDACi trichostatin A and valproic acid induced a sensitization of multidrug-resistant cancer cells to the topoisomerase II inhibitor etoposide/VP16. This effect was associated with increased acetylation of certain lysines on histones H3 and H4, including lysine 16 on histone H4 (H4K16). Overexpression of the histone acetyltransferase hMOF, known to target H4K16, was sufficient to mimic HDACi treatment on sensitization and H4K16 acetylation, and importantly, small-interfering RNA (siRNA)-mediated knockdown of hMOF abolished the HDACi-mediated sensitizing effects as well as the increase in H4K16 acetylation. Conversely, siRNA-mediated knockdown of the H4K16 deacetylase SIRT1 mimicked HDACi treatment whereas overexpression of SIRT1 abolished H4K16 acetylation and significantly reduced the sensitizing effects of HDACi. Interestingly, the effects of hMOF on H4K16 acetylation and sensitization to the topoisomerase II inhibitor could be directly counteracted by exogenous expression of increasing amounts of SIRT1 and vice versa. Our study results suggest that hMOF and SIRT1 activities are critical parameters in HDACi-mediated sensitization of multidrug-resistant cancer cells to topoisomerase II inhibitor and increased H4K16 acetylation.

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“…The SIRT1 selective inhibitor, EX527 (Merck Millipore, Billerica, MA, USA) was used at functional concentrations as described previously. 19 The anticancer drugs, cisplatin (CDDP) (Sigma-Aldrich) and paclitaxel (PTX) (Wako, Osaka, Japan), diluted with 5% dimethylformamide (DMFA) and saline were added to the culture medium at various concentrations, and cell viability was measured after 72 h.…”

Section: Assay For Cell Proliferation and Anticancer Drug Resistance mentioning

confidence: 99%

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

Asaka

Miyamoto

Yumura

et al. 2015

Laboratory Investigation

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Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (Po0.05), and its overexpression was associated with a shorter survival (Po0.05). Our experiments in vivo revealed that SIRT1 accelerated the proliferation of endometrial carcinoma cell lines (HHUA, HEC151, and HEC1B). SIRT1 overexpression significantly enhanced the resistance for cisplatin and paclitaxel in HHUA cells. Although p53 is an important target protein for SIRT1, the selective SIRT1 inhibitor (EX527) significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status. In addition, SIRT1 overexpression in HHUA cells accelerated tumor growth and cisplatin resistance in nude mice, and EX527 significantly suppressed the growth of tumors of HHUA and HEC1B cells. No adverse effect of EX527 was observed in these mice. In conclusion, SIRT1 is involved in the acquisition of the aggressive behavior associated with endometrial carcinoma, and the SIRT1 inhibitor, EX527, may be a useful agent for the treatment of this malignancy.

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Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRT1.

Cited by 108 publications

References 0 publications

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

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