Inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells

Kalle, Arunasree M.; Alvala, Mallika; Badiger, Jayasree; Alinakhi,; Talukdar, Pinaki; Sachchidanand,

doi:10.1016/j.bbrc.2010.08.118

Cited by 79 publications

(38 citation statements)

References 37 publications

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“…SIRT1 was found to be overexpressed in many cancers including prostate, colon, acute myeloid leukemia, and lung cancers (16,17). In addition, SIRT1 overexpression in tumor cells correlated with the silencing of tumor suppressor genes (TSG) and resistance to chemotherapy and ionizing radiation (16,18). The inhibition of SIRT1 by small-molecule inhibitors, dominant negative expression vectors, and siRNA not only rescues TSG expression but also affects key phenotypic aspects of cancer cells (19,20).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SIRT1 Signaling Sensitizes the Antitumor Activity of Silybin against Human Lung Adenocarcinoma Cells In Vitro and In Vivo

Liang

Yang

Wang

et al. 2014

Molecular Cancer Therapeutics

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Although silybin, a natural flavonolignan, has been shown to exhibit potent antitumor activities against various types of cancers, including lung cancer, the molecular mechanisms behind these activities remain unclear. Silent information regulator 1 (SIRT1) is a conserved NAD þ -dependent deacetylase that has been implicated in the modulation of transcriptional silencing and cell survival. Furthermore, it plays a key role in carcinogenesis through the deacetylation of important regulatory proteins, including p53. In this study, we investigated the antitumor activity of silybin towards human lung adenocarcinoma cells in vitro and in vivo and explored the role of the SIRT1 signaling pathway in this process. Silybin treatment resulted in a dose-and timedependent decrease in lung adenocarcinoma A549 cell viability. In addition, silybin exhibited strong antitumor activity illustrated by reductions in tumor cell adhesion, migratory capability, and glutathione levels and by increased apoptotic indices and reactive oxygen species levels. Silybin treatment also downregulated SIRT1 and upregulated p53 acetylation. SIRT1 siRNA (in vitro) or cambinol (a known SIRT1 inhibitor used for in vivo studies) further enhanced the antitumor activity of silybin. In summary, silybin is a potent inhibitor of lung adenocarcinoma cell growth that interferes with SIRT1 signaling, and this inhibition is a novel mechanism of silybin action that may be used for therapeutic intervention in lung adenocarcinoma treatment. Mol Cancer Ther; 13(7); 1860-72. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Inhibition of SIRT1 Signaling Sensitizes the Antitumor Activity of Silybin against Human Lung Adenocarcinoma Cells In Vitro and In Vivo

Liang

Yang

Wang

et al. 2014

Molecular Cancer Therapeutics

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“…Cambinol, another SIRT1/2 inhibitor, exerted antitumor activity against BCL6-expressing Burkitt lymphoma cells [23], which was attributed to the inactivation of BCL6, as well as the activation of cell cycle checkpoint proteins via the repression of SIRT1 and SIRT2 deacetylase activity. Although several other SIRT1 inhibitors, including JGB1741 and tenovins, have been shown to possess anticancer activity, no direct evidence has been provided to show that SIRT1 activators could act as anticancer agents [24, 25]. Our study, however, reveals the potential benefits of investigating SIRT1 activators in the context of individualized NSCLC treatment.…”

Section: Discussionmentioning

confidence: 67%

Prognostic Impact of DNA Repair Protein Expression in Non-Small Cell Lung Cancers Treated with Platinum-Based Chemotherapy and Subsequent Curative Lung Resection

et al. 2018

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Objective: Multimodal treatments that include preoperative platinum-based chemotherapy are fundamental to the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the predictive value of DNA repair protein expression in surgically resected NSCLCs in terms of prognosis and responses to platinum-containing chemotherapy. Methods: This retrospective study included 136 patients with NSCLC who were treated with preoperative platinum-based chemotherapy, followed by curative lung resection. ATM, RAD51, LKB1, H2AX, and SIRT1 expression levels were analyzed in resected tumor specimens via immunostaining and were used to classify patients and compare survival and responses to chemotherapy. Results: SIRT1 expression correlated significantly with improved responses to platinum-based chemotherapy (odds ratio, 2.28; p = 0.024), progression-free survival (hazard ratio [HR], 0.74; p = 0.036), overall survival (HR, 0.63; p = 0.006), and tumor-bearing survival (HR, 0.62; p = 0.014). After adjusting for clinical variables, the HR of SIRT1 expression remained significant for overall survival (HR, 0.59; p = 0.039) but not for progression-free survival (HR, 0.74; p = 0.183). No prognostic stratification was observed for the other 4 markers. Conclusion: Patients with SIRT1-expressing NSCLC had superior responses to chemotherapy and longer survival durations than those with SIRT1-negative cancer.

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“…5-oxocoronari- analogs, 17 sirtinol, 18 tenovin, 19 salermide, 20 thiobarbiturate, 21 cambinol, 19 2-anilinobenzamide 22 and other compounds. 23,24,25 Simulation of molecular dynamics carried out by Karaman and Sippl (2015) by calculating MMGBSA with thieno core molecules [3,2-d] pyrimidine-6-carboxamide to SIRT1 shows all hydrogen bond interactions between the thieno [3,2-d] pyrimidine-6-carboxamide and residue Ile347, Asp348 as well as water molecules required for inhibitor activity. The region amino acids residue Thr344 -Asp348 referred to as "floor" of the binding pocket possibility ligand binding for interaction site.…”

Section: Resultsmentioning

confidence: 99%

Molecular Dynamics Simulation of SIRT1 Inhibitor from Indonesian Herbal Database

Andika¹,

Erlina²,

Azminah³

et al. 2018

JYP

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Objective: Sirtuins are protein deacetylases regulating cellular metabolism, lifespan, stress responses, and linked with diseases pathogenesis such as cancer and neurodegenerative diseases. SIRT1, one of human seven sirtuins, the most widely studied today. Hence, identification of SIRT1 drug compound has attracted in drug discovery community. To find good drug candidates could use in insilico methods as a quick tool for analyzing the biological activity of drugs virtually. Method: In silico methods in this research using molecular dynamics simulations that use Indonesia herbal database to identification hits compounds as the SIRT1 inhibitor. Analysis of molecular dynamics simulations in this study includes RMSD (root mean square deviation), RMSF (root mean square fluctuation), molecular mechanism Poisson-Boltzmann/surface area (MMPBSA) and hydrogen bonding. Results:The results showed that hits compounds, dregamine and 5-oxocoronaridine against two of macromolecules SIRT1 (PDB ID: 4I5I and 4ZZI) obtained free energy MMPBSA calculation about -23 kcal/mol Meanwhile occupancy hydrogen bonding of residues Ile347 and Asp348 about 80%. Conclusion: Hits compounds dregamine and 5-oxocoronaridine against two of macromolecules SIRT1 inhibitor (PDB ID: 4I5I and 4ZZI) obtained free energy MMPBSA calculation about -23 kcal/mol meanwhile occupancy hydrogen bonding of residues Ile347 and Asp348 about 80%. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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Inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells

Cited by 79 publications

References 37 publications

Inhibition of SIRT1 Signaling Sensitizes the Antitumor Activity of Silybin against Human Lung Adenocarcinoma Cells In Vitro and In Vivo

Inhibition of SIRT1 Signaling Sensitizes the Antitumor Activity of Silybin against Human Lung Adenocarcinoma Cells In Vitro and In Vivo

Prognostic Impact of DNA Repair Protein Expression in Non-Small Cell Lung Cancers Treated with Platinum-Based Chemotherapy and Subsequent Curative Lung Resection

Molecular Dynamics Simulation of SIRT1 Inhibitor from Indonesian Herbal Database

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