Inhibition of sirtuins 1 and 2 impairs cell survival and migration and modulates the expression of P-glycoprotein and MRP3 in hepatocellular carcinoma cell lines

Ceballos, María Paula; Decándido, Giulia; Quiroga, Ariel D.; Comanzo, Carla G.; Livore, Verónica Inés; Lorenzetti, Florencia; Lambertucci, Flavia; Chazarreta-Cifre, Lorena; Banchio, Claudia; Álvarez, María Clara; Mottino, Aldo D.; Carrillo, María C.

doi:10.1016/j.toxlet.2018.03.011

Cited by 36 publications

(30 citation statements)

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“…The SIRT1 inhibitor EX-527 increased the acetyl-p53/ p53 ratio and FoxO1 acetylation levels, probably exacerbating its ability to induce apoptosis, and reduced the expression of P-gp and MRP3 [21]. Thus, EX-527 could be used during HCC treatment to favor the uptake of a chemotherapeutic agent in cells.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-Specific Protease 22/Silent Information Regulator 1 Axis Plays a Pivotal Role in the Prognosis and 5-Fluorouracil Resistance in Hepatocellular Carcinoma

Wang

Ling

et al. 2019

Dig Dis Sci

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Background Ubiquitin-specific protease 22 (USP22) is described as a key subunit of the Spt-Ada-Gcn5 acetyl transferase complex, which plays an important role in the prognosis and resistance to chemotherapy drugs in hepatocellular carcinoma (HCC). Silent information regulator 1 (SIRT1) is a member of the sirtuin family that is deubiquitinated by USP22. However, it is still unknown whether USP22 and SIRT1 co-expression is associated with disease progression and 5-Fluorouracil (5-FU) resistance in HCC. Methods 141 patients who received hepatectomy at our hospital from January 2010 to December 2014 were enrolled in this study. The expression of USP22 and SIRT1 was detected by immunohistochemical staining. Clinicopathological features, including age, gender, tumor number, tumor size, tumor differentiation, tumor stage, alpha-fetoprotein and microscopic vascular invasion, were assessed. Further experiments confirmed the role of SIRT1 in 5-FU drug resistance in vivo. Results Immunohistochemical staining showed that the high expression of USP22 and SIRT1 was frequently observed in HCC tissues relative to normal liver tissues. Overexpression of USP22 is associated with microscopic vascular invasion (MVI). Further analysis showed that the co-expression of USP22 and SIRT1 was more effective in predicting the prognosis of HCC. The SIRT1 inhibitor EX-527 dramatically inhibited the expression of Cyclin B1 and resistance-associated protein 3 (MRP3) to reduce 5-FU drug resistance in vivo. Conclusion These findings suggest that the co-expression of USP22 and SIRT1 is significantly associated with unfavorable HCC progression. The inhibition of SIRT1 in vivo could be valuable in improving 5-FU drug sensitivity and inhibiting tumor cell proliferation and inducing apoptosis.

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Section: Discussionmentioning

confidence: 99%

Ubiquitin-Specific Protease 22/Silent Information Regulator 1 Axis Plays a Pivotal Role in the Prognosis and 5-Fluorouracil Resistance in Hepatocellular Carcinoma

Wang

Ling

et al. 2019

Dig Dis Sci

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“…u Fluorometric assay kits, undisclosed substrates. On tumour cell lines, several reports demonstrated the ability of EX-527 to increase p53 acetylation from 1 to 25 mM concentrations, when used either alone or in combination with cytotoxic molecules 16,23,44,46,51,56,63 . EX-527 was shown to improve the efficiency of cytotoxic agents on cancer cells, with several chemotherapeutic and genotoxic agents 40,42,60 .…”

Section: Cellular Assays Of Ex-527mentioning

confidence: 99%

“…Ten years after this report, the list of EX-527 studies has grown to reinforce this view (Table 3). For example, a decrease in cell survival and migration and an increase in apoptosis was recently observed on hepatocellular carcinoma (HCC: HepG2 and Huh7) cell lines with EX-527 alone 63 . Moreover, the same study demonstrated that EX-527 induced the downregulation of ABC transporters P-gp and MRP3 in HepG2 cells, suggesting an additional potential application of this SIRT1 inhibitor in combination with conventional therapeutic drugs to overcome multi-drug resistance (MDR) during HCC therapy 63 .…”

Section: Cellular Assays Of Ex-527mentioning

confidence: 99%

Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat)

Broussy

Laaroussi

Vidal

2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The human sirtuin silent information regulator 1 (SIRT1) is a NAD þ-dependent deacetylase enzyme. It deacetylates many protein substrates, including histones and transcription factors, thereby controlling many physiological and pathological processes. Several synthetic inhibitors and activators of SIRT1 have been developed, and some therapeutic applications have been explored. The indole EX-527 and its derivatives are among the most potent and selective SIRT1 inhibitors. EX-527 has been often used as a pharmacological tool to explore the effect of SIRT1 inhibition in various cell types. Its therapeutic potential has, therefore, been evaluated in animal models for several pathologies, including cancer. It has also been tested in phase II clinical trial for the treatment of Huntington's disease (HD). In this review, we will provide an overview of the literature on EX-527, including its mechanism of inhibition and biological studies.

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“…In the breast carcinoma cell line MCF-7 though, the opposite effect was observed, Sirt1 inhibition by EX-527 led to cell cycle arrest while treatment with Sirtinol or Salermide (Sirt1/2 inhibitors with a stronger effect on Sirt2) resulted in cell death (36,37). In melanoma, chronic lymphocytic leukemia as well as hepatocellular carcinoma cell lines both Sirt1 inhibitors (EX-527) and Sirt2 inhibitors impaired cell growth and viability (38)(39)(40).…”

Section: Introductionmentioning

confidence: 99%

Sirtuin 1 Inhibiting Thiocyanates (S1th)—A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases

et al. 2020

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Sirtuin 1 (Sirt1) is a NAD + dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instances even a dual role for the same cancer type has been reported. Increased Sirt1 activity has been linked to extension of the life span of cells, respectively, organisms by promoting DNA repair processes and downregulation of tumor suppressor proteins. This may have the downside of enhancing tumor growth and metastasis. In mice embryonic fibroblasts depletion of Sirt1 was shown to decrease levels of the DNA damage sensor histone H2AX. Impairment of DNA repair mechanisms by Sirt1 can promote tumorigenesis but also lower chemoresistance toward DNA targeting therapies. Despite many biological studies, there is currently just one small molecule Sirt1 inhibitor in clinical trials. Selisistat (EX-527) reached phase III clinical trials for treatment of Huntington's Disease. New small molecule Sirt1 modulators are crucial for further investigation of the contradicting roles of Sirt1 in cancer. We tested a small library of commercially available compounds that were proposed by virtual screening and docking studies against Sirt1, 2 and 3. A thienopyrimidone featuring a phenyl thiocyanate moiety was found to selectively inhibit Sirt1 with an IC 50 of 13 µM. Structural analogs lacking the thiocyanate function did not show inhibition of Sirt1 revealing this group as key for the selectivity and affinity toward Sirt1. Further analogs with higher solubility were identified through iterative docking studies and in vitro testing. The most active compounds (down to 5 µM IC 50) were further studied in cells. The ratio of phosphorylated γH2AX to unmodified H2AX is lower when Sirt1 is depleted or inhibited. Our new Sirtuin 1 inhibiting thiocyanates (S1th) lead to similarly lowered γH2AX/H2AX ratios in mouse embryonic fibroblasts as Sirt1 knockout and treatment with the reference inhibitor EX-527. In Wössner et al. Sirtuin 1 Inhibiting Thiocyanates (S1th) addition to that we were able to show antiproliferative activity, inhibition of migration and colony forming as well as hyperacetylation of Sirt1 targets p53 and H3 by the S1th in cervical cancer cells (HeLa). These results reveal thiocyanates as a promising new class of selective Sirt1 inhibitors.

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Inhibition of sirtuins 1 and 2 impairs cell survival and migration and modulates the expression of P-glycoprotein and MRP3 in hepatocellular carcinoma cell lines

Cited by 36 publications

References 53 publications

Ubiquitin-Specific Protease 22/Silent Information Regulator 1 Axis Plays a Pivotal Role in the Prognosis and 5-Fluorouracil Resistance in Hepatocellular Carcinoma

Ubiquitin-Specific Protease 22/Silent Information Regulator 1 Axis Plays a Pivotal Role in the Prognosis and 5-Fluorouracil Resistance in Hepatocellular Carcinoma

Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat)

Sirtuin 1 Inhibiting Thiocyanates (S1th)—A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases

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