Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells

Zwergel, Clemens; Czepukojc, Brigitte; Evain‐Bana, Emilie; Xu, Zhanjie; Stazi, Giulia; Mori, Mattia; Patsilinakos, Alexandros; Mai, Antonello; Botta, Bruno; Ragno, Rino; Bagrel, Denyse; Kirsch, Gilbert; Meiser, Peter; Jacob, Claus; Montenarh, Mathias; Valente, Sérgio

doi:10.1016/j.ejmech.2017.04.012

Cited by 25 publications

(34 citation statements)

References 75 publications

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“…Propidium iodide (PI) staining was used for flow-cytometry based cell cycle analysis as described previously 12 . Further, cell cycle halt was confirmed by Western blotting by probing for G 0 -G 1 (Cdk2 pTyr15) and G 2 -M (Histone H3 pSer10) phase markers using cell cycle marker cocktail (Abcam), as described earlier 13 .…”

Section: Methodsmentioning

confidence: 99%

Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer

et al. 2019

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Anaplastic Thyroid Cancer (ATC) is an aggressive malignancy with limited therapeutic options and dismal patient survival. We have previously shown MADD to be differentially overexpressed in multiple cancer histologies and to contribute to tumor cell growth and survival. Therefore, we targeted MADD by gene silencing, explored its effect on cellular proliferation and metastases and examined its therapeutic potential in an orthotopic ATC model in athymic nude mice. When compared to untreated control and scramble siRNA, MADD siRNA treatment inhibited the proliferative capacity of 8505C, C643 and HTH7 cells in vitro and 8505C-derived-orthotopic tumor growth in vivo. MADD ablation caused a significant reduction in cellular migration and invasion potential; clonogenic capacity; as well as, mitochondrial length and potential in vitro. This MADD siRNA-induced anti-migratory/invasive effect corresponded with inhibition of epithelial–mesenchymal transition (EMT) and Wnt signaling. Mechanistically, MADD siRNA inhibited TNFα induced activation of pERK, pGSK3β and β-catenin, suggesting that MADD knockdown might exert its anti-migratory/invasive effects, by blocking TNFα/ERK/GSK3β axis. MADD siRNA can inhibit β-catenin nuclear translocation and consequently, the expression of its target genes in ATC cells. In in vivo experiments, along with tumor regression, MADD siRNA treatment also decreased evidence of lung metastases. Immunohistochemically, MADD siRNA-treated tumor tissues exhibited a reduction in Ki67 and N-Cadherin expression, and an increase in E-Cadherin expression. In conclusion, we show the crucial role of MADD in ATC tumorigenesis and metastasis and its potential implications as a molecular target for ATC therapy.

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Section: Methodsmentioning

confidence: 99%

Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer

et al. 2019

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“…Compounds 1r and 1h were synthesized in three steps by using the procedure by us described in previous works. 18,28 ARSA Biochemical Inhibition and Biophysical Binding Assay with 1r. Biochemical Inhibition Assay.…”

Section: Structure-based Studies To Disclose 1rmentioning

confidence: 99%

“…Reported crystallographic analyses revealed structural similarity between alkaline phosphatases and arylsulfatases strongly suggesting that these enzymes are evolutionarily related. 17 For these reasons, an SBVS was set up and applied to an inhouse compound library of coumarin-based polycycles with known inhibition activity against CDC25 isoforms A and C. 18 Through an SBVS protocol as depicted in Figure 1 the hit compound 1r was identified. Herein is reported the capability of this compound to bind and inhibit ARSA through Surface Plasmon Resonance (SPR) (K D ) and the catalytic biochemical inhibition assay (IC 50 ), respectively.…”

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confidence: 99%

Discovery of the First Human Arylsulfatase A Reversible Inhibitor Impairing Mouse Oocyte Fertilization

et al. 2020

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Arylsulfatase A (ARSA) plays a crucial role in the reproduction of mammals due to its involvement in the specific gamete interaction preceding sperm and egg fusion leading to fertilization. Recently, it has been shown that zona pellucida (ZP) sperm binding and in vivo fertilization in mice are markedly hampered by using a specific anti-ARSA antibody. Herein, the design and discovery of the first ARSA small molecule inhibitor based on a coumarin-containing polycycle are presented. Through a structure-based approach applied on our in-house library, compound 1r was identified as an ARSA reversible inhibitor (ARSAi); then its activity was validated through both surface plasmon resonance and biochemical inhibition experiments, the first providing a K D value of 21 μM and the latter an IC50 value of 13.2 μM. Further investigations highlighted that compound 1r induced 20% sperm death at 25 μM and also impaired sperm motility; nevertheless both the effects were mediated by ROS production, since they were rescued by the cotreatment of 1r and N-acetyl cysteine (NAC). Interestingly, while 1r was not able to hamper the ZP/sperm binding, it markedly decreased the in vitro oocyte fertilization by mouse sperm up to 60%. Notably, this effect was not hampered by 1r/NAC coadministration, hence allowing the ruling out of an ROS-dependent mechanism. In conclusion, herein is reported the first ever hit of ARSAi as a chemical tool that will enable better exploration of ARSA’s biological role in fertilization as well as provide a starting point for developing 1r structure optimization aimed at increasing enzyme inhibition potency but also providing a deeper understanding of the involvement of ARSA in the fertilization pathway mechanism.

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“…This class of compounds presents noteworthy pharmacological activities associated to their unique redox properties, bioreduction/biooxidation mechanisms, destruction of cancer cells with elevated endogenous levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) and inhibition of enzymatic targets, as for instance, deubiquitinases . Recently, Zwergel and co‐workers discovered novel naphthoquinoidal derivatives as CDC25 inhibitors . The CDC25 phosphatase is a key regulator of the human cell cycle and, as such, is a valuable target for the development of 1,4‐NQs inhibitors with potential antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

“…[2] Recently,Z wergela nd co-workersd iscovered novel naphthoquinoidal derivatives as CDC25 inhibitors. [3] The CDC25 phosphatase is ak ey regulator of the human cell cycle and,ass uch, is av aluable targetf or the development of 1,4-NQsi nhibitors with potential antitumoractivity.…”

mentioning

confidence: 99%

Combination of Aryl Diselenides/Hydrogen Peroxide and Carbon‐Nanotube/Rhodium Nanohybrids for Naphthol Oxidation: An Efficient Route towards Trypanocidal Quinones

Carvalho

Jardim

Santos

et al. 2018

Chemistry A European J

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This work reports a combination of aryl diselenides/hydrogen peroxide and carbon-nanotube (CNT)/rhodium nanohybrids (RhCNT) for naphthol oxidation towards the synthesis of 1,4-naphthoquinones and evaluation of their relevant trypanocidal activity. Under a combination of (PhSe) /H O in the presence of O in iPrOH/hexane, several benzenoid (A-ring)-substituted quinones were prepared in moderate to high yields. We also studied the contribution of RhCNT as co-catalyst in this process and, in some cases, yields were improved. This method provides an efficient and versatile alternative for preparing A-ring-modified naphthoquinonoid compounds with relevant biological profile.

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Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells

Cited by 25 publications

References 75 publications

Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer

Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer

Discovery of the First Human Arylsulfatase A Reversible Inhibitor Impairing Mouse Oocyte Fertilization

Combination of Aryl Diselenides/Hydrogen Peroxide and Carbon‐Nanotube/Rhodium Nanohybrids for Naphthol Oxidation: An Efficient Route towards Trypanocidal Quinones

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