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Chirumamilla, C.S.; Palagani, A.; Kamaraj, B.; Declerck, K.; Verbeek, M.W.C.; Ryabtsova, O.; De Bosscher, K.; Bougarne, N.; Ruttens, B.; Gevaert, K.; Houtman, R.; De Vos, W.H.; Joossens, J.; van der Veken, P.; Augustyns, K.; van Ostade, X.; Bogaerts, A.; De Winter, H.; Vanden Berghe, W. |
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Title |
Selective glucocorticoid receptor properties of GSK866 analogs with cysteine reactive warheads |
Type |
Administrative Services |
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Year |
2017 |
Publication |
Frontiers in immunology |
Abbreviated Journal |
Front Immunol |
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Volume |
8 |
Issue |
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Pages |
1324 |
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Keywords |
Administrative Services; A1 Journal article; Pharmacology. Therapy; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Medicinal Chemistry (UAMC) |
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Abstract |
Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). In the current study, GSK866 analogs with electrophilic covalent-binding warheads were developed with potential SEGRA properties to improve their clinical safety profile for long-lasting topical skin disease applications. Since the off-rate of a covalently binding drug is negligible compared to that of a non-covalent drug, its therapeutic effects can be prolonged and typically, smaller doses of the drug are necessary to reach the same level of therapeutic efficacy, thereby potentially reducing systemic side effects. Different analogs of SEGRA GSK866 coupled to cysteine reactive warheads were characterized for GR potency and selectivity in various biochemical and cellular assays. GR- and NFκB-dependent reporter gene studies show favorable anti-inflammatory properties with reduced GR transactivation of two non-steroidal GSK866 analogs UAMC-1217 and UAMC-1218, whereas UAMC-1158 and UAMC-1159 compounds failed to modulate cellular GR activity. These results were further supported by GR immuno-localization and S211 phospho-GR western analysis, illustrating significant GR phosphoactivation and nuclear translocation upon treatment of GSK866, UAMC-1217, or UAMC-1218, but not in case of UAMC-1158 or UAMC-1159. Furthermore, mass spectrometry analysis of tryptic peptides of recombinant GR ligand-binding domain (LBD) bound to UAMC-1217 or UAMC-1218 confirmed covalent cysteine-dependent GR binding. Finally, molecular dynamics simulations, as well as glucocorticoid receptor ligand-binding domain (GR-LBD) coregulator interaction profiling of the GR-LBD bound to GSK866 or its covalently binding analogs UAMC-1217 or UAMC-1218 revealed subtle conformational differences that might underlie their SEGRA properties. Altogether, GSK866 analogs UAMC-1217 and UAMC-1218 hold promise as a novel class of covalent-binding SEGRA ligands for the treatment of topical inflammatory skin disorders. |
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Place of publication unknown |
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Wos |
000414136300001 |
Publication Date |
2017-11-01 |
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Edition |
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ISSN |
1664-3224 |
ISBN |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
6.429 |
Times cited |
2 |
Open Access  |
OpenAccess |
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Notes |
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Approved |
Most recent IF: 6.429 |
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Call Number |
UA @ lucian @ c:irua:146485 |
Serial |
4750 |
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Author |
De Backer, J.; Maric, D.; Zuhra, K.; Bogaerts, A.; Szabo, C.; Vanden Berghe, W.; Hoogewijs, D. |
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Title |
Cytoglobin Silencing Promotes Melanoma Malignancy but Sensitizes for Ferroptosis and Pyroptosis Therapy Response |
Type |
A1 Journal article |
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Year |
2022 |
Publication |
Antioxidants |
Abbreviated Journal |
Antioxidants |
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Volume |
11 |
Issue |
8 |
Pages |
1548 |
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Keywords |
A1 Journal article; Pharmacology. Therapy; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Proteinscience, proteomics and epigenetic signaling (PPES) |
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Abstract |
Despite recent advances in melanoma treatment, there are still patients that either do not respond or develop resistance. This unresponsiveness and/or acquired resistance to therapy could be explained by the fact that some melanoma cells reside in a dedifferentiated state. Interestingly, this dedifferentiated state is associated with greater sensitivity to ferroptosis, a lipid peroxidation-reliant, iron-dependent form of cell death. Cytoglobin (CYGB) is an iron hexacoordinated globin that is highly enriched in melanocytes and frequently downregulated during melanomagenesis. In this study, we investigated the potential effect of CYGB on the cellular sensitivity towards (1S, 3R)-RAS-selective lethal small molecule (RSL3)-mediated ferroptosis in the G361 melanoma cells with abundant endogenous expression. Our findings show that an increased basal ROS level and higher degree of lipid peroxidation upon RSL3 treatment contribute to the increased sensitivity of CYGB knockdown G361 cells to ferroptosis. Furthermore, transcriptome analysis demonstrates the enrichment of multiple cancer malignancy pathways upon CYGB knockdown, supporting a tumor-suppressive role for CYGB. Remarkably, CYGB knockdown also triggers activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and subsequent induction of pyroptosis target genes. Altogether, we show that silencing of CYGB expression modulates cancer therapy sensitivity via regulation of ferroptosis and pyroptosis cell death signaling pathways. |
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Wos |
000846411000001 |
Publication Date |
2022-08-10 |
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Series Volume |
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Series Issue |
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Edition |
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ISSN |
2076-3921 |
ISBN |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
7 |
Times cited |
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Open Access |
OpenAccess |
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Notes |
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Most recent IF: 7 |
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Call Number |
PLASMANT @ plasmant @c:irua:190686 |
Serial |
7102 |
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Author |
Biscop, E.; Baroen, J.; De Backer, J.; Vanden Berghe, W.; Smits, E.; Bogaerts, A.; Lin, A. |
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Title |
Characterization of regulated cancer cell death pathways induced by the different modalities of non-thermal plasma treatment |
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A1 Journal Article |
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Year |
2024 |
Publication |
Cell Death Discovery |
Abbreviated Journal |
Cell Death Discov. |
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Volume |
10 |
Issue |
1 |
Pages |
416 |
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Keywords |
A1 Journal Article; Plasma, laser ablation and surface modeling Antwerp (PLASMANT) ; |
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Abstract |
Non-thermal plasma (NTP) has shown promising anti-cancer effects, but there is still limited knowledge about the underlying cell death mechanisms induced by NTP and inherent differences between NTP treatment modalities. This study aimed to investigate four major regulated cell death (RCD) pathways, namely apoptosis, pyroptosis, necroptosis, and ferroptosis, in melanoma cancer cells following NTP treatment, and to provide an overview of molecular mechanistic differences between direct and indirect NTP treatment modalities. To discriminate which cell death pathways were triggered after treatment, specific inhibitors of apoptosis, pyroptosis, necroptosis, and ferroptosis were evaluated. RCD-specific molecular pathways were further investigated to validate the findings with inhibitors. Both direct and indirect NTP treatment increased caspase 3/7 and annexin V expression, indicative of apoptosis, as well as lipid peroxidation, characteristic of ferroptosis. Pyroptosis, on the other hand, was only induced by direct NTP treatment, evidenced by increased caspase 1 activity, whereas necroptosis was stimulated in a cell line-dependent manner. These findings highlight the molecular differences and implications of direct and indirect NTP treatment for cancer therapy. Altogether, activation of multiple cell death pathways offers advantages in minimizing treatment resistance and enhancing therapeutic efficacy, particularly in a combination setting. Understanding the mechanisms underlying NTP-induced RCD will enable the development of strategic combination therapies targeting multiple pathways to achieve cancer lethality. |
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Wos |
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Publication Date |
2024-09-30 |
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ISSN |
2058-7716 |
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Notes |
This work was partially funded by the Research Foundation—Flanders (FWO) and supported by the following Grants: 12S9221N (AL), G044420N (AL and AB), and G033020N (AB). We would also like to acknowledge the help of Iuliia Efimova and Prof. Dmitri Krysko (Cell Death Investigation and Therapy Laboratory, Ghent University), where discussions and optimization for these experiments started, but unfortunately and abruptly halted due to the COVID pandemic. Still we appreciate their valuable discussions. Figure 6 was made in BioRender. We would also like to acknowledge the support from the European Cooperation in Science & Technology (COST) Action on “Therapeutical applications of Cold Plasmas” (CA20114; PlasTHER). |
Approved |
Most recent IF: NA |
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Call Number |
PLASMANT @ plasmant @ |
Serial |
9329 |
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