Improved Synthesis of ADAM10 Inhibitor GI254023X

Hoettecke, Nicole; Ludwig, Andreas; Foro, Sabine; Schmidt, Boris

doi:10.1159/000267865

Cited by 32 publications

(33 citation statements)

References 22 publications

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“…4E). The involvement of ADAM10 was further confirmed using the specific ADAM10 inhibitor GI254023X (36), which affected MICB release in a dose-dependent manner in both untreated and drugtreated MM cells (Fig. 4F).…”

Section: Adam10 Is Involved In Drug-induced Micb Release From MM Cellsmentioning

confidence: 68%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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Genotoxic stress can promote antitumor NK cell responses by upregulating the surface expression of activating ligands on cancer cells. Moreover, a number of studies suggested a role for soluble NK group 2D ligands in the impairment of NK cell tumor recognition and killing. We investigated whether genotoxic stress could promote the release of NK group 2D ligands (MHC class I-related chain [MIC]A and MICB), as well as the molecular mechanisms underlying this event in human multiple myeloma (MM) cells. Our results show that genotoxic agents used in the therapy of MM (i.e., doxorubicin and melphalan) selectively affect the shedding of MIC molecules that are sensitive to proteolytic cleavage, whereas the release of the short MICA*008 allele, which is frequent in the white population, is not perturbed. In addition, we found that a disintegrin and metalloproteinase 10 expression is upregulated upon chemotherapeutic treatment both in patient-derived CD138(+)/CD38(+) plasma cells and in several MM cell lines, and we demonstrate a crucial role for this sheddase in the proteolytic cleavage of MIC by means of silencing and pharmacological inhibition. Interestingly, the drug-induced upregulation of a disintegrin and metalloproteinase 10 on MM cells is associated with a senescent phenotype and requires generation of reactive oxygen species. Moreover, the combined use of chemotherapeutic drugs and metalloproteinase inhibitors enhances NK cell-mediated recognition of MM cells, preserving MIC molecules on the cell surface and suggesting that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses

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Section: Adam10 Is Involved In Drug-induced Micb Release From MM Cellsmentioning

confidence: 68%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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“…M ␤ CD, zaragozic acid A (ZA), mevalonate, lovastatin, fl uvastatin, and atorvastatin were from Sigma-Aldrich (Germany). The inhibitor GM6001 (broadspectrum metalloproteinase inhibitor) was from Calbiochem and GI254023X (a preferential ADAM10 inhibitor) was a kind gift from B. Schmidt (University Darmstadt, Germany) ( 23 ).…”

Section: Methodsmentioning

confidence: 99%

Statins stimulate the production of a soluble form of the receptor for advanced glycation end products

Quade-Lyssy

Kanarek

Baiersdörfer

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org complications, atherosclerosis, and Alzheimer's disease (AD) ( 1 ). Proteins and peptides like advanced glycation end products (AGEs), amyloid-␤ peptides (A ␤ s), S100/ calgranulin family members, and HMGB1 (amphoterin) have been identifi ed as ligands for RAGE ( 2 ). Diabetes is characterized by a high blood glucose level. This enhanced concentration of glucose is responsible for the nonenzymatic generation of AGEs. AGEs represent a heterogeneous group of proteins, lipids, and nucleic acids resulting from chemical reactions between reducing sugars and amino groups. Studies with animal models have shown that RAGE is the best known target for AGEs in the vasculature and it is well established that the AGE/RAGE interaction contributes to the progression of atherosclerotic plaques ( 3-5 ). Ligand/RAGE interaction induces activation of various pro-infl ammatory and pro-atherogenic mediators, such as the nuclear factor-B (NF-B)-dependent mediators vascular cell adhesion molecule-1, tumor necrosis factor-␣ , interleukin-6, and RAGE ( 6 ). Because RAGE itself is regulated by NF-B, this further increases its expression and promotes cellular dysfunction ( 7 ).Blockade of RAGE by using the soluble form of the receptor ameliorates the vascular complications of diabetes in animal models ( 8-10 ) and suppresses the accumulation of A ␤ s in the brain of an AD mouse model ( 11 ). These benefi cial effects of soluble RAGE are thought to be mediated by trapping ligands, thus preventing ligand binding of membrane-bound RAGE. The circulating soluble form of RAGE containing only the extracellular part of fulllength RAGE, is either produced by alternative splicing The type I transmembrane protein receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, has been shown to play a crucial role in chronic infl ammatory diseases, late diabetic Press, August 21, 2013 DOI 10.1194 Statins stimulate the production of a soluble form of the receptor for advanced glycation end products Abbreviations: A ␤ , amyloid-␤ peptide; AD, Alzheimer's disease; AGE, advanced glycation end product; APP, amyloid precursor protein; esRAGE, endogenous secretory receptor for advanced glycation end products; FCS, fetal calf serum; LDS, lipid-defi cient serum; M ␤ CD, methyl-␤ -cyclodextrin; NF-B, nuclear factor-B; RAGE, receptor for advanced glycation end products; RNAi, RNA interference; siRNA, small interfering RNA; SQS, squalene synthase; sRAGE, shed receptor-the soluble form of the receptor for advanced glycation end products after proteolytic shedding of the full length receptor; ZA, zaragozic acid A . Published, JLR Papers in

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“…1C), indicating that the survival of oocytes was not affected by inhibiting ADAM10. In addition, we cultured ovaries with another ADAM10 selective inhibitor GI254023X (Hoettecke et al, 2010;Hundhausen et al, 2003;Lo Sardo et al, 2012). The results showed that 7 days of GI254023X treatment also significantly decreased the number of follicles (1138.0±184.0 per ovary for GI254023X versus 8188.0±1152.3 per ovary for control; Fig.…”

Section: Suppressing Adam10 Disrupts Germline Cyst Breakdown and Primmentioning

confidence: 88%

ADAM10–Notch signaling governs the recruitment of ovarian pregranulosa cells and controls folliculogenesis in mice

Feng

Wang

Cai

et al. 2016

Journal of Cell Science

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Ovarian follicles are the basic functional units of female reproduction in the mammalian ovary. We show here that the protein a disintegrin and metalloproteinase domain 10 (ADAM10), a cell surface sheddase, plays an indispensable role in controlling primordial follicle formation by regulating the recruitment of follicle supporting cells in mice. We demonstrate that suppressing ADAM10 in vitro or deletion of Adam10 in vivo disrupts germline cyst breakdown and primordial follicle formation. Using a cell lineage tracing approach, we show that ADAM10 governs the recruitment of ovarian follicle cells by regulating the differentiation and proliferation of LGR5-positive follicle supporting progenitor cells. By detecting the development of FOXL2-positive pregranulosa cells, we found that inhibiting ADAM10 reduced the number of FOXL2-positive cells in perinatal ovaries. Furthermore, inhibiting ADAM10 suppressed the activation of Notch signaling, and blocking Notch signaling also disrupted the recruitment of follicle progenitor cells. Taken together, these results show that ADAM10-Notch signaling in ovarian somatic cells governs the primordial follicle formation by controlling the development of ovarian pregranulosa cells. The proper recruitment of ovarian follicle supporting cells is essential for establishment of the ovarian reserve in mice.

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Improved Synthesis of ADAM10 Inhibitor GI254023X

Cited by 32 publications

References 22 publications

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Statins stimulate the production of a soluble form of the receptor for advanced glycation end products

ADAM10–Notch signaling governs the recruitment of ovarian pregranulosa cells and controls folliculogenesis in mice

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