TY  - JOUR
A1  - Scheurer, Mario Joachim Johannes
A1  - Brands, Roman Camillus
A1  - El-Mesery, Mohamed
A1  - Hartmann, Stefan
A1  - Müller-Richter, Urs Dietmar Achim
A1  - Kübler, Alexander Christian
A1  - Seher, Axel
T1  - The selection of NFκB inhibitors to block inflammation and induce sensitisation to FasL-induced apoptosis in HNSCC cell lines is critical for their use as a prospective cancer therapy
JF  - International Journal of Molecular Science
N2  - Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors — Cortisol, MLN4924, QNZ and TPCA1 — on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.
KW  - HNSCC
KW  - NFκB
KW  - inhibitor
KW  - TPCA1
KW  - apoptosis
KW  - inflammation
KW  - TNFα
KW  - FasL
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201524
SN  - 1422-0067
VL  - 20
IS  - 6
ER  - 
TY  - JOUR
A1  - El-Mesery, Mohamed
A1  - Rosenthal, Tina
A1  - Rauert-Wunderlich, Hilka
A1  - Schreder, Martin
A1  - Stühmer, Thorsten
A1  - Leich, Ellen
A1  - Schlosser, Andreas
A1  - Ehrenschwender, Martin
A1  - Wajant, Harald
A1  - Siegmund, Daniela
T1  - The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death
JF  - Cell Death & Disease
N2  - The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.
KW  - cancer therapy
KW  - tumour-necrosis factors
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226666
VL  - 10
ER  - 
TY  - JOUR
A1  - El-Hawary, Seham S.
A1  - Sayed, Ahmed M.
A1  - Mohammed, Rabab
A1  - Hassan, Hossam M.
A1  - Rateb, Mostafa E.
A1  - Amin, Elham
A1  - Mohammed, Tarek A.
A1  - El-Mesery, Mohamed
A1  - Bin Muhsinah, Abdullatif
A1  - Alsayari, Abdulrhman
A1  - Wajant, Harald
A1  - Anany, Mohamed A.
A1  - Abdelmohsen, Usama Ramadan
T1  - Bioactive brominated oxindole alkaloids from the Red Sea sponge Callyspongia siphonella
JF  - Marine Drugs
N2  - In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents.
KW  - Callyspongia siphonella
KW  - LC-HRESIMS
KW  - metabolomic profiling
KW  - oxindole alkaloids
KW  - tisindoline
KW  - antibacterial
KW  - antibiofilm
KW  - antitrypanosomal
KW  - anticancer
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201485
VL  - 17
IS  - 8
ER  -