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Article ; Online: Mitochondrial apoptosis: facilitator of NK cell-mediated immunotherapy.

Ullrich, Evelyn / Vogler, Meike / von Metzler, Ivana

Signal transduction and targeted therapy

2022 Volume 7, Issue 1, Page(s) 291

MeSH term(s)	Apoptosis/genetics ; Immunotherapy ; Killer Cells, Natural
Language	English
Publishing date	2022-08-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2886872-9
ISSN	2059-3635 ; 2095-9907
ISSN (online)	2059-3635
ISSN	2095-9907
DOI	10.1038/s41392-022-01126-4
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Article ; Online: It's time to die: BH3 mimetics in solid tumors.

Kehr, Sarah / Vogler, Meike

Biochimica et biophysica acta. Molecular cell research

2021 Volume 1868, Issue 5, Page(s) 118987

Abstract: The removal of cells by apoptosis is an essential process regulating tissue homeostasis. Cancer cells acquire the ability to circumvent apoptosis and survive in an unphysiological tissue context. Thereby, the Bcl-2 protein family plays a key role in the ... ...

Abstract	The removal of cells by apoptosis is an essential process regulating tissue homeostasis. Cancer cells acquire the ability to circumvent apoptosis and survive in an unphysiological tissue context. Thereby, the Bcl-2 protein family plays a key role in the initiation of apoptosis, and overexpression of the anti-apoptotic Bcl-2 proteins is one of the molecular mechanisms protecting cancer cells from apoptosis. Recently, small molecules targeting the anti-apoptotic Bcl-2 family proteins have been identified, and with venetoclax the first of these BH3 mimetics has been approved for the treatment of leukemia. In solid tumors the anti-apoptotic Bcl-2 family proteins Mcl-1 and Bcl-xL are frequently overexpressed or genetically amplified. In this review, we summarize the role of Mcl-1 and Bcl-xL in solid tumors and compare the different BH3 mimetics targeting Mcl-1 or Bcl-xL.
MeSH term(s)	Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Gene Amplification ; Gene Expression Regulation, Neoplastic ; Humans ; Molecular Mimicry ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Neoplasms/drug therapy ; Neoplasms/genetics ; Protein Domains ; Small Molecule Libraries/pharmacology ; Small Molecule Libraries/therapeutic use ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; Up-Regulation ; bcl-X Protein/antagonists & inhibitors ; bcl-X Protein/genetics
Chemical Substances	BCL2L1 protein, human ; Bridged Bicyclo Compounds, Heterocyclic ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; Small Molecule Libraries ; Sulfonamides ; bcl-X Protein ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2021-02-15
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2021.118987
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Book ; Online ; Thesis: Molecular dissection of BV6 induced sensitization of rhabdomyosarcoma spheroids towards NK cell attack

Särchen, Vinzenz [Verfasser] / Fürst, Robert [Gutachter] / Vogler, Meike [Gutachter]

2022

Author's details	Vinzenz Särchen ; Gutachter: Robert Fürst, Meike Vogler
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universitätsbibliothek Johann Christian Senckenberg
Publishing place	Frankfurt am Main
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article: Targeting BCL2-Proteins for the Treatment of Solid Tumours.

Vogler, Meike

Advances in medicine

2014 Volume 2014, Page(s) 943648

Abstract: Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, BCL-XL, BCL-w, ...

Abstract	Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, BCL-XL, BCL-w, and MCL1. While early clinical trials in haematological malignancies demonstrated exciting single-agent activity of BCL2-inhibitors, the response in solid tumours was limited, indicating that, in solid tumours, different strategies have to be developed in order to successfully treat patients with BCL2-inhibitors. In this review, the function of the different antiapoptotic BCL2-proteins and their role in solid tumours will be discussed. In addition, a comprehensive analysis of current small molecules targeting these antiapoptotic BCL2-proteins (e.g., ABT-737, ABT-263, ABT-199, TW-37, sabutoclax, obatoclax, and MIM1) will be provided including a discussion of the results of any clinical trials. This analysis will summarise the potential of BCL2-inhibitors for the treatment of solid tumours and will unravel novel approaches to utilise these inhibitors in clinical applications.
Language	English
Publishing date	2014-08-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2776733-4
ISSN	2314-758X ; 2356-6752
ISSN (online)	2314-758X
ISSN	2356-6752
DOI	10.1155/2014/943648
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Article ; Online: Targeting BCL2-Proteins for the Treatment of Solid Tumours

Meike Vogler

Advances in Medicine, Vol

2014 Volume 2014

Abstract	Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, BCL-XL, BCL-w, and MCL1. While early clinical trials in haematological malignancies demonstrated exciting single-agent activity of BCL2-inhibitors, the response in solid tumours was limited, indicating that, in solid tumours, different strategies have to be developed in order to successfully treat patients with BCL2-inhibitors. In this review, the function of the different antiapoptotic BCL2-proteins and their role in solid tumours will be discussed. In addition, a comprehensive analysis of current small molecules targeting these antiapoptotic BCL2-proteins (e.g., ABT-737, ABT-263, ABT-199, TW-37, sabutoclax, obatoclax, and MIM1) will be provided including a discussion of the results of any clinical trials. This analysis will summarise the potential of BCL2-inhibitors for the treatment of solid tumours and will unravel novel approaches to utilise these inhibitors in clinical applications.
Keywords	Medicine ; R
Subject code	610
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
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Article ; Online: A direct comparison of selective BH3-mimetics reveals BCL-X

Bierbrauer, Annika / Jacob, Maureen / Vogler, Meike / Fulda, Simone

British journal of cancer

2020 Volume 122, Issue 10, Page(s) 1544–1551

Abstract: Background: Despite advances in the treatment of neuroblastoma, patients with high-risk disease still have dismal survival prognosis. Neuroblastoma cells display elevated expression of the antiapoptotic BCL-2 proteins, suggesting that BH3-mimetics may ... ...

Abstract	Background: Despite advances in the treatment of neuroblastoma, patients with high-risk disease still have dismal survival prognosis. Neuroblastoma cells display elevated expression of the antiapoptotic BCL-2 proteins, suggesting that BH3-mimetics may be a promising treatment option. Here, we investigated the role of BCL-2, BCL-X Methods: A panel of neuroblastoma cell lines and primary patient-derived cells were exposed to BH3-mimetics targeting BCL-2 (ABT-199), BCL-X Results: All tested BH3-mimetics were able to induce apoptosis in neuroblastoma cell lines, indicating that not only BCL-2 but also BCL-X Conclusions: By using selective BH3-mimetics, this study demonstrates that BCL-2, BCL-X
MeSH term(s)	Apoptosis/drug effects ; Bcl-2-Like Protein 11/genetics ; Biomimetics ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Neuroblastoma/drug therapy ; Neuroblastoma/genetics ; Neuroblastoma/pathology ; Peptide Fragments/pharmacology ; Proto-Oncogene Proteins/pharmacology ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/genetics ; Pyrimidines/pharmacology ; Sulfonamides/pharmacology ; Thiophenes/pharmacology ; bcl-2 Homologous Antagonist-Killer Protein/genetics ; bcl-X Protein/genetics
Chemical Substances	BAK1 protein, human ; BCL2 protein, human ; Bax protein (53-86) ; Bcl-2-Like Protein 11 ; Bridged Bicyclo Compounds, Heterocyclic ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; Peptide Fragments ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Pyrimidines ; S63845 ; Sulfonamides ; Thiophenes ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-X Protein ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2020-03-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-020-0795-9
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Article ; Online: Characterization of BV6-Induced Sensitization to the NK Cell Killing of Pediatric Rhabdomyosarcoma Spheroids.

Särchen, Vinzenz / Reindl, Lisa Marie / Wiedemann, Sara / Shanmugalingam, Senthan / Bukur, Thomas / Becker, Julia / Suchan, Martin / Ullrich, Evelyn / Vogler, Meike

Cells

2023 Volume 12, Issue 6

Abstract: Although the overall survival in pediatric rhabdomyosarcoma (RMS) has increased over the last decades, the most aggressive subtype of alveolar RMS is in dire need of novel treatment strategies. RMS cells evade cell death induction and immune control by ... ...

Abstract	Although the overall survival in pediatric rhabdomyosarcoma (RMS) has increased over the last decades, the most aggressive subtype of alveolar RMS is in dire need of novel treatment strategies. RMS cells evade cell death induction and immune control by increasing the expression of inhibitors of apoptosis proteins (IAPs), which can be exploited and targeted with stimulation with Smac mimetics. Here, we used the Smac mimetic BV6 to re-sensitize RMS spheroids to cell death, which increased killing induced by natural killer (NK) cells. Single BV6 treatment of RMS spheroids did not reduce spheroidal growth. However, we observed significant spheroidal decomposition upon BV6 pre-treatment combined with NK cell co-cultivation. Molecularly, IAPs s are rapidly degraded by BV6, which activates NF-κB signal transduction pathways in RMS spheroids. RNA sequencing analysis validated NF-κB activation and identified a plethora of BV6-regulated genes. Additionally, BV6 released caspases from IAP-mediated inhibition. Here, caspase-8 might play a major role, as knockdown experiments resulted in decreased NK cell-mediated attack. Taken together, we improved the understanding of the BV6 mechanism of RMS spheroid sensitization to cytotoxic immune cells, which could be suitable for the development of novel combinatory cellular immunotherapy with Smac mimetics.
MeSH term(s)	Child ; Humans ; Apoptosis/physiology ; NF-kappa B/metabolism ; Apoptosis Regulatory Proteins ; Cell Death ; Killer Cells, Natural/metabolism ; Rhabdomyosarcoma
Chemical Substances	NF-kappa B ; Apoptosis Regulatory Proteins
Language	English
Publishing date	2023-03-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12060906
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Article ; Online: Computational modeling of DLBCL predicts response to BH3-mimetics.

Cloete, Ielyaas / Smith, Victoria M / Jackson, Ross A / Pepper, Andrea / Pepper, Chris / Vogler, Meike / Dyer, Martin J S / Mitchell, Simon

NPJ systems biology and applications

2023 Volume 9, Issue 1, Page(s) 23

Abstract: In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. ... ...

Abstract	In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphoma (DLBCL) likely contributes to variability in response to BH3-mimetics. Successful deployment of BH3-mimetics in DLBCL requires reliable predictions of which lymphoma cells will respond. Here we show that a computational systems biology approach enables accurate prediction of the sensitivity of DLBCL cells to BH3-mimetics. We found that fractional killing of DLBCL, can be explained by cell-to-cell variability in the molecular abundances of signaling proteins. Importantly, by combining protein interaction data with a knowledge of genetic lesions in DLBCL cells, our in silico models accurately predict in vitro response to BH3-mimetics. Furthermore, through virtual DLBCL cells we predict synergistic combinations of BH3-mimetics, which we then experimentally validated. These results show that computational systems biology models of apoptotic signaling, when constrained by experimental data, can facilitate the rational assignment of efficacious targeted inhibitors in B cell malignancies, paving the way for development of more personalized approaches to treatment.
MeSH term(s)	Humans ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Apoptosis ; Computer Simulation ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/pathology
Chemical Substances	Proto-Oncogene Proteins c-bcl-2 ; Apoptosis Regulatory Proteins
Language	English
Publishing date	2023-06-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2056-7189
ISSN (online)	2056-7189
DOI	10.1038/s41540-023-00286-5
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Article ; Online: Identification of a novel form of caspase-independent cell death triggered by BH3-mimetics in diffuse large B-cell lymphoma cell lines.

Yildirim, Nahide / Sarojam, Lakshmi / Smith, Victoria M / Pieper, Nadja M / Anders, Marius / Jackson, Ross A / Fuhrmann, Dominik C / Särchen, Vinzenz / Brücher, Daniela / Weigert, Andreas / Dyer, Martin J S / Vogler, Meike

Cell death & disease

2024 Volume 15, Issue 4, Page(s) 266

Abstract: BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro- ... ...

Abstract	BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro-apoptotic binding partners thus inducing BAX/BAK-mediated mitochondrial permeabilization followed by cytochrome c release, activation of the caspase cascade and apoptosis. Here, we describe a novel mode of caspase-independent cell death (CICD) induced by BH3-mimetics in a subset of diffuse large B-cell lymphoma (DLBCL) cells. Of note, rather than occurring via necroptosis, CICD induced immediately after mitochondrial permeabilization was associated with transcriptional reprogramming mediated by activation of c-Jun N-terminal Kinase (JNK) signaling and Activator Protein 1 (AP1). Thereby, CICD resulted in the JNK/AP1-mediated upregulation of inflammatory chemokines and increased migration of cytotoxic Natural Killer (NK) cells. Taken together, our study describes a novel mode of CICD triggered by BH3-mimetics that may alter the immune response towards dying cells.
MeSH term(s)	Humans ; bcl-2-Associated X Protein/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; Apoptosis ; Antineoplastic Agents/pharmacology ; Caspases ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Cell Line ; Proto-Oncogene Proteins c-bcl-2/metabolism
Chemical Substances	bcl-2-Associated X Protein ; bcl-2 Homologous Antagonist-Killer Protein ; Antineoplastic Agents ; Caspases (EC 3.4.22.-) ; Proto-Oncogene Proteins c-bcl-2
Language	English
Publishing date	2024-04-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-024-06652-3
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Article ; Online: Characterization of BV6-Induced Sensitization to the NK Cell Killing of Pediatric Rhabdomyosarcoma Spheroids

Vinzenz Särchen / Lisa Marie Reindl / Sara Wiedemann / Senthan Shanmugalingam / Thomas Bukur / Julia Becker / Martin Suchan / Evelyn Ullrich / Meike Vogler

Cells, Vol 12, Iss 906, p

2023 Volume 906

Abstract	Although the overall survival in pediatric rhabdomyosarcoma (RMS) has increased over the last decades, the most aggressive subtype of alveolar RMS is in dire need of novel treatment strategies. RMS cells evade cell death induction and immune control by increasing the expression of inhibitors of apoptosis proteins (IAPs), which can be exploited and targeted with stimulation with Smac mimetics. Here, we used the Smac mimetic BV6 to re-sensitize RMS spheroids to cell death, which increased killing induced by natural killer (NK) cells. Single BV6 treatment of RMS spheroids did not reduce spheroidal growth. However, we observed significant spheroidal decomposition upon BV6 pre-treatment combined with NK cell co-cultivation. Molecularly, IAPs s are rapidly degraded by BV6, which activates NF-κB signal transduction pathways in RMS spheroids. RNA sequencing analysis validated NF-κB activation and identified a plethora of BV6-regulated genes. Additionally, BV6 released caspases from IAP-mediated inhibition. Here, caspase-8 might play a major role, as knockdown experiments resulted in decreased NK cell-mediated attack. Taken together, we improved the understanding of the BV6 mechanism of RMS spheroid sensitization to cytotoxic immune cells, which could be suitable for the development of novel combinatory cellular immunotherapy with Smac mimetics.
Keywords	NK cells ; Smac mimetic ; BV6 ; cell death ; rhabdomyosarcoma ; tumor spheroids ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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