RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-05

AUTHORS

S Löder, M Fakler, H Schoeneberger, S Cristofanon, J Leibacher, N Vanlangenakker, M J M Bertrand, P Vandenabeele, I Jeremias, K-M Debatin, S Fulda

ABSTRACT

Evasion of apoptosis may contribute to poor treatment response in pediatric acute lymphoblastic leukemia (ALL), calling for novel treatment strategies. Here, we report that inhibitors of apoptosis (IAPs) at subtoxic concentrations cooperate with various anticancer drugs (that is, AraC, Gemcitabine, Cyclophosphamide, Doxorubicin, Etoposide, Vincristine and Taxol) to induce apoptosis in ALL cells in a synergistic manner as calculated by combination index and to reduce long-term clonogenic survival. Importantly, we identify RIP1 as a critical regulator of this synergism of IAP inhibitors and AraC that mediates the formation of a RIP1/FADD/caspase-8 complex via an autocrine/paracrine loop of tumor necrosis factor-α (TNFα). Knockdown of RIP1 abolishes formation of this complex and subsequent activation of caspase-8 and -3, mitochondrial perturbations and apoptosis. Similarly, inhibition of RIP1 kinase activity by Necrostatin-1 or blockage of TNFα by Enbrel inhibits IAP inhibitor- and AraC-triggered interaction of RIP1, FADD and caspase-8 and apoptosis. In contrast to malignant cells, IAP inhibitors and AraC at equimolar concentrations are non-toxic to normal peripheral blood lymphocytes or mesenchymal stromal cells. Thus, our findings provide first evidence that IAP inhibitors present a promising strategy to prime childhood ALL cells for chemotherapy-induced apoptosis in a RIP1-dependent manner. These data have important implications for developing apoptosis-targeted therapies in childhood leukemia. More... »

PAGES

leu2011353

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2011.353

DOI

http://dx.doi.org/10.1038/leu.2011.353

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1049850273

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22173242


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Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

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N-Triples is a line-based linked data format ideal for batch operations.

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Turtle is a human-readable linked data format.

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RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/leu.2011.353'


 

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305 University Children's Hospital, Ulm, Germany
306 rdf:type schema:Organization
 




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