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The mitochondrial disruptor devimistat (CPI-613®) synergizes with genotoxic anticancer drugs in colorectal cancer therapy in a Bim-dependent manner

The mitochondrial disruptor devimistat (CPI-613®) synergizes with genotoxic anticancer drugs in colorectal cancer therapy in a Bim-dependent manner

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ARNOLD, Carina, Philipp DEMUTH, Nina SEIWERT, Simon WITTMANN, Kerstin BOENGLER, Birgit RASENBERGER, Markus CHRISTMANN, Magdalena HUBER, Thomas BRUNNER, Jörg FAHRER, 2022. The mitochondrial disruptor devimistat (CPI-613®) synergizes with genotoxic anticancer drugs in colorectal cancer therapy in a Bim-dependent manner. In: Molecular Cancer Therapeutics. American Association for Cancer Research (AACR). 21(1). ISSN 1535-7163. eISSN 1538-8514. Available under: doi: 10.1158/1535-7163.MCT-21-0393

@article{Arnold2022-01mitoc-55660, title={The mitochondrial disruptor devimistat (CPI-613®) synergizes with genotoxic anticancer drugs in colorectal cancer therapy in a Bim-dependent manner}, year={2022}, doi={10.1158/1535-7163.MCT-21-0393}, number={1}, volume={21}, issn={1535-7163}, journal={Molecular Cancer Therapeutics}, author={Arnold, Carina and Demuth, Philipp and Seiwert, Nina and Wittmann, Simon and Boengler, Kerstin and Rasenberger, Birgit and Christmann, Markus and Huber, Magdalena and Brunner, Thomas and Fahrer, Jörg} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/55660"> <dc:creator>Brunner, Thomas</dc:creator> <dc:contributor>Arnold, Carina</dc:contributor> <dc:contributor>Wittmann, Simon</dc:contributor> <dc:creator>Rasenberger, Birgit</dc:creator> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-11-25T14:03:51Z</dc:date> <dc:language>eng</dc:language> <dc:creator>Wittmann, Simon</dc:creator> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-11-25T14:03:51Z</dcterms:available> <dc:creator>Christmann, Markus</dc:creator> <dc:creator>Fahrer, Jörg</dc:creator> <dcterms:title>The mitochondrial disruptor devimistat (CPI-613®) synergizes with genotoxic anticancer drugs in colorectal cancer therapy in a Bim-dependent manner</dcterms:title> <dc:contributor>Demuth, Philipp</dc:contributor> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:contributor>Brunner, Thomas</dc:contributor> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dcterms:abstract xml:lang="eng">Colorectal cancer (CRC) is one of the most frequent tumor entities, with an increasing incidence and mortality in younger adults in Europe and the US. 5-year survival rates for advanced CRC are still low, highlighting the need for novel targets in CRC therapy. Here, we investigated the therapeutic potential of the compound devimistat (CPI 613®) that targets altered mitochondrial cancer cell metabolism and its synergism with the antineoplastic drugs 5-fluorouracil (5-FU) and irinotecan (IT) in CRC. Devimistat exerted a comparable cytotoxicity in a panel of established CRC cell lines and patient-derived short-term culture independent of their genetic and epigenetic status, whereas human colonic epithelial cells were more resistant indicating tumor selectivity. These findings were corroborated in intestinal organoid and tumoroid models. Mechanistically, devimistat disrupted mitochondrial membrane potential and severely impaired mitochondrial respiration, resulting in CRC cell death induction independent of p53. Combination treatment of devimistat with 5-FU or IT demonstrated synergistic cell killing in CRC cells as shown by Combenefit modelling and Chou-Talalay analysis. Increased cell death induction was revealed as major mechanism involving downregulation of anti-apoptotic genes and accumulation of pro-apoptotic Bim, which was confirmed by its genetic knockdown. In human CRC xenograft mouse models, devimistat showed anti-tumor activity and synergized with IT, resulting in prolonged survival and enhanced therapeutic efficacy. In human tumor xenografts, devimistat prevented IT-triggered p53 stabilization and caused synergistic Bim induction. Taken together, our study revealed devimistat as a promising candidate in CRC therapy by synergizing with established antineoplastic drugs in vitro and in vivo.</dcterms:abstract> <dc:creator>Demuth, Philipp</dc:creator> <dc:contributor>Christmann, Markus</dc:contributor> <dc:creator>Arnold, Carina</dc:creator> <dc:contributor>Rasenberger, Birgit</dc:contributor> <dc:contributor>Huber, Magdalena</dc:contributor> <dc:contributor>Fahrer, Jörg</dc:contributor> <dc:contributor>Boengler, Kerstin</dc:contributor> <dcterms:issued>2022-01</dcterms:issued> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/55660"/> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:creator>Boengler, Kerstin</dc:creator> <dc:rights>terms-of-use</dc:rights> <dc:creator>Huber, Magdalena</dc:creator> <dc:contributor>Seiwert, Nina</dc:contributor> <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/> <dc:creator>Seiwert, Nina</dc:creator> </rdf:Description> </rdf:RDF>

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