Projekte

First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro

Autor(en)
Debora Wernitznig, Konstantinos Kiakos, Giorgia Del Favero, Nathalie Harrer, Herwig Machat, Annika Osswald, Michael A. Jakupec, Andreas Wernitznig, Wolfgang Sommergruber, Bernhard K. Keppler
Abstrakt

The ruthenium complex sodium trans-[tetrachloridobis(1H-indazole)ruthenate(iii)] (KP1339/IT-139) showed preclinical activity in a variety of in vivo tumor models including a highly predictive colon cancer model. The compound has entered clinical trials, where patients experienced disease stabilization accompanied by mild side effects. KP1339, a GRP78 inhibitor, disrupts endoplasmic reticulum (ER) homeostasis leading to cell death. The PERK/eIF2 alpha-branch of the ER plays an essential role in the cascade of events triggering immunogenic cell death (ICD). ICD makes dying cancer cells 'visible' to the immune system, initiating a prolonged immune response against the tumor. As some metal-based chemotherapeutics such as oxaliplatin are able to induce ICD, we investigate whether KP1339 could also trigger induction of the ICD signature. For this, we employ a three-dimensional colon cancer spheroid model and show for the first time that the treatment with KP1339, a ruthenium-based complex, triggers an ICD signature hallmarked by phosphorylation of PERK and eIF2 alpha, exposure of calreticulin on the cell membrane, release of high mobility group box 1 and secretion of ATP.

Organisation(en)
Institut für Anorganische Chemie, Institut für Lebensmittelchemie und Toxikologie, Department für Mikrobiologie und Ökosystemforschung
Externe Organisation(en)
Boehringer Ingelheim Austria, Research Cluster Translational Cancer Therapy Research
Journal
Metallomics: integrated biometal science
Band
11
Seiten
1044-1048
Anzahl der Seiten
5
ISSN
1756-5901
DOI
https://doi.org/10.1039/c9mt00051h
Publikationsdatum
06-2019
Peer-reviewed
Ja
ÖFOS 2012
Krebsforschung, Anorganische Chemie, Molekularbiologie
Schlagwörter
Link zum Portal
https://ucris.univie.ac.at/portal/de/publications/firstinclass-ruthenium-anticancer-drug-kp1339it139-induces-an-immunogenic-cell-death-signature-in-colorectal-spheroids-in-vitro(e5110f11-9113-4cc9-8f5d-4154adc19ac5).html

Publikationen

First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro

Autor(en)
Debora Wernitznig, Konstantinos Kiakos, Giorgia Del Favero, Nathalie Harrer, Herwig Machat, Annika Osswald, Michael A. Jakupec, Andreas Wernitznig, Wolfgang Sommergruber, Bernhard K. Keppler
Abstrakt

The ruthenium complex sodium trans-[tetrachloridobis(1H-indazole)ruthenate(iii)] (KP1339/IT-139) showed preclinical activity in a variety of in vivo tumor models including a highly predictive colon cancer model. The compound has entered clinical trials, where patients experienced disease stabilization accompanied by mild side effects. KP1339, a GRP78 inhibitor, disrupts endoplasmic reticulum (ER) homeostasis leading to cell death. The PERK/eIF2 alpha-branch of the ER plays an essential role in the cascade of events triggering immunogenic cell death (ICD). ICD makes dying cancer cells 'visible' to the immune system, initiating a prolonged immune response against the tumor. As some metal-based chemotherapeutics such as oxaliplatin are able to induce ICD, we investigate whether KP1339 could also trigger induction of the ICD signature. For this, we employ a three-dimensional colon cancer spheroid model and show for the first time that the treatment with KP1339, a ruthenium-based complex, triggers an ICD signature hallmarked by phosphorylation of PERK and eIF2 alpha, exposure of calreticulin on the cell membrane, release of high mobility group box 1 and secretion of ATP.

Organisation(en)
Institut für Anorganische Chemie, Institut für Lebensmittelchemie und Toxikologie, Department für Mikrobiologie und Ökosystemforschung
Externe Organisation(en)
Boehringer Ingelheim Austria, Research Cluster Translational Cancer Therapy Research
Journal
Metallomics: integrated biometal science
Band
11
Seiten
1044-1048
Anzahl der Seiten
5
ISSN
1756-5901
DOI
https://doi.org/10.1039/c9mt00051h
Publikationsdatum
06-2019
Peer-reviewed
Ja
ÖFOS 2012
Krebsforschung, Anorganische Chemie, Molekularbiologie
Schlagwörter
Link zum Portal
https://ucris.univie.ac.at/portal/de/publications/firstinclass-ruthenium-anticancer-drug-kp1339it139-induces-an-immunogenic-cell-death-signature-in-colorectal-spheroids-in-vitro(e5110f11-9113-4cc9-8f5d-4154adc19ac5).html

Vortraege

First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro

Autor(en)
Debora Wernitznig, Konstantinos Kiakos, Giorgia Del Favero, Nathalie Harrer, Herwig Machat, Annika Osswald, Michael A. Jakupec, Andreas Wernitznig, Wolfgang Sommergruber, Bernhard K. Keppler
Abstrakt

The ruthenium complex sodium trans-[tetrachloridobis(1H-indazole)ruthenate(iii)] (KP1339/IT-139) showed preclinical activity in a variety of in vivo tumor models including a highly predictive colon cancer model. The compound has entered clinical trials, where patients experienced disease stabilization accompanied by mild side effects. KP1339, a GRP78 inhibitor, disrupts endoplasmic reticulum (ER) homeostasis leading to cell death. The PERK/eIF2 alpha-branch of the ER plays an essential role in the cascade of events triggering immunogenic cell death (ICD). ICD makes dying cancer cells 'visible' to the immune system, initiating a prolonged immune response against the tumor. As some metal-based chemotherapeutics such as oxaliplatin are able to induce ICD, we investigate whether KP1339 could also trigger induction of the ICD signature. For this, we employ a three-dimensional colon cancer spheroid model and show for the first time that the treatment with KP1339, a ruthenium-based complex, triggers an ICD signature hallmarked by phosphorylation of PERK and eIF2 alpha, exposure of calreticulin on the cell membrane, release of high mobility group box 1 and secretion of ATP.

Organisation(en)
Institut für Anorganische Chemie, Institut für Lebensmittelchemie und Toxikologie, Department für Mikrobiologie und Ökosystemforschung
Externe Organisation(en)
Boehringer Ingelheim Austria, Research Cluster Translational Cancer Therapy Research
Journal
Metallomics: integrated biometal science
Band
11
Seiten
1044-1048
Anzahl der Seiten
5
ISSN
1756-5901
DOI
https://doi.org/10.1039/c9mt00051h
Publikationsdatum
06-2019
Peer-reviewed
Ja
ÖFOS 2012
Krebsforschung, Anorganische Chemie, Molekularbiologie
Schlagwörter
Link zum Portal
https://ucris.univie.ac.at/portal/de/publications/firstinclass-ruthenium-anticancer-drug-kp1339it139-induces-an-immunogenic-cell-death-signature-in-colorectal-spheroids-in-vitro(e5110f11-9113-4cc9-8f5d-4154adc19ac5).html