Issue 6, 2019

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

Abstract

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/eIF2α-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 eIF2α, exposure of calreticulin on the cell membrane, release of high mobility group box 1 and secretion of ATP.

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

Supplementary files

Article information

Article type
Communication
Submitted
06 Mar 2019
Accepted
26 Mar 2019
First published
03 Apr 2019
This article is Open Access
Creative Commons BY-NC license

Metallomics, 2019,11, 1044-1048

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