Programmed cell death

Cell biology

Biotechnology

Biology

Colorectal cancer

Apoptosis

Cancer research

Biochemistry

Endoplasmic reticulum

Unfolded protein response

In vivo

Immunogenic cell death

Internal medicine

Medicine

Chemistry

Calreticulin

Cancer

Cancer cell

Metallomics

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.

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

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