Molecular mode of action of NKP-1339-a clinically investigated ruthenium-based drug - involves ER- and ROS-related effects in colon carcinoma cell lines
- Author(s)
- Lea S. Flocke, Robert Trondl, Michael A. Jakupec, Bernhard K. Keppler
- Abstract
Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) is a clinically investigated ruthenium-based metal complex, which shows promising results in solid tumors, such as non-small cell lung cancer, colorectal carcinoma, and most distinctively in gastrointestinal neuroendocrine tumors. In previous studies, fast binding to albumin as well as transferrin could be shown. The enhanced permeability and retention (EPR) effect, which is diversely being exploited for tumor targeting, could therefore be applicable for NKP-1339. Here we studied the serum dependence of its biological activity in various methods, influencing its cellular accumulation, cytotoxicity as well as the generation of reactive oxygen species (ROS). ROS lead to Nrf2 activation, which is known to activate antioxidant response gene transcription. GRP78 down-regulation on the protein level suggests ER associated protein degradation (ERAD) as a mode of action, as RNA levels are only mildly affected. Another important part for the mode of action is endoplasmic reticulum (ER) stress, as different factors are highly upregulated on the protein level. For example PERK, a transmembrane receptor which is released by GRP78 when the ER is disturbed, is upregulated and phosphorylated. EIF2α is phosphorylated, which leads to an inhibition of CAP-dependent translation and other stress responses. The transcription factor CHOP (DDIT3), which promotes ER stress dependent apoptosis, is time and concentration dependently upregulated. Finally cytotoxicity tests could prove that inhibition of ER stress and ER stress-mediated apoptosis leads to decreased cytotoxic effects of NKP-1339, which highlights the involvement of this mechanism in the mode of action.
- Organisation(s)
- Department of Inorganic Chemistry
- Journal
- Investigational New Drugs: the journal of new anti-cancer agents
- Volume
- 34
- Pages
- 261-268
- No. of pages
- 8
- ISSN
- 0167-6997
- DOI
- https://doi.org/10.1007/s10637-016-0337-8
- Publication date
- 06-2016
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301209 Pharmacy, 301206 Pharmacology, 302055 Oncology
- Keywords
- ASJC Scopus subject areas
- Pharmacology (medical), Oncology, Pharmacology
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/c88d51c9-84d9-4191-a4d2-45446d431d25