Molecular mode of action of NKP-1339 - a clinically investigated ruthenium-based drug - involves ER- and ROS-related effects in colon carcinoma cell lines.

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.

• Authors: Lea S Flocke, Robert Trondl, Michael A Jakupec, Bernhard K Keppler
• Journal: Investigational new drugs (Invest New Drugs) Vol. 34 Issue 3 Pg. 261-8 (06 2016) ISSN: 1573-0646 [Electronic] United States
• PMID: 26988975 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• DDIT3 protein, human
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heat-Shock Proteins
• Reactive Oxygen Species
• Transcription Factor CHOP
• NKP-1339

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, pathology)
• Coordination Complexes (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Down-Regulation
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Heat-Shock Proteins (genetics)
• Humans
• Reactive Oxygen Species (metabolism)
• Time Factors
• Transcription Factor CHOP (metabolism)