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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-016-0337-8) contains supplementary material, which is available to authorized users.
Highlights
The idea of ruthenium-based cancer chemotherapy is fueled by the facts that some ruthenium compounds accumulate preferably in tumor tissue, ruthenium has, compared to platinum(II), additional coordination sites, and a variety of ruthenium complexes show redox behavior under physiological conditions
It was shown previously that NKP-1339 reacts fast with the protein albumin [16], which is the most abundant protein in human serum with a concentration of about 600 μM [17] and contained in FCS used for cell culture as well
Albumin is accumulated in tumor tissue based on the enhanced permeability and retention (EPR) effect, which, is not reflected in cell culture settings
Summary
The idea of ruthenium-based cancer chemotherapy is fueled by the facts that some ruthenium compounds accumulate preferably in tumor tissue, ruthenium has, compared to platinum(II), additional coordination sites, and a variety of ruthenium complexes show redox behavior under physiological conditions. Three ruthenium-based compounds have been investigated in clinical studies recently, namely NAMI-A, KP1019 and NKP-1339. KP1019 and NKP-1339 bind to transferrin and albumin very fast, whereby adduct formation with albumin is preferred to transferrin [3, 4], and can thereby take advantage of drug delivery by the enhanced permeability and retention (EPR) effect. The EPR effect leads to enhanced accumulation of macromolecules (> 40 kDa), such as albumin, in solid tumors, where they are retained for many hours due to a lack of efficient lymphatic drainage [5]. The serum concentration was shown to have a significant impact on the P-glycoprotein-modulating
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