Treatment with plecstatin-1 resulted in disruption of the cytoskeleton and phosphorylation of the stress marker eIF2α, and induction of an immunogenic cell death signature, including calreticulin, high mobility group protein B and extracellular ATP.
The main purpose of this study was to synthesize a new set of naphthoquinone-based ruthenium(II) arene complexes and to develop an understanding of their mode of action. This study systematically reviews the steps of synthesis, aiming to provide a simplified approach using microwave irradiation. The chemical structures and the physicochemical properties of this novel group of compounds were examined by 1H-NMR and 13C-NMR spectroscopy, X-ray diffractometry, HPLC-MS and supporting DFT calculations. Several aspects of the biological activity were investigated in vitro, including short- and long-term cytotoxicity tests, cellular accumulation studies, detection of reactive oxygen species generation, apoptosis induction and NAD(P)H:quinone oxidoreductase 1 (NQO1) activity as well as cell cycle analysis in A549, CH1/PA-1, and SW480 cancer cells. Furthermore, the DNA interaction ability was studied in a cell-free assay. A positive correlation was found between cytotoxicity, lipophilicity and cellular accumulation of the tested complexes, and the results offer some important insights into the effects of the arene. The most obvious finding to emerge from this study is that the usually very chemosensitive CH1/PA-1 teratocarcinoma cells showed resistance to these phthiocol-based organometallics in comparison to the usually less chemosensitive SW480 colon carcinoma cells, which pilot experiments suggest as being related to NQO1 activity.
The impact of different leaving groups on stability and anticancer properties of 15 thiopyridone-based RuII, RhIII or IrIII organometallics has been investigated.
A series of nine
Ru
II
arene complexes bearing tridentate
naphthoquinone-based
N
,
O
,
O
-ligands was synthesized and characterized. Aqueous stability
and their hydrolysis mechanism were investigated via UV/vis photometry,
HPLC-MS, and density functional theory calculations. Substituents
with a positive inductive effect improved their stability at physiological
pH (7.4) intensely, whereas substituents such as halogens accelerated
hydrolysis and formation of dimeric pyrazolate and hydroxido bridged
dimers. The observed cytotoxic profile is unusual, as complexes exhibited
much higher cytotoxicity in SW480 colon cancer cells than in the broadly
chemo- (incl. platinum-) sensitive CH1/PA-1 teratocarcinoma cells.
This activity pattern as well as reduced or slightly enhanced ROS
generation and the lack of DNA interactions indicate a mode of action
different from established or previously investigated classes of metallodrugs.
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