TrxR is an NADPH-dependent selenoenzyme upregulated in a number of cancers. It plays a pivotal role in cancer progression and represents an increasingly attractive target for anticancer drugs. The limitations of cisplatin in cancer treatment have motivated the extensive investigation to other metal complexes, especially ruthenium (Ru) complexes. In this study, we present the in vitro biological evaluation of four Ru(II) polypridyl complexes with diimine ligands, namely, [Ru(bpy)3](2+) (1), [Ru(phen)3](2+) (2), [Ru(ip)3](2+) (3), [Ru(pip)3](2+) (4) (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, ip = imidazole[4,5-f][1,10]phenanthroline, pip = 2-phenylimidazo[4,5-f][1,10]phenanthroline), and demonstrate that they exhibit antiproliferative activities against A375 human melanoma cells through inhibition of TrxR. As the planarity of the structure increases, their TrxR-inhibitory effects and in vitro anticancer activities were enhanced. Among them, complex 4 exhibited higher antiproliferative activity than cisplatin, and the TrxR-inhibitory potency of 4 was more effective than auranofin, a positive TrxR inhibitor. Complex 4 suppressed the cancer cell growth through induction of apoptosis as evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Moreover, complex 4 was able to localize in mitochondria and therein induced ROS-dependent apoptosis by inhibition of TrxR activity. Activation of MAPKs, AKT, DNA damage-mediated p53 phosphorylation and inhibition of VEGFR signaling were also triggered in cells exposed to complex 4. On the basis of this evidence, we suggest that Ru polypyridyl complexes could be developed as TrxR-targeted agents that demonstrate application potentials for treatment of cancers.

Ruthenium (Ru) polypyridyl complexes have emerged as leading players among the potential metal-based candidates for cancer treatment. However, the roles of cellular translocation in their action mechanisms remain elusive. Herein we present the synthesis and characterization of a series of ruthenium (Ru) complexes containing phenanthroline derivatives with varying lipophilicities, and examine their mechanism of anticancer action. Results showed that increasing the lipophilicity of complexes can enhance the rates of cellular uptake. The in vitro anticancer efficacy of these complexes depended on the levels of ROS overproduction, rather than on cellular Ru uptake levels. The introduction of a phenolic group on the ligand effectively enhanced their intracellular ROS generation and anticancer activities. In particular, complex 4, with an ortho-phenolic group on the ligand, exhibited better selectivity between cancer and normal cells in comparison with cisplatin. Notably, complex 4 entered the cancer cells partially through transferrin receptor-mediated endocytosis, and then it translocated from lysosomes to the mitochondria, where it activated mitochondrial dysfunction by regulation of Bcl-2 family proteins, thus leading to intracellular ROS overproduction. Excess ROS amplified apoptotic signals by activating many downstream pathways such as p53 and MAPK pathways to promote cell apoptosis. Overall, this study provides a drug design strategy for discovery of Ru-based apoptosis inducers, and elucidates the intracellular translocation of these complexes.

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Thioredoxin reductase (TrxR) is a selenoenzyme that could regulate intracellular oxidative balance and found to be overexpressed in many human tumor cells. Due to its important role in cancer progression, TrxR is becoming an attractive target in chemotherapeutic drug design. In this study, a new class of Fe(II) complexes with phenanthroline derivatives as ligands were synthesized and characterized. The mechanism of cell death induced by complex 3 revealed that the growth of cancer cells was suppressed by apoptosis and specifically inhibited the activities of TrxR. Furthermore, complex 3 exhibited brilliant antiangiogenic activity against HUVEC cells and inhibited cell migration and invasion. In addition, results of hematological analysis and H&E staining demonstrated that complex 3 has negligible toxicity on function of the major organs of mice. Taken together, this study provides a strategy for drug design to exploit Fe-based phenanthroline derivative as a chemotherapeutic agent in cancer treatment.

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Herein we demonstrated that dinuclear zinc complexes could overcome drug resistance in R-HepG2 drug resistance hepatocellular carcinoma cells through induction of mitochondria-mediated apoptosis or by triggering mitochondria fragmentation, depletion of the membrane potential and intracellular ATP levels.

The effects of selenium species on the Belousov–Zhabotinsky (B–Z) reaction were investigated by adding them to the system before and during oscillation. When selenium species were added into the system before oscillation, sodium selenite prolonged the induction period, whose effect was strong as sodium selenite could consume malonic acid to prohibit the accumulation of bromomalonic acid. For selenomethionine and selenocystine, their effects were derived from their reaction with •CH2COOH and •Br2 – producing a radical cation of selenoamino acids, which prohibited the accumulation of bromomalonic acid. Here, the selenium atoms in selenoamino acids, as reactive centers, took part in the redox reaction. As a result, the induction period was prolonged. However, as a diselenide, selenocystine can reduce bromate in acidic medium, which led to shortening of the induction period. Therefore, the effect of selenocystine on the induction period was the result of two opposite effects. Nanoselenium shortened the induction period in a certain concentration range because bromate was directly reduced by nanoselenium and the accumulation of bromomalonic acid was promoted. Furthermore, the dose perturbation effect was investigated by the injection of nanoselenium during oscillation. It was found that the amplitude was increased or decreased in a dose-dependent fashion when nanoselenium was injected at peak or trough of the time-dependent redox potential curve.

This data article contains complementary figures and results related to the research article entitled, “Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms” [1] (Chen et al., 2015).The characterization of Fe(II) complexes by ESI-MS, 1H NMR, 13C NMR spectroscopy, FT-IR spectra, UV–vis spectra was provided. Also,the data for the stability of Fe(II) complexes 1–5 in DMSO/Milli-Q water/ culture medium (without serum or phenol red) at 37 °C at different periods of time by UV–vis spectra and 1H NMR was showed. At the same time, the anticancer efficacy, cellular distribution and ROS generation in MCF-7 cells of complexes are reported. In addition, we also show the cellular localization of complex 4, the relative fluorescence intensity of complex 1 and complex 3 pretreated with anti-TfR (2 μg/mL) in MCF-7 cells using flow cytometry. The compilation of this data provides an invaluable resource for the wider research community and the interpretation of these data could be found in the research article noted above.