Wedelactone (WL), a plant polyphenolic derivative of coumestan, represents a promising anti-cancer agent. The underlying mechanisms of its action are not fully understood and appear to involve interplay with copper ions. Herein, we examined coordination and redox interactions of WL with Cu in phosphate buffer (pH 7), and in two breast cancer cell lines. EPR, UV-Vis and fluorescence spectroscopy showed that WL and Cu build a coordination complex with 2 : 1 stoichiometry and distorted tetrahedral geometry. WL showed strong fluorescence that was quenched by Cu. The sequestration of the intracellular copper pool with neocuproine led to a significant drop in the cytotoxic effects of WL, whereas the co-application of Cu and WL and the formation of an extracellular complex suppressed both the cytotoxic effects of WL and copper loading. Fluorescence microscopy showed that WL is mainly localized in the cytosol and significantly less in the nuclei. WL fluorescence was stronger in cells pretreated with neocuproine, implying that the complex of WL and Cu is formed inside the cells. WL caused a two-fold increase in the lysosomal level of copper as well as copper-dependent lysosome membrane permeabilization. On the other hand, the protective effects of overexpression of thioredoxin 1 imply that WL exerts the main oxidative impact inside the nucleus. The interactions of WL with copper may be essential for therapeutic performance and selectivity against cancer cells, taking into account that a number of cancer types, including breast cancer, exhibit increased intratumoral copper levels or altered copper distribution.
Microalgae have evolved mechanisms to respond to changes in copper ion availability, which are very important for normal cellular function, to tolerate metal pollution of aquatic ecosystems, and for modulation of copper bioavailability and toxicity to other organisms. Knowledge and application of these mechanisms will benefit the use of microalgae in wastewater processing and biomass production, and the use of copper compounds in the suppression of harmful algal blooms. Here, using electron microscopy, synchrotron radiation-based Fourier transform infrared spectroscopy, electron paramagnetic resonance spectroscopy, and X-ray absorption fine structure spectroscopy, we show that the microalga Chlorella sorokiniana responds promptly to Cu2+ at high non-toxic concentration, by mucilage release, alterations in the architecture of the outer cell wall layer and lipid structures, and polyphosphate accumulation within mucilage matrix. The main route of copper detoxification is by Cu2+ coordination to polyphosphates in penta-coordinated geometry. The sequestrated Cu2+ was accessible and could be released by extracellular chelating agents. Finally, the reduction of Cu2+ to Cu1+ appears also to take place. These findings reveal the biochemical basis of the capacity of microalgae to adapt to high external copper concentrations and to serve as both, sinks and pools of environmental copper.
Metabolism of metals in microalgae and the adaptation to metal excess are of significant environmental importance. We report here a three-step mechanism that the green microalga Chlorella sorokiniana activates during the acquisition of and adaptation to manganese (Mn), which is both, an essential trace metal and a pollutant of waters. In the early stage, Mn 2+ was mainly bound to membrane phospholipids and phosphates in released mucilage. The outer cell wall was reorganized, and lipids were accumulated with a relative increase in lipid saturation. Intracellular redox settings were rapidly altered in the presence of Mn excess, with increased production of reactive oxygen species that resulted in lipid peroxidation and a decrease in the level of thiols. In the later stage, Mn 2+ was chelated by polyphosphates and accumulated in the cells. The structure of the inner cell wall was modified and the redox milieu established a new balance. Polyphosphates serve as a transient Mn 2+ storage ligand, as proposed previously. At the final stage, Mn was stored in multi-valent Mn clusters that resemble the structure of tetramanganese-calcium core of the oxygen-evolving complex. The present findings elucidate bioinorganic chemistry and metabolism of Mn in microalgae, and may shed new light on water-splitting Mn clusters.
The impact of ionizing radiation on microorganisms such as microalgae is a topic of increasing importance for understanding the dynamics of aquatic ecosystems in response to environmental radiation, and for the development of efficient approaches for bioremediation of mining and nuclear power plants wastewaters. Currently, nothing is known about the effects of ionizing radiation on the microalgal cell wall, which represents the first line of defence against chemical and physical environmental stresses. Using various microscopy, spectroscopy and biochemical techniques we show that the unicellular alga Chlorella sorokiniana elicits a fast response to ionizing radiation.Within one day after irradiation with doses of 1 to 5 Gy, the fibrilar layer of the cell wall became thicker, the fraction of uronic acids was higher, and the capacity to remove the main reactive product of water radiolysis increased. In addition, the isolated cell wall fraction showed significant binding capacity for Cu 2+ , Mn 2+ , and Cr 3+ . The irradiation 36 further increased the binding capacity for Cu 2+ , which appears to be mainly bound to 37 glucosamine moieties within a chitosan-like polymer in the outer rigid layer of the wall. 38These results imply that the cell wall represents a dynamic structure that is involved in 39 the protective response of microalgae to ionizing radiation. It appears that microalgae 40 may exhibit a significant control of metal mobility in aquatic ecosystems via biosorption 41 by the cell wall matrix.
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