| Autor: |
Tsymbal SA; International Institute of Solution Chemistry of Advanced Materials and Technologies, ITMO University, 197101 Saint Petersburg, Russia., Moiseeva AA; Department of Chemistry, Moscow State University, 119991 Moscow, Russia., Agadzhanian NA; International Institute of Solution Chemistry of Advanced Materials and Technologies, ITMO University, 197101 Saint Petersburg, Russia., Efimova SS; Institute of Cytology, Russian Academy of Sciences, 194064 Saint Petersburg, Russia., Markova AA; Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia.; A.N.Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119334 Moscow, Russia., Guk DA; Department of Chemistry, Moscow State University, 119991 Moscow, Russia., Krasnovskaya OO; Department of Chemistry, Moscow State University, 119991 Moscow, Russia., Alpatova VM; A.N.Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119334 Moscow, Russia., Zaitsev AV; A.N.Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119334 Moscow, Russia., Shibaeva AV; Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia., Tatarskiy VV; Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia., Dukhinova MS; International Institute of Solution Chemistry of Advanced Materials and Technologies, ITMO University, 197101 Saint Petersburg, Russia., Ol'shevskaya VA; A.N.Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119334 Moscow, Russia., Ostroumova OS; Institute of Cytology, Russian Academy of Sciences, 194064 Saint Petersburg, Russia., Beloglazkina EK; Department of Chemistry, Moscow State University, 119991 Moscow, Russia., Shtil AA; Department of Chemistry, Moscow State University, 119991 Moscow, Russia.; Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia. |
| Abstrakt: |
Copper-containing agents are promising antitumor pharmaceuticals due to the ability of the metal ion to react with biomolecules. In the current study, we demonstrate that inorganic Cu 2+ in the form of oxide nanoparticles (NPs) or salts, as well as Cu ions in the context of organic complexes (oxidation states +1, +1.5 and +2), acquire significant cytotoxic potency (2-3 orders of magnitude determined by IC 50 values) in combinations with N-acetylcysteine (NAC), cysteine, or ascorbate. In contrast, other divalent cations (Zn, Fe, Mo, and Co) evoked no cytotoxicity with these combinations. CuO NPs (0.1-1 µg/mL) together with 1 mM NAC triggered the formation of reactive oxygen species (ROS) within 2-6 h concomitantly with perturbation of the plasma membrane and caspase-independent cell death. Furthermore, NAC potently sensitized HCT116 colon carcinoma cells to Cu-organic complexes in which the metal ion coordinated with 5-(2-pyridylmethylene)-2-methylthio-imidazol-4-one or was present in the coordination sphere of the porphyrin macrocycle. The sensitization effect was detectable in a panel of mammalian tumor cell lines including the sublines with the determinants of chemotherapeutic drug resistance. The components of the combination were non-toxic if added separately. Electrochemical studies revealed that Cu cations underwent a stepwise reduction in the presence of NAC or ascorbate. This mechanism explains differential efficacy of individual Cu-organic compounds in cell sensitization depending on the availability of Cu ions for reduction. In the presence of oxygen, Cu +1 complexes can generate a superoxide anion in a Fenton-like reaction Cu +1 L + O 2 → O 2 -. + Cu +2 L, where L is the organic ligand. Studies on artificial lipid membranes showed that NAC interacted with negatively charged phospholipids, an effect that can facilitate the penetration of CuO NPs across the membranes. Thus, electrochemical modification of Cu ions and subsequent ROS generation, as well as direct interaction with membranes, represent the mechanisms of irreversible membrane damage and cell death in response to metal reduction in inorganic and organic Cu-containing compounds. |
