Induction of caspase 8 and reactive oxygen species by ruthenium-derived anticancer compounds with improved water solubility and cytotoxicity
| Autor: | Claude B. Sirlin, Marcelina Klajner, Gianni Sava, Cynthia Licona, Jean-Philippe Loeffler, Marjorie Sidhoum, Pascal Hébraud, Michel Pfeffer, Ludivine Fetzer, Xiangjun Meng, Christian Gaiddon, Georg Mellitzer, Vania Vidimar, Sébastien Harlepp |
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| Přispěvatelé: | Vidimar, V, Meng, X, Klajner, M, Licona, C, Fetzer, L, Harlepp, S, Hébraud, P, Sidhoum, M, Sirlin, C, Loeffler, Jp, Mellitzer, G, Sava, Gianni, Pfeffer, M, Gaiddon, C. |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Programmed cell death
Cytotoxicity chemistry.chemical_element Antineoplastic Agents Real-Time Polymerase Chain Reaction Caspase 8 Sciences du Vivant [q-bio]/Cancer Biochemistry Ruthenium Tumour ROS Cell Line Tumor Fluorescence Resonance Energy Transfer Animals Humans Mode of action Membrane Potential Mitochondrial Pharmacology chemistry.chemical_classification Reactive oxygen species Chemistry Water Solubility Enzyme Induction Cancer cell Ruthenium Compounds Drug Screening Assays Antitumor Signal transduction Reactive Oxygen Species |
| Popis: | Organometallic compounds which contain metals, such as ruthenium or gold, have been investigated as a replacement for platinum-derived anticancer drugs. They often show good antitumor effects, but the identification of their precise mode of action or their pharmacological optimization is still challenging. We have previously described a class of ruthenium(II) compounds with interesting anticancer properties. In comparison to cisplatin, these molecules have lower side effects, a reduced ability to interact with DNA, and they induce cell death in absence of p53 through CHOP/DDIT3. We have now optimized these molecules by improving their cytotoxicity and their water solubility. In this article, we demonstrate that by changing the ligands around the ruthenium we modify the ability of the compounds to interact with DNA. We show that these optimized molecules reduce tumor growth in different mouse models and retain their ability to induce CHOP/DDIT3. However, they are more potent inducers of cancer cell death and trigger the production of reactive oxygen species and the activation of caspase 8. More importantly, we show that blocking reactive oxygen species production or caspase 8 activity reduces significantly the activity of the compounds. Altogether our data suggest that water-soluble ruthenium(II)-derived compounds represent an interesting class of molecules that, depending on their structures, can target several pro-apoptotic signaling pathways leading to reactive oxygen species production and caspase 8 activation. (C) 2012 Elsevier Inc. All rights reserved. |
| Databáze: | OpenAIRE |
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