Novel Mechanism of Cytotoxicity for the Selective Selenosemicarbazone, 2-Acetylpyridine 4,4-Dimethyl-3-selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization
| Autor: | Des R. Richardson, Danuta S. Kalinowski, Akanksha Arvind, George Iskander, Sumit Sahni, Christian Stefani, Patric J. Jansson, Paul V. Bernhardt, Naresh Kumar, Zaklina Kovacevic, Maram T. Basha, Philip C. Sharpe, Zaynab Al-Eisawi, Darius J.R. Lane |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular 0301 basic medicine Pyridines Iron Genes myc Molecular Conformation Antineoplastic Agents Crystallography X-Ray Iron Chelating Agents Antioxidants Permeability Methemoglobin Structure-Activity Relationship 03 medical and health sciences Cell Line Tumor Lysosome Antimetastatic Agent Receptors Transferrin Drug Discovery medicine Humans Structure–activity relationship Cytotoxicity Semicarbazones chemistry.chemical_classification Reactive oxygen species Lysosome-Associated Membrane Glycoproteins 030104 developmental biology medicine.anatomical_structure Mechanism of action chemistry Biochemistry Transferrin Ferritins Molecular Medicine medicine.symptom Lysosomes Reactive Oxygen Species |
| Zdroj: | Journal of Medicinal Chemistry. 59:294-312 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.5b01399 |
| Popis: | Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-L-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure-activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent. |
| Databáze: | OpenAIRE |
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