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Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism.
Terenzi, Alessio; La Franca, Mery; van Schoonhoven, Sushilla; Panchuk, Rostyslav; Martínez, Álvaro; Heffeter, Petra; Gober, Redding; Pirker, Christine; Vician, Petra; Kowol, Christian R; Stoika, Rostyslav; Salassa, Luca; Rohr, Jürgen; Berger, Walter.
Affiliation
  • Terenzi A; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze, Ed. 17, 90128, Palermo, Italy.
  • La Franca M; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze, Ed. 17, 90128, Palermo, Italy.
  • van Schoonhoven S; Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.
  • Panchuk R; Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.
  • Martínez Á; Department of Regulation of Cell Proliferation and Apoptosis, Institute of Cell Biology, Drahomanov St., 14/16, Lviv, 79005, Ukraine.
  • Heffeter P; Donostia International Physics Center and Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, Euskal Herriko Unibertsitatea UPV/EHU, Paseo Manuel de Lardizabal 4, Donostia, 20018, Spain.
  • Gober R; Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.
  • Pirker C; Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna, Austria.
  • Vician P; College of Pharmacy, University of Kentucky, South Limestone Str. 789, Lexington, 40536-0596, USA.
  • Kowol CR; Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.
  • Stoika R; Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.
  • Salassa L; Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna, Austria.
  • Rohr J; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, 1090, Vienna, Austria.
  • Berger W; Department of Regulation of Cell Proliferation and Apoptosis, Institute of Cell Biology, Drahomanov St., 14/16, Lviv, 79005, Ukraine.
Commun Chem ; 4(1): 162, 2021 Nov 25.
Article in En | MEDLINE | ID: mdl-36697631
Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While extracellular adduct formation completely blocked the cytotoxic activity of landomycins, intracellularly it led to massively decreased reduced glutathione levels. Accordingly, landomycin E strongly synergized with glutathione-depleting agents like menadione but exerted reduced activity under hypoxia. Summarizing, landomycins represent natural glutathione-depleting agents and fluorescence probes for intracellular anthraquinone-based angucycline metabolism.

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Commun Chem Year: 2021 Document type: Article Affiliation country: Italy Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Commun Chem Year: 2021 Document type: Article Affiliation country: Italy Country of publication: United kingdom