Abstract
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.
Highlights
Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria
We have demonstrated that landomycin E (LE) shows a different mechanism of action when compared with doxorubicin: it does not intercalate into DNA and induces massive mitochondrial dysfunction and membrane depolarization followed by apoptosis induction[11]
HeLa cells were more resistant against LE, but again, full protection from the massive cytotoxicity of 10 μM LE was observed by NAC/GSH coexposure (Fig. 2a, b)
Summary
Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. 1234567890():,; Angucyclines are a family of natural antibiotics produced by Streptomyces bacteria and were discovered following the success of tetracyclines and anthracyclines (e.g., daunorubicin and doxorubicin) both in broad medical use as antibiotics and anticancer compounds[1,2,3] Similar to these wellknown substance classes, angucyclines are characterized by a tetracyclic ring skeleton but assembled in a benz[a]anthracene system owning a distinctive angular structure, reflected in the name angu-cyclines[4,5]. LE showed potent activity against numerous cancer cell models in vitro and demonstrated to be unaffected by resistance to structurally related anthracyclines (e.g., doxorubicin), used in clinics for the treatment of several malignancies[3,5,11] Despite these efforts, the mechanisms-of-action underlying the antineoplastic activity of angucyclines are not fully understood yet. It was shown that the SCH3 group of the angucycline antibiotic urdamycin E derives from methanthiol Michael addition to urdamycin A, a compound similar to the landomycins[25]
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