0000000000058642
AUTHOR
Christine Pirker
Intrinsic fluorescence of the clinically approved multikinase inhibitor nintedanib reveals lysosomal sequestration as resistance mechanism in FGFR-driven lung cancer
Background Studying the intracellular distribution of pharmacological agents, including anticancer compounds, is of central importance in biomedical research. It constitutes a prerequisite for a better understanding of the molecular mechanisms underlying drug action and resistance development. Hyperactivated fibroblast growth factor receptors (FGFRs) constitute a promising therapy target in several types of malignancies including lung cancer. The clinically approved small-molecule FGFR inhibitor nintedanib exerts strong cytotoxicity in FGFR-driven lung cancer cells. However, subcellular pharmacokinetics of this compound and its impact on therapeutic efficacy remain obscure. Methods 3-dimens…
Subcellular duplex DNA and G‐quadruplex interaction profiling of a hexagonal PtII metallacycle
[Abstract] Metal‐driven self‐assembly afforded a multitude of fascinating supramolecular coordination complexes (SCCs) with applications as catalysts, host–guest, and stimuli‐responsive systems. However, the interest in the biological applications of SCCs is only starting to emerge and thorough characterization of their behavior in biological milieus is still lacking. Herein, we report on the synthesis and detailed in‐cell tracking of a Pt2L2 metallacycle. We show that our hexagonal supramolecule accumulates in cancer cell nuclei, exerting a distinctive blue fluorescence staining of chromatin resistant to UV photobleaching selectively in nucleolar G4‐rich regions. SCC co‐localizes with epit…
Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism
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 b…
Metal drugs and the anticancer immune response
The immune system deploys a multitude of innate and adaptive mechanisms not only to ward off pathogens but also to prevent malignant transformation ("immune surveillance"). Hence, a clinically apparent tumor already reflects selection for those malignant cell clones capable of evading immune recognition ("immune evasion"). Metal drugs, besides their well-investigated cytotoxic anticancer effects, massively interact with the cancer-immune interface and can reverse important aspects of immune evasion. This topic has recently gained intense attention based on combination approaches with anticancer immunotherapy (e.g., immune checkpoint inhibitors), a strategy recently delivering first exciting…
Anticancer metal drugs and immunogenic cell death
Conventional chemotherapeutics, but also innovative precision anticancer compounds, are commonly perceived to target primarily the cancer cell compartment. However, recently it was discovered that some of these compounds can also exert immunomodulatory activities which might be exploited to synergistically enhance their anticancer effects. One specific phenomenon of the interplay between chemotherapy and the anticancer immune response is the so-called “immunogenic cell death” (ICD). ICD was discovered based on a vaccination effect exerted by cancer cells dying from pretreatment with certain chemotherapeutics, termed ICD inducers, in syngeneic transplantation mouse models. Interestingly, onl…
124I Radiolabeling of a AuIII‐NHC Complex for In Vivo Biodistribution Studies†
Abstract AuIII complexes with N‐heterocyclic carbene (NHC) ligands have shown remarkable potential as anticancer agents, yet their fate in vivo has not been thoroughly examined and understood. Reported herein is the synthesis of new AuIII‐NHC complexes by direct oxidation with radioactive [124I]I2 as a valuable strategy to monitor the in vivo biodistribution of this class of compounds using positron emission tomography (PET). While in vitro analyses provide direct evidence for the importance of AuIII‐to‐AuI reduction to achieve full anticancer activity, in vivo studies reveal that a fraction of the AuIII‐NHC prodrug is not immediately reduced after administration but able to reach the major…
CCDC 1989307: Experimental Crystal Structure Determination
Related Article: Federica Guarra, Alessio Terenzi, Christine Pirker, Rossana Passannante, Dina Baier, Ennio Zangrando, Vanessa G��mez���Vallejo, Tarita Biver, Chiara Gabbiani, Walter Berger, Jordi Llop, Luca Salassa|2020|Angew.Chem.,Int.Ed.|59|17130|doi:10.1002/anie.202008046
CCDC 1989306: Experimental Crystal Structure Determination
Related Article: Federica Guarra, Alessio Terenzi, Christine Pirker, Rossana Passannante, Dina Baier, Ennio Zangrando, Vanessa G��mez���Vallejo, Tarita Biver, Chiara Gabbiani, Walter Berger, Jordi Llop, Luca Salassa|2020|Angew.Chem.,Int.Ed.|59|17130|doi:10.1002/anie.202008046