Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors.

Autor: Goehringer N; Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany., Biersack B; Organic Chemistry 1, University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany., Peng Y; Laboratory of Lymphocyte Signaling and Oncoproteome, University Hospital Cologne, Weyertal 115c, 50931 Cologne, Germany., Schobert R; Organic Chemistry 1, University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany., Herling M; Laboratory of Lymphocyte Signaling and Oncoproteome, University Hospital Cologne, Weyertal 115c, 50931 Cologne, Germany.; Clinic and Polyclinic for Hematology, Cell Therapy and Hemostaseology, Liebigstraße 22, House 7, 04103 Leipzig, Germany., Ma A; Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany., Nitzsche B; Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany., Höpfner M; Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Aug 05; Vol. 22 (16). Date of Electronic Publication: 2021 Aug 05.
DOI: 10.3390/ijms22168432
Abstrakt: New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC 50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.
Databáze: MEDLINE
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