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 IC50 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 andWestern 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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89221 |
| Date | 24 January 2024 |
| Creators | Goehringer, Nils, Biersack, Bernhard, Peng, Yayi, Schobert, Rainer, Herling, Marco, Ma, Andi, Nitzsche, Bianca, Höpfner, Michael |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8432 |
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