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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors
Nils Goehringer1, Bernhard Biersack2, Yayi Peng3
1Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Abstract:
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 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.
Insights
New chimeric drugs combining epidermal growth factor (EGFR) and histone deacetylase (HDAC) inhibition show potent anticancer activity against solid and blood cancers. These novel compounds demonstrate significant tumor growth inhibition with minimal toxicity, paving the way for new cancer therapies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Targeting multiple pathways simultaneously offers a promising strategy for overcoming cancer drug resistance.
- Epidermal growth factor receptor (EGFR) and histone deacetylase (HDAC) are validated targets in various cancers.
Purpose of the Study:
- To synthesize and evaluate novel chimeric inhibitors combining EGFR and HDAC pharmacophores for antineoplastic efficiency.
- To investigate the mechanism of action and anti-cancer effects of these dual-target inhibitors in solid and hematological cancer models.
Main Methods:
- Synthesis of chimeric EGFR-HDAC inhibitors.
- In vitro antineoplastic activity assessment using IC50 values in prostate cancer (PCa), hepatocellular carcinoma (HCC), and leukemia/lymphoma cell lines.
- Target engagement validation via cell-free kinase assays and Western blot.
- Cytotoxicity assessment using lactate dehydrogenase (LDH) release assays.
- Evaluation of apoptosis induction (ROS, caspase-3 activity) and anti-angiogenic effects (CAM assay).
Main Results:
- Chimeric inhibitors 3BrQuin-SAHA and 3ClQuin-SAHA exhibited potent tumor cell growth inhibition at low micromolar concentrations.
- Compounds demonstrated target-specific EGFR and HDAC inhibition with no unspecific cytotoxicity.
- Apoptosis induction via reactive oxygen species (ROS) and caspase-3 activation was observed in PCa and HCC cells.
- Inhibition of angiogenesis was confirmed in the chorioallantoic membrane (CAM) assay.
- Significant antineoplastic effects were observed in both solid tumor and leukemia/lymphoma models.
Conclusions:
- Novel chimeric inhibitors targeting both EGFR and HDACs exhibit significant antineoplastic activity against diverse cancer types.
- The dual-targeting approach offers a promising strategy for cancer treatment with a favorable safety profile.
- Further research is warranted to elucidate the full mechanism of action and explore clinical applications of these novel compounds.
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