Synergistic induction of apoptosis in resistant head and neck carcinoma and leukemia by alkoxyamide-based histone deacetylase inhibitors

  • Eur J Med Chem. 2021 Feb 5:211:113095. doi: 10.1016/j.ejmech.2020.113095.
Leandro A Alves Avelar  1 ,  Christian Schrenk  1 ,  Melf Sönnichsen  1 ,  Alexandra Hamacher  1 ,  Finn K Hansen  2 ,  Julian Schliehe-Diecks  3 ,  Arndt Borkhardt  3 ,  Sanil Bhatia  4 ,  Matthias U Kassack  5 ,  Thomas Kurz  6
Affiliations
  • 1. Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany.
  • 2. Pharmazeutisches Institut, Abteilung für Pharmazeutische und Zellbiologische Chemie, Universität Bonn, An der Immenburg 4, 53121, Bonn (Endenich), Germany.
  • 3. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 4. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Electronic address: [email protected].
  • 5. Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany. Electronic address: [email protected].
  • 6. Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany. Electronic address: [email protected].
PMID: 33360560 DOI: 10.1016/j.ejmech.2020.113095
Abstract

Targeting epigenetic dysregulation has emerged as a valuable therapeutic strategy in Cancer treatment. Especially epigenetic combination therapy of histone deacetylase inhibitors (HDACi) with established anti-cancer drugs has provided promising results in preclinical and clinical studies. The structural optimization of alkoxyamide-based class I/IIb inhibitors afforded improved analogs with potent efficacy in cisplatin-resistant head and neck carcinoma cells and bortezomib-resistant leukemia cells. The most promising HDACi showed a superior synergistic cytotoxic activity as compared to vorinostat and class I HDACi in combination with cisplatin, leading to a full reversal of the chemoresistant phenotype in head and neck Cancer cell lines, as well in combination with the Proteasome inhibitors (bortezomib and carfilzomib) in a panel of leukemic cell lines. Furthermore, the most valuable alkoxyamide-based HDACi exhibited strong ex vivo Anticancer efficacy against primary patient samples obtained from different therapy-resistant leukemic entities.

Keywords
Cancer resistance; Chemosensitizing effects; Class I; Class IIb inhibitors; HDAC isozyme Profile; Histone deacetylases; Leukemia; Solid cancer.