2. Academic Validation
  3. HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer

HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer

  • Biochem Pharmacol. 2024 May 4:225:116257. doi: 10.1016/j.bcp.2024.116257.
Robert Jenke 1,  Denys Oliinyk 2,  Tamara Zenz 3,  Justus Körfer 4,  Linda Schäker-Hübner 5,  Finn K Hansen 5,  Florian Lordick 6,  Florian Meier-Rosar 7,  Achim Aigner 8,  Thomas Büch 9
Affiliations

Affiliations

  • 1 University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany; Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany.
  • 2 Jena University Hospital, Functional Proteomics, Research Center Lobeda, Jena, Germany.
  • 3 Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany.
  • 4 University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany; University Hospital Leipzig, Institute for Anatomy, Leipzig, Germany.
  • 5 University of Bonn, Pharmaceutical Institute, Department of Pharmaceutical and Cell Biological Chemistry, Bonn, Germany.
  • 6 University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany.
  • 7 Jena University Hospital, Functional Proteomics, Research Center Lobeda, Jena, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany.
  • 8 Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany. Electronic address: achim.aigner@medizin.uni-leipzig.de.
  • 9 Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena, Germany.
PMID: 38705532 DOI: 10.1016/j.bcp.2024.116257
Abstract

Gastric Cancer remains among the deadliest neoplasms worldwide, with limited therapeutic options. Since efficacies of targeted therapies are unsatisfactory, drugs with broader mechanisms of action rather than a single oncogene inhibition are needed. Preclinical studies have identified histone deacetylases (HDAC) as potential therapeutic targets in gastric Cancer. However, the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. This is particularly true with regard to Ferroptosis as an emerging concept of cell death. In a panel of gastric Cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured and proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important Ferroptosis genes were validated on the mRNA and protein level. Upon HDACi treatment, lipid peroxidation was found increased in all cell lines. Class I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to Ferroptosis induction. Key Enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Results were also confirmed in primary human gastric Cancer tissue cultures as a relevant ex vivo model. We identify the induction of Ferroptosis as new mechanism of action of class I HDACi in gastric Cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle.

Keywords

Entinostat; Ferroptosis; Gastric cancer; Histone deacetylase (HDAC) inhibitor; Lipid peroxidation.

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