In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

International Journal of Molecular Sciences

WolfgangA. Schulz¹  FinnK. Hansen²  Thomas Kurz³  MatthiasU. Kassack³  Marc Pflieger³  Lena Schumacher⁴  Annabelle Friedrich⁴  Janav. Stuijvenberg⁴  Gerhard Fritz⁴  Ann-Sophie Assmann⁴  WynandP. Roos⁵ 

[1] Department of Urology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany;Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, D-04103 Leipzig, Germany;Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany;Institute of Toxicology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany;Institute of Toxicology, University Medical Center, Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany;

关键词: HDAC inhibitors;    normal tissue toxicity;    genotoxic hazard;    genetic instability;    DNA strand breaks;    DNA damage response;   

DOI  :  10.3390/ijms21134747

来源: DOAJ

【 摘 要 】

Histone deacetylase inhibitors (HDACi) are already approved for the therapy of leukemias. Since they are also emerging candidate compounds for the treatment of non-malignant diseases, HDACi with a wide therapeutic window and low hazard potential are desirable. Here, we investigated a panel of 12 novel hydroxamic acid- and benzamide-type HDACi employing non-malignant V79 hamster cells as toxicology guideline-conform in vitro model. HDACi causing a ≥10-fold preferential cytotoxicity in malignant neuroblastoma over non-malignant V79 cells were selected for further genotoxic hazard analysis, including vorinostat and entinostat for control. All HDACi selected, (i.e. KSK64, TOK77, DDK137 and MPK77) were clastogenic and evoked DNA strand breaks in non-malignant V79 cells as demonstrated by micronucleus and comet assays, histone H2AX foci formation analyses (γH2AX), DNA damage response (DDR) assays as well as employing DNA double-strand break (DSB) repair-defective VC8 hamster cells. Genetic instability induced by hydroxamic acid-type HDACi seems to be independent of bulky DNA adduct formation as concluded from the analysis of nucleotide excision repair (NER) deficient mutants. Summarizing, KSK64 revealed the highest genotoxic hazard and DDR stimulating potential, while TOK77 and MPK77 showed the lowest DNA damaging capacity. Therefore, these compounds are suggested as the most promising novel candidate HDACi for subsequent pre-clinical in vivo studies.

【 授权许可】

Unknown