HDAC Screening identifies the HDAC Class I Inhibitor Romidepsin as a promising Epigenetic Drug for Biliary Tract Cancer

• DOI: 10.1096/fasebj.2021.35.s1.05128
• Publication Date: 2021-06-11T01:15:09Z
• Authors: Christian Mayr; Tobias Kiesslich; Sara Erber; Dino Bekric; Heidemarie Dobias; Marlena Beyreis; Markus Ritter; Tarkan Jäger; Bettina Neumayer; Paul Winkelmann; Eckhard Klieser; Daniel Neureiter
• Keywords: Romidepsin; Vorinostat; Panobinostat

Introduction Biliary tract cancer (BTC) is a fatal disease with limited therapeutic options. Inhibition of histone deacetylases (HDACs) represents an effective anti-cancer approach. Data regarding HDAC and BTC are sparse but promising. There, we performed comprehensive investigation expression pharmacological inhibition in vitro model. Methods Expression HDACs cells was measured via quantitative real-time PCR immunohistochemistry. Cytotoxicity pan-inhibitors (belinostat, vorinostat) inhibitors targeting different classes (mocetinostat, romidepsin, LMK-235, tubastatin A) analyzed using the resazurin assay. HDAC1/2 activity HDAC-Glo I/II Assay Screening System (Promega). Mode cytotoxicity romidepsin evaluated time-resolved assay RealTime-Glo Annexin V Apoptosis Necrosis Changes H3K9Ac levels were to investigate epigenetic effect romidepsin. Combinatory treatment cisplatin changes IC50-values. n = 78 patient samples done Appropriate statistical tests used correlate clinicopathological data. Results profiling revealed heterogeneous across studied cell lines (n 8). Furthermore, found that show sensitivities towards inhibitors. The class I inhibitor showed significant (low) nM-range therefore chosen for further investigation. We causes apoptosis secondary necrosis significantly reduces cells. observed sub-lethal concentrations augmented toxic standard chemotherapeutic cisplatin. also HDAC1 2 patients. correlated tumor localization grading. Moreover, patients high HDAC2 had shorter overall survival time. Conclusions Our results demonstrate promising anti-BTC substance. In addition, expressed associate clinical parameters.