Study of the antilymphoma activity of pracinostat reveals different sensitivities of DLBCL cells to HDAC inhibitors
Autor: | Valdemar Priebe, Emanuele Zucca, Andrea Rinaldi, Claudio Pietra, Eugenio Gaudio, Filippo Spriano, Luciano Cascione, Anastasios Stathis, Francesco Bertoni, Luca Aresu, Giulio Sartori, Afua Adjeiwaa Mensah, Giovanna Damia, Emanuela Lovati, Chiara Tarantelli, Elisa Civanelli |
---|---|
Rok vydání: | 2021 |
Předmět: |
Lymphoid Neoplasia
biology Pracinostat breakpoint cluster region Antineoplastic Agents Hematology medicine.disease Lymphoma Histone Deacetylase Inhibitors Transcriptome chemistry.chemical_compound Histone chemistry hemic and lymphatic diseases medicine biology.protein Cancer research Humans Benzimidazoles Lymphoma Large B-Cell Diffuse Histone deacetylase Diffuse large B-cell lymphoma Vorinostat medicine.drug |
Zdroj: | Blood Adv |
ISSN: | 2473-9537 2473-9529 |
Popis: | Histone deacetylase inhibitors (HDACis) are antitumor agents with distinct efficacy in hematologic tumors. Pracinostat is a pan-HDACi with promising early clinical activity. However, similar to other HDACis, its activity as a single agent is limited. Diffuse large B-cell lymphoma (DLBCL) includes distinct molecular subsets or metabolically defined subtypes that rely in different ways on the B-cell receptor signaling pathway, oxidative phosphorylation, and glycolysis for their survival. The antitumor activity of pracinostat has not been determined in lymphomas. We performed preclinical in vitro activity screening of 60 lymphoma cell lines that included 25 DLBCLs. DLBCL cells belonging to distinct metabolic subtypes were treated with HDACis for 6 hours or 14 days followed by transcriptional profiling. DLBCL xenograft models enabled assessment of the in vivo antilymphoma activity of pracinostat. Combination treatments with pracinostat plus 10 other antilymphoma agents were performed. Western blot was used to assess acetylation levels of histone and nonhistone proteins after HDACi treatment. Robust antiproliferative activity was observed across all lymphoma histotypes represented. Focusing on DLBCL, we identified a low-sensitivity subset that almost exclusively consists of the oxidative phosphorylation (OxPhos)-DLBCL metabolic subtype. OxPhos-DLBCL cells also showed poorer sensitivity to other HDACis, including vorinostat. Transcriptomic analysis revealed fewer modulated transcripts but an enrichment of antioxidant pathway genes after HDACi treatment of OxPhos-DLBCLs compared with high-sensitivity B-cell receptor (BCR)–DLBCLs. Pharmacologic inhibition of antioxidant production rescued sensitivity of OxPhos-DLBCLs to pracinostat whereas BCR-DLBCLs were unaffected. Our study provides novel insights into the antilymphoma activity of pracinostat and identifies a differential response of DLBCL metabolic subtypes to HDACis. |
Databáze: | OpenAIRE |
Externí odkaz: |