Panobinostat enhances olaparib efficacy by modifying expression of homologous recombination repair and immune transcripts in ovarian cancer
| Autor: | Andrew J. Wilson, Vijayalaxmi G Gupta, Qi Liu, Fiona Yull, Marta A. Crispens, Dineo Khabele |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Antineoplastic Agents Piperazines Immunomodulation Mice Ovarian cancer HDACi histone deacetylase inhibitors Histone deacetylase inhibitors Cell Line Tumor Panobinostat HRP homologous recombination proficient Animals Humans Immune response PARP inhibitors RC254-282 Original Research Pano panobinostat Ovarian Neoplasms Neoplasms. Tumors. Oncology. Including cancer and carcinogens Recombinational DNA Repair Drug Synergism Xenograft Model Antitumor Assays Ola olaparib PO per os (oral gavage) Gene Expression Regulation Neoplastic Disease Models Animal Homologous recombination repair PARPi polymerase ADP ribose phosphate inhibitor Phthalazines Female IP intraperitoneal |
| Zdroj: | Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 24, Iss 2, Pp 63-75 (2022) |
| ISSN: | 1476-5586 1522-8002 |
| Popis: | Highlights • Panobinostat in combination with olaparib reduces homologous recombination (HR) proficient tumor cell viability. • This combination favors anti-tumorigenic macrophages and enhances CD8+ T cell infiltration into tumors. • As a result, this combination targets HR-proficient ovarian tumors directly and through the tumor microenvironment. Histone deacetylase inhibitors (HDACi) sensitize homologous recombination (HR)-proficient human ovarian cancer cells to PARP inhibitors (PARPi). To investigate mechanisms of anti-tumor effects of combined HDACi/PARPi treatment we performed transcriptome analysis in HR- proficient human ovarian cancer cells and tested drug effects in established immunocompetent mouse ovarian cancer models. Human SKOV-3 cells were treated with vehicle (Con), olaparib (Ola), panobinostat (Pano) or Pano+Ola and RNA-seq analysis performed. DESeq2 identified differentially expressed HR repair and immune transcripts. Luciferised syngeneic mouse ovarian cancer cells (ID8-luc) were treated with the HDACi panobinostat alone or combined with olaparib and effects on cell viability, apoptosis, DNA damage and HR efficiency determined. C57BL/6 mice with intraperitoneally injected ID8-luc cells were treated with panobinostat and/or olaparib followed by assessment of tumor burden, markers of cell proliferation, apoptosis and DNA damage, tumor-infiltrating T cells and macrophages, and other immune cell populations in ascites fluid. There was a significant reduction in expression of 20/37 HR pathway genes by Pano+Ola, with immune and inflammatory-related pathways also significantly enriched by the combination. In ID8 cells, Pano+Ola decreased cell viability, HR repair, and enhanced DNA damage. Pano+Ola also co-operatively reduced tumor burden and proliferation, increased tumor apoptosis and DNA damage, enhanced infiltration of CD8+ T cells into tumors, and decreased expression of M2-like macrophage markers. In conclusion, panobinostat in combination with olaparib targets ovarian tumors through both direct cytotoxic and indirect immune-modulating effects. |
| Databáze: | OpenAIRE |
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