The histone deacetylase inhibitors vorinostat and romidepsin downmodulate IL-10 expression in cutaneous T-cell lymphoma cells

Tiffon, CE, Adams, JE, van der Fits, L, Wen, S, Townsend, PA, Ganesan, A ORCID:, Hodges, E, Vermeer, MH and Packham, G (2011) The histone deacetylase inhibitors vorinostat and romidepsin downmodulate IL-10 expression in cutaneous T-cell lymphoma cells. British Journal of Pharmacology, 162 (7). pp. 1590-1602. ISSN 1476-5381

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BACKGROUND AND PURPOSE Vorinostat and romidepsin are histone deacetylase inhibitors (HDI), approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, the mechanism(s) by which these drugs exert their anti-cancer effects are not fully understood. Since CTCL is associated with immune dysregulation, we investigated whether these HDI modulated cytokine expression in CTCL cells. EXPERIMENTAL APPROACH CTCL cell lines and primary CTCL cells were treated in vitro with vorinostat or romidepsin, or with STAT3 pathway inhibitors. Cell cycle parameters and apoptosis were analysed by propidium iodide and annexin V/propidium iodide staining respectively. Cytokine expression was analysed using QRT-PCR and elisa assays. STAT3 expression/phosphorylation and transcriptional activity were analysed using immunoblotting and transfection/reporter assays respectively. KEY RESULTS Vorinostat and romidepsin strongly down-regulated expression of the immunosuppressive cytokine, interleukin (IL)-10, frequently overexpressed in CTCL, at both the RNA and protein level in CTCL cell lines and at the RNA level in primary CTCL cells. Vorinostat and romidepsin also increased expression of IFNG RNA and decreased expression of IL-2 and IL-4 RNA, although to a lesser extent compared to IL-10. Transient exposure to vorinostat was sufficient to suppress IL-10 secretion but was not sufficient to irreversibly commit cells to undergo cell death. STAT3 pathway inhibitors decreased production of IL-10 and vorinostat/romidepsin partially decreased STAT3-dependent transcription without effects on STAT3 expression or phosphorylation. CONCLUSIONS AND IMPLICATIONS These results demonstrate that HDI modulate cytokine expression in CTCL cells, potentially via effects on STAT3. Immunomodulation may contribute to the clinical activity of HDI in this disease.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017)
Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Depositing User: Users 2731 not found.
Date Deposited: 20 Oct 2011 10:41
Last Modified: 22 Oct 2022 21:33
DOI: 10.1111/j.1476-5381.2010.01188.x

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