Ungerstedt, J. (Johanna)

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    Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels
    (Frontiers, 2018) Díaz-Argelich, N. (Nuria); Klynning, C. (Charlotte); Ungerstedt, J. (Johanna); Radestad, E. (Emelie); Nair, D. (Deepika); Schröder, A. (Axer); Khalkar, P. (Prajakta); Fernandes, A.P. (Aristi P.); Uhlin, M. (Michael)
    Redox active selenium (Se) compounds at sub toxic doses act as pro-oxidants with cytotoxic effects on tumor cells and are promising future chemotherapeutic agents. However, little is known about how Se compounds affect immune cells in the tumor microenvironment. We demonstrate that the inorganic Se compound selenite and the organic methylseleninic acid (MSA) do not, despite their pro-oxidant function, influence the viability of immune cells, at doses that gives cytotoxic effects in ovarian cancer cell lines. Treatment of the ovarian cancer cell line A2780 with selenite and MSA increases NK cell mediated lysis, and enhances the cytolytic activity of T cells. Increased T cell function was observed after incubation of T cells in preconditioned media from tumor cells treated with MSA, an effect that was coupled to decreased levels of PDL1, HIF-1α, and VEGF. In conclusion, redox active selenium compounds do not kill or inactivate immune cells at doses required for anti-cancer treatment, and we demonstrate that MSA enhances T cell-mediated tumor cell killing via PDL1 and VEGF inhibition.
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    Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia: A genome wide epigenetic analysis
    (Elsevier BV, 2018) Díaz-Argelich, N. (Nuria); Ungerstedt, J. (Johanna); Karimi-Arzenani, M. (Mohsen); Abdulkadir-Ali, H. (Hani); Codó, P. (Paula); Khalkar, P. (Prajakta); Fernandes, A.P. (Aristi P.); Walfridsson, J. (Julian); Martikainen, A. (Anni); Lehmann, S. (Sören)
    Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri-methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents