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Lithium Modulates Cancer Cell Growth, Apoptosis, Gene Expression and Cytokine Production in HL-60 Promyelocytic Leukaemia Cells and Their Drug-Resistant Sub-clones

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Abstract

Lithium has been an FDA-approved and preferred drug for the treatment of mood disorders for many years, and cumulative evidence has pointed towards its potential use as an anti-cancer agent. Previous studies in our laboratory have demonstrated that lithium induces apoptotic cell death in HL-60 promyelocytes at concentrations of 10 mM and above. A lithium-tolerant HL-60 sub-clone, resistant to up to 15 mM lithium, was also generated and its growth profile reported. Treatment of cells with lithium resulted in a dose-dependent induction of p53, retinoblastoma (Rb) and bax expression which was accompanied by concomitant inhibition of bcl-2 expression as demonstrated using immunohistochemical microscopy. These results seem to suggest that lithium induced cell death in these cells by inhibiting expression of anti-apoptotic protein, bcl-2, while inducing higher expression of its pro-apoptotic counterparts which include bax. Expression of bax and bcl-2 is also linked to expression of inflammation-regulating cytokines. Using ELISA assays, lithium was demonstrated to induce production of pro-inflammatory cytokines, IL-6 and TNF-α, while inhibiting release of anti-inflammation-related IL-2 and IL-10 in a dose-dependent fashion. Our findings identify a critical function for lithium in modulating pro- versus anti-apoptotic gene expression and pro- versus anti-inflammatory cytokines in vitro and provide a rationale for suggesting a promising role of lithium in regulation of inflammation and cancer growth.

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Authors and Affiliations

  1. Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, P/bag x1106, Sovenga, 0727, South Africa

    Thabe Matsebatlela & Rolf Becker

  2. Biological Sciences Department, Clemson University, SC-19634, Clemson, SC, USA

    Vincent Gallicchio

Authors
  1. Thabe Matsebatlela
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  2. Vincent Gallicchio
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  3. Rolf Becker
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Correspondence to Thabe Matsebatlela.

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Matsebatlela, T., Gallicchio, V. & Becker, R. Lithium Modulates Cancer Cell Growth, Apoptosis, Gene Expression and Cytokine Production in HL-60 Promyelocytic Leukaemia Cells and Their Drug-Resistant Sub-clones. Biol Trace Elem Res 149, 323–330 (2012). https://doi.org/10.1007/s12011-012-9438-1

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  • DOI: https://doi.org/10.1007/s12011-012-9438-1

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