title: Lithium modulates cancer cell growth, apoptosis, gene expression and cytokine production in HL-60 promyelocytic leukaemia cells and their drug-resistant sub-clones.
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.
authors.affiliation: Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, P/bag x1106, Sovenga 0727, South Africa. thabe.matsebatlela@ul.ac.za
authors.forename: Thabe
authors.initials: T
authors.lastname: Matsebatlela
authors.forename: Vincent
authors.initials: V
authors.lastname: Gallicchio
authors.forename: Rolf
authors.initials: R
authors.lastname: Becker
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D016753:Interleukin-10; D008094:Lithium