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

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-??, 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.