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.

PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells

“…Similarly, other studies have shown that high doses of lithium (50 and 100 mM) increases apoptosis through activation of caspase‐2 and ‐7 in caspase‐3‐deficient MCF‐7 cells [Suganthi et al, ]. Furthermore, lithium has been shown to inhibit cellular proliferation in combination with the regulation of the expression of genes involved not only with the apoptosis signaling pathway [Zhang et al, ] but also with the production of inflammatory cytokines [Matsebatlela et al, ] . In CRC, lithium induced apoptosis through a mechanism that is independent of p53 activity with increased production of TNF‐α and FasL, two death‐receptor ligands that activate the extrinsic apoptosis pathway [Kaufmann et al, ].…”

“…In cancer, lithium acts as an anti-cancer agent alone [Matsebatlela et al, 2012] or auxiliary to chemotherapy and radiotherapy [Gupta et al, 2014]. Lithium is a reversible inhibitor of GSK-3b with an IC50 of 2 mM and acts by both directly competing with Mg2þ to reduce the Mg2þ ATP-dependent kinase activity of GSK-3b and indirectly reducing phosphatase activity to increase the inactive form of GSK-3-b [Gupta et al, 2012].…”

Lithium modulates the production of peripheral and cerebral cytokines in an animal model of mania induced by dextroamphetamine

“…It is well known that Li is an effective medication for the treatment of BD , and several studies suggest that Li exerts anti‐inflammatory effects [e.g., suppression of cyclooxygenase‐2 expression, inhibition of IL‐1β and TNF‐α production, and enhancement of IL‐2 and IL‐10 synthesis ]. However, some studies indicate that, under certain experimental conditions, Li also exhibits pro‐inflammatory properties [e.g., induction of the synthesis of IL‐4, IL‐6 and other pro‐inflammatory cytokines ]. Furthermore, a clinical study that assessed serum proteins in patients with BD demonstrated that the concentrations of IL‐10 were higher in patients in remission after mania whereas the concentrations of IFN‐γ were higher in those in remission after depression as compared to healthy controls .…”

Brain Intraventricular Injection of Amyloid-β in Zebrafish Embryo Impairs Cognition and Increases Tau Phosphorylation, Effects Reversed by Lithium

“…It is known that both apoptosis [55] and tau-phosphorylation in those residues [56] occur naturally during development and aging. It is also known that LiCl treatment can play different roles depending on cell type, system and developmental stage [57] [58] [59] [60]. In a developmental changing scenario, where neuron pathways are being formed and connection refinement is necessary [55], opposing effects on apoptotic pathways may be observed.…”