Lithium: A Promising Anticancer Agent

Abstract

Lithium is a therapeutic cation used to treat bipolar disorders but also has some important features as an anti-cancer agent. In this review, we provide a general overview of lithium, from its transport into cells, to its innovative administration forms, and based on genomic, transcriptomic, and proteomic data. Lithium formulations such as lithium acetoacetate (LiAcAc), lithium chloride (LiCl), lithium citrate (Li₃C₆H₅O₇), and lithium carbonate (Li₂CO₃) induce apoptosis, autophagy, and inhibition of tumor growth and also participate in the regulation of tumor proliferation, tumor invasion, and metastasis and cell cycle arrest. Moreover, lithium is synergistic with standard cancer therapies, enhancing their anti-tumor effects. In addition, lithium has a neuroprotective role in cancer patients, by improving their quality of life. Interestingly, nano-sized lithium enhances its anti-tumor activities and protects vital organs from the damage caused by lipid peroxidation during tumor development. However, these potential therapeutic activities of lithium depend on various factors, such as the nature and aggressiveness of the tumor, the type of lithium salt, and its form of administration and dosage. Since lithium has been used to treat bipolar disorder, the current study provides an overview of its role in medicine and how this has changed. This review also highlights the importance of this repurposed drug, which appears to have therapeutic cancer potential, and underlines its molecular mechanisms.

Keywords: anti-cancer effects; apoptosis; autophagy; cancer; lithium; nano-delivery.

Figure 1

Expression of monocarboxylate transporters (MCTs) in various cancers. MCTs are involved in the passive transport of lithium acetoacetate across cell membranes, and their abundance is associated with cancer. (-), no expression; (*), medium expression; (**), high expression; (***), very high expression level; ND, not data.

Figure 2

Effects of lithium on cancer cells. Treatment with salts of lithium such as lithium acetoacetate (LiAcAc), lithium chloride (LiCl), lithium citrate (Li₃C₆H₅O₇), and lithium carbonate (Li₂CO₃) inhibit cell proliferation, cell migration, metastasis, and cell growth, in addition to decreasing tumorigenicity and clonogenicity, arresting the cell cycle and inducing autophagy, cell death, and apoptosis. Lithium affects cancer cells at the transcriptional (gene expression level) (pink boxes) and at post-transcriptional (protein function, expression, and cell localization) (green boxes) levels. In addition, lithium affects metabolic pathways and other metabolic products (purple circle). Black arrows (→) indicate the effect of lithium on the molecule (gray downward arrow (↓) denotes decrease or down-regulation, and gray upward arrow (↑) denotes increase or up-regulation). The truncated black line (⊥) indicates an inhibitory effect of lithium.