Lithium in Cancer Therapy: Friend or Foe?

Abstract

Lithium, a trace element important for fetal health and development, is considered a metal drug with a well-established clinical regime, economical production process, and a mature storage system. Several studies have shown that lithium affects tumor development by regulating inositol monophosphate (IMPase) and glycogen synthase kinase-3 (GSK-3). Lithium can also promote proliferation and programmed cell death (PCD) in tumor cells through a number of new targets, such as the nuclear receptor NR4A1 and Hedgehog-Gli. Lithium may increase cancer treatment efficacy while reducing side effects, suggesting that it can be used as an adjunctive therapy. In this review, we summarize the effects of lithium on tumor progression and discuss the underlying mechanisms. Additionally, we discuss lithium's limitations in antitumor clinical applications, including its narrow therapeutic window and potential pro-cancer effects on the tumor immune system.

Keywords: cancer therapy; cell death; lithium; tumor immune microenvironment.

Figure 1

Pathways that are directly regulated by lithium. (I) High-concentration lithium ions take away metal binding sites, causing magnesium-dependent enzymes to lose their functions. (II) Inhibition of IMPase by lithium promotes calcium signaling and autophagy, but suppresses proliferation in cells. (III) Inhibition of GSK-3β by lithium activates the MAPK/ERK and β-catenin pathways, but inactivates STAT3 signaling, thus affecting the survival, proliferation, and migration of cells. (IV) Lithium affects the intracellular homeostasis of other ions, such as calcium, sodium, and chlorine.

Figure 2

Effects and underlying mechanisms of lithium on the cell cycle in tumor cells. Lithium regulates cell proliferation mainly through cell cycle arresting and DNA replication blocking. A higher portion of G2/M phase and S phase cells has been observed in different tumor cells. (I) Lithium inactivates CDK1 by preventing CDC25c from hydrolyzing phosphorylated fragments, then prevents cells from entering the M phase. (II) For DNA replication, the S phase-specific interaction between TCF-3 and β-catenin shows an anti-proliferation effect, which might explain the S phase arresting by lithium. (III) Lithium disrupts the interaction between DNA and E2F systems. Lithium also improves the level of Rb to influence Cyclin A and Cyclin B indirectly. (IV) There is also a promotion effect of lithium to up-regulate the level of Cyclin D and then help tumor cells re-enter a new cell cycle.

Figure 3

Effects of lithium on tumors of different organ origins. Studies at the cellular and animal levels have shown that lithium exerts antitumor effects in some tumors of specific organ origin (shown in the blue zone), but the effects on others remain elusive (shown in the red zone).

Figure 4

The landscape of lithium in cancer. The tumor-biological roles of lithium provide new sights into its potential for cancer therapy. Lithium inhibits tumor development mainly by suppressing proliferation and metastasis, and promoting programmed cell death. Lithium may reduce side effects and enhance the efficiency of several traditional therapies against cancer.