The Role of Glycyrrhizin, an Inhibitor of HMGB1 Protein, in Anticancer Therapy

Certain anticancer drugs, such as the peptide CAMEL (aa sequence KWKLFKKIGAULKVL) induce necrotic type of cell death. During this process, a protein termed high mobility group box 1 (HMGB1) is released from cell nucleus into cytoplasm and then into extracellular milieu. Outside of cells, it becomes a proinflammatory cytokine. Its effects range from stimulation of cancer as well as endothelial cell proliferation, to activation of angiogenesis, cell motility and induction of inflammatory conditions. Release of HMGB1 cytokine during the course of anticancer therapy has negative effects upon the therapy itself, since it leads to tumor relapse. We assumed that the inhibition of HMGB1 activity may be conducive towards better therapeutic results in case of drugs inducing necrotic cell death. In this context we studied glycyrrhizin (GR), a triterpenoid saponin glycoside of glycyrrhizic acid and a well-known inhibitor of HMGB1. We have shown that GR inhibits proliferation and migration of cells stimulated by HMGB1 cytokine, as well as HMGB1-induced formation of blood vessels and reduces inflammatory condition (lowering tumor necrosis factor alpha levels). GR-mediated inhibition of HMGB1 activity (CAMEL-induced release) impedes, in turn, tumor regrowth in mice. As expected, inhibited tumor regrowth is linked to diminished tumor levels of the released HMGB1 and reduced inflammatory condition. To conclude, the use of GR significantly improved anticancer effectiveness of the CAMEL peptide.