Mimosine Induces Apoptosis through Metal Ion Chelation, Mitochondrial Activation and Reactive Oxygen Species Production in Human Leukemic Cells

Mimosine, a non-protein amino acid, acts as a reversible inhibitor of DNA replication, and is widely used to synchronize cells at G1 phase of the cell cycle. We tested the possibility that mimosine might have an apoptotic effect on two types of AML cells: the monoblastic U-937 and the promyelocytic HL-60 cell lines. We show that mimosine induces apoptosis in both cell lines, with U-937 cells being more sensitive. The apoptotic effect of mimosine was antagonized by the addition of exogenous iron, indicating that it may act through iron chelation. Its mode of action was thus compared to that of desferrioxamine (DFO), a therapeutic iron chelating agent. Mimosine and DFO differed in their sensitivity to the suppressive effect of exogenous sources of iron in the form of hemin and ferrous sulfate suggesting different targets of action. Addition of another metal ion cupric sulfate was also able to antagonize the apoptotic effect of mimosine, undermining the notion that apoptosis is mediated through inhibition of ribonucleotide reductase, since this enzyme is solely dependent on iron for its activity. Moreover, when higher concentrations of iron were added to mimosine, cell death shifted from apoptosis to necrosis. Induction of apoptosis by both mimosine and DFO caused an early reduction in mitochondrial transmembrane potential and increase in caspase-3 activity, while only mimosine induced oxidative stress. In summary, our results imply that besides its known effect on DNA synthesis and G1 arrest, mimosine also activates apoptosis through an intrinsic pathway as well as reactive oxygen species production and thus elicits its anticancer effect by multiple pathways.