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.

Effects of mimosine administered to a perfused area of skin in Angora goats

The effect of mimosine on a perfused area of skin tissue was studied using an isolated perfusion technique. Four mature Angora wethers (body weight 35 (SE 2·3) kg) were cannulated bilaterally with indwelling silicone catheters in the superficial branches of the deep circumflex iliac artery and vein. Mimosine (40 mg/kg metabolic weight (W0·75) per d) was infused intra-arterially into one iliac artery of each goat for 3 d and saline was infused in the contralateral (control) iliac artery. Iliac venous blood samples were taken from both sides along with arterial samples from the carotid artery. Mimosine infusion elevated plasma mimosine in the carotid artery (52·6 (SEM 19·21)µmol/I) and iliac vein on the saline-treated side to 54·1 (SEM 16·31)µ/I and in the iliac vein on the mimosine-treated side to 191·3 (SEM19·14) µmol/I (P < 0·01). Mimosine decreased feed intake (2·3 v. 0·6 kg/d, SEM 0·29; P < 0·001) and water consumption (5·2 v. 1·3 litres/d, SEM 0·67; P < 0·001). Mimosine did not cause defleecing in the area of infusion and was cleared from the bloodstream within 12 h of cessation of infusion. The following effects were also observed during mimosine infusion: decrease in plasma amino acids to half pre-infusion values (methionine 22·7 v. 13·1 µmol/l, SEM 1·41; lysine 95·9 p. 37·4 µmol/l, SEM 4·28; P < 0·001); decreases in plasma triiodothyronine (1495 v. 695 ng/l, SEM 43·1; P < 0·001), thyroxine (61·5 v. 19·5 µg/l, SEM 1·8; P < 0·001) and insulin (28·7 v. 17·3 µIU/ml, SEM 1·89; P < 0·01) concentrations; increase in plasma cortisol (14 v. 62 µg/l, SEM 0·35; P < 0·001) concentration; decreases in levels of plasma Zn and Mg (0·97. v. 0·49 mg/l, SEM 0·063; P < 0·001 and 21·4 v. 14·6 mg/l, SEM 1·74; P < 0·001 respectively). All reported variables returned to their normal values 24 h after cessation of mimosine infusion except feed intake which was affected for a longer period. Mohair length and diameter were not affected by mimosine infusion. The toxicity of mimosine may be due to the drastic depletion of Zn and Mg in the blood as mimosine possesses very strong chelating properties and is excreted in the urine as a chelate.