Metal Complex Formation and Anticancer Activity of Cu(I) and Cu(II) Complexes with Metformin

Abstract

Metformin has been used for decades in millions of type 2 diabetes mellitus patients. In this time, correlations between metformin use and the occurrence of other disorders have been noted, as well as unpredictable metformin side effects. Diabetes is a significant cancer risk factor, but unexpectedly, metformin-treated diabetic patients have lower cancer incidence. Here, we show that metformin forms stable complexes with copper (II) ions. Both copper(I)/metformin and copper(II)/metformin complexes form adducts with glutathione, the main intracellular antioxidative peptide, found at high levels in cancer cells. Metformin reduces cell number and viability in SW1222 and K562 cells, as well as in K562-200 multidrug-resistant cells. Notably, the antiproliferative effect of metformin is enhanced in the presence of copper ions.

Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

“…Binding of mitochondrial copper by metformin will slow down the mitochondrial electron transport chain and inhibit the differentiation of tumor cells from the epithelial to the metastatic prone mesenchymal state [ 38 ]. Additionally, metformin–copper complexes may bind intracellular antioxidants, making the cell more susceptible to ROS damage and apoptosis [ 56 ].…”

Metals and Metal-Nanoparticles in Human Pathologies: From Exposure to Therapy

“…The toxic mechanisms of copper-drug complexes can be effectively used in cancer therapy but must be taken into consideration in drug therapies in the pathologies correlated with copper unbalance, e.g., diabetes. For instance, metformin is the first-line treatment in type 2 diabetes mellitus (T2DM), while Copper(II)/metformin complexes have high stability and can bind to biologically important molecules (e.g., DNA and GSH) and have shown promising results in vitro as anti-cancer therapies [124].…”

Study of the DNA binding mechanism and in vitro activity against cancer cells of iron(iii) and aluminium(iii) kojic acid derivative complexes

“…Unexpectedly, widely and long-term used drugs with metal-binding sites showed anti-cancer activity, when complexed to essential metal ions. For instance, metformin-first-line therapy for the treatment of type 2 diabetes-forms stable complexes with copper ions, 12 which bind to DNA. [13][14][15] Kojic acid (5-hydroxy-2-(hydroxymethy1)-4H-pyran-4-one; KA) is a metal chelator of natural origin, produced by several species of fungi, particularly Aspergillus oryzae.…”

“…Unexpectedly, widely and long-term used drugs with metal-binding sites showed anti-cancer activity, when complexed to essential metal ions. For instance, metformin-first-line therapy for the treatment of type 2 diabetes-forms stable complexes with copper ions, 12 which bind to DNA. 13–15…”