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.
Highlights
Metformin (N,N-dimethylbiguanide; 3-(diaminomethylidene)-1,1-dimethylguanidine) is an oral drug used daily as a first line treatment for type 2 diabetes mellitus (T2DM) by at least 120 million patients worldwide [1]
We aimed to explore the potential of metformin and its copper complexes as an anticancer agent, using the K562/Adr200 leukemic cell line, which exhibits multidrug resistance (MDR)—a major challenge in chemotherapy
Our results suggest that metformin has anticancer potential against human colorectal adenocarcinoma (SW1222) and chronic myelogenous leukemia (K562) cell lines
Summary
Metformin (N,N-dimethylbiguanide; 3-(diaminomethylidene)-1,1-dimethylguanidine) is an oral drug used daily as a first line treatment for type 2 diabetes mellitus (T2DM) by at least 120 million patients worldwide [1]. Different mechanisms of metformin action have been proposed at the cellular level. These include: the suppression of mitochondrial respiration by inhibition of complex I [2]; the regulation of AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) by multiple, mutually nonexclusive mechanisms The exact mechanisms of metformin therapeutic action are still poorly understood. Metformin and other biguanide derivatives were developed in the 1950s after the finding that the blood glucose-lowering ingredient in goat’s rue is guanidine. Guanidine and biguanide lead to liver damage, while metformin is a derivative with lower toxicity. In half a century of use, numerous metformin side-effects have been noted [5]
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