Abstract
Metformin, apart from its glucose-lowering properties, has also been found to demonstrate anti-cancer properties. Anti-cancer efficacy of metformin depends on its uptake in cancer cells, which is mediated by plasma membrane monoamine transporters (PMAT) and organic cation transporters (OCTs). This study presents an analysis of transporter mediated cellular uptake of ten sulfonamide-based derivatives of metformin in two breast cancer cell lines (MCF-7 and MDA-MB-231). Effects of these compounds on cancer cell growth inhibition were also determined. All examined sulfonamide-based analogues of metformin were characterized by greater cellular uptake in both MCF-7 and MDA-MB-231 cells, and stronger cytotoxic properties than those of metformin. Effective intracellular transport of the examined compounds in MCF-7 cells was accompanied by high cytotoxic activity. For instance, compound 2 with meta-methyl group in the benzene ring inhibited MCF-7 growth at micromolar range (IC50 = 87.7 ± 1.18 µmol/L). Further studies showed that cytotoxicity of sulfonamide-based derivatives of metformin partially results from their ability to induce apoptosis in MCF-7 and MDA-MB-231 cells and arrest cell cycle in the G0/G1 phase. In addition, these compounds were found to inhibit cellular migration in wound healing assay. Importantly, the tested biguanides are more effective in MCF-7 cells at relatively lower concentrations than in MDA-MB-231 cells, which proves that the effectiveness of transporter-mediated accumulation in MCF-7 cells is related to biological effects, including MCF-7 cell growth inhibition, apoptosis induction and cell cycle arrest. In summary, this study supports the hypothesis that effective transporter-mediated cellular uptake of a chemical molecule determines its cytotoxic properties. These results warrant a further investigation of biguanides as putative anti-cancer agents.
Highlights
Drug repositioning or repurposing, in contrast to a drug discovery process, is an effective approach to explore a new biological activity and identify novel indications for already well-known drugs [1]
Apart from the above-mentioned applications related to its glucose-lowering properties, the drug is characterized by multidirectional biological activity which contributes to favorable effects on the mortality rate in diabetic patients and improves the serum lipids profile, blood coagulation, and function of endothelium [4]
In the case of MATE transporters similar significant expression of MATE 1 in both cell lines was reported [26]. These results are in agreement with outcomes of Cai et al [19] who concluded that there is a relationship between the presence of cation-selective transporters, the effectiveness of metformin uptake and its antiproliferative activity
Summary
In contrast to a drug discovery process, is an effective approach to explore a new biological activity and identify novel indications for already well-known drugs [1]. There are numerous examples of effective drug repurposing with two well-known cases—anti-Parkinson amantadine, initially developed for influenza, and anti-HIV zidovudine, originally developed as an anti-cancer drug [2]. Apart from the above-mentioned applications related to its glucose-lowering properties, the drug is characterized by multidirectional biological activity which contributes to favorable effects on the mortality rate in diabetic patients and improves the serum lipids profile, blood coagulation, and function of endothelium [4]. Beneficial characteristics of metformin caused an increased scientific interest due to its potential application of metformin as an anti-cancer agent. The majority of preclinical studies have consistently shown promising anti-proliferative effects of the drug in some cancer cell lines, and this has been replicated to some degree in in vivo studies [5,6,7]
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