Sulfonamide metformin derivatives induce mitochondrial-associated apoptosis and cell cycle arrest in breast cancer cells.

ABSTRACT

Metformin, an oral anti-diabetic drug, has attracted scientific attention due to its anti-cancer effects. This biguanide exerts preventive effects against cancer, and interferes with cancer-promoting signaling pathways at the cellular level. However, the direct cytotoxic or anti-proliferative effect of the drug is observed at very high concentrations, often exceeding 5-10 mM. This paper presents the synthesis of eight novel sulfonamide-based biguanides with improved cellular uptake in two breast cancer cell lines (MCF-7 and MDA-MB-231), and evaluates their effects on cancer cell growth. The synthesized sulfonamide-based analogues of metformin (1-5) were efficiently taken up in MCF-7 and MDA-MB-231 cells, and were characterized by stronger cytotoxic properties than those of metformin. Generally, compounds were more effective in MCF-7 than in MDA-MB-231. Compound 2, with an n-octyl chain, was the most active molecule with IC50 = 114.0 µmol/L in MCF-7 cells. The cytotoxicity of compound 2 partially results from its ability to induce early and late apoptosis. Increased intracellular reactive oxygen species (ROS) production and reduced mitochondrial membrane potential suggest that compound 2 promotes mitochondrial dysfunction and activates the mitochondrial-associated apoptosis-signaling pathway. In addition, compound 2 was also found to arrest cell cycle in the G0/G1 and G2/M phase and significantly inhibit cancer cell migration. In conclusion, this study supports the hypothesis that improved transporter-mediated cellular uptake of potential drug molecule is accompanied by its increased cytotoxicity. Therefore, compound 2 is a very good example of how chemical modification of a biguanide scaffold can affect its biological properties and improve anti-neoplastic potential.