Incorporation of Sulfonamide Moiety into Biguanide Scaffold Results in Apoptosis Induction and Cell Cycle Arrest in MCF-7 Breast Cancer Cells.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Antineoplastic Agents*/chemical synthesis ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/pharmacology ; Biguanides*/chemistry ; Biguanides*/pharmacology ; Breast Neoplasms*/drug therapy ; Breast Neoplasms*/metabolism ; Breast Neoplasms*/pathology ; Sulfonamides*/chemistry ; Sulfonamides*/pharmacology; Apoptosis/*drug effects ; Cell Cycle Checkpoints/*drug effects; Female ; Humans ; MCF-7 Cells

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 (IC 50 = 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.

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503/3-015-01/503-31-001-19-00 Uniwersytet Medyczny w Lodzi; 294227 Academy of Finland

Keywords: apoptosis; cell cycle arrest; cellular uptake; metformin; sulfonamides

0 (Antineoplastic Agents)
0 (Biguanides)
0 (Sulfonamides)

Date Created: 20210602 Date Completed: 20210617 Latest Revision: 20210617

20221213

PMC8198066

10.3390/ijms22115642

34073245