Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells

Metformin is a substrate for plasma membrane monoamine transporters (PMAT) and organic cation transporters (OCTs); therefore, the expression of these transporters and interactions between them may affect the uptake of metformin into tumor cells and its anticancer efficacy. The aim of this study was...

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Autores principales: Markowicz-Piasecka, Magdalena, Komeil, Ibrahim, Huttunen, Johanna, Sikora, Joanna, Huttunen, Kristiina M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177633/
https://www.ncbi.nlm.nih.gov/pubmed/32235654
http://dx.doi.org/10.3390/ijms21072389
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author Markowicz-Piasecka, Magdalena
Komeil, Ibrahim
Huttunen, Johanna
Sikora, Joanna
Huttunen, Kristiina M.
author_facet Markowicz-Piasecka, Magdalena
Komeil, Ibrahim
Huttunen, Johanna
Sikora, Joanna
Huttunen, Kristiina M.
author_sort Markowicz-Piasecka, Magdalena
collection PubMed
description Metformin is a substrate for plasma membrane monoamine transporters (PMAT) and organic cation transporters (OCTs); therefore, the expression of these transporters and interactions between them may affect the uptake of metformin into tumor cells and its anticancer efficacy. The aim of this study was to evaluate how chemical modification of metformin scaffold into benzene sulfonamides with halogen substituents (compounds 1–9) may affect affinity towards OCTs, cellular uptake in two breast cancer cell lines (MCF-7 and MDA-MB-231) and antiproliferative efficacy of metformin. The uptake of most sulfonamides was more efficient in MCF-7 cells than in MDA-MB-231 cells. The presence of a chlorine atom in the aromatic ring contributed to the highest uptake in MCF-7 cells. For instance, the uptake of compound 1 with o-chloro substituent in MCF-7 cells was 1.79 ± 0.79 nmol/min/mg protein, while in MDA-MB-231 cells, the uptake was considerably lower (0.005 ± 0.0005 nmol/min/mg protein). The elevated uptake of tested compounds in MCF-7 was accompanied by high antiproliferative activity, with compound 1 being the most active (IC(50) = 12.6 ± 1.2 µmol/L). Further studies showed that inhibition of MCF-7 growth is associated with the induction of early and late apoptosis and cell cycle arrest at the G0/G1 phase. In summary, the chemical modification of the biguanide backbone into halogenated sulfonamides leads to improved transporter-mediated cellular uptake in MCF-7 and contributes to the greater antiproliferative potency of studied compounds through apoptosis induction and cell cycle arrest.
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spelling pubmed-71776332020-04-28 Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells Markowicz-Piasecka, Magdalena Komeil, Ibrahim Huttunen, Johanna Sikora, Joanna Huttunen, Kristiina M. Int J Mol Sci Article Metformin is a substrate for plasma membrane monoamine transporters (PMAT) and organic cation transporters (OCTs); therefore, the expression of these transporters and interactions between them may affect the uptake of metformin into tumor cells and its anticancer efficacy. The aim of this study was to evaluate how chemical modification of metformin scaffold into benzene sulfonamides with halogen substituents (compounds 1–9) may affect affinity towards OCTs, cellular uptake in two breast cancer cell lines (MCF-7 and MDA-MB-231) and antiproliferative efficacy of metformin. The uptake of most sulfonamides was more efficient in MCF-7 cells than in MDA-MB-231 cells. The presence of a chlorine atom in the aromatic ring contributed to the highest uptake in MCF-7 cells. For instance, the uptake of compound 1 with o-chloro substituent in MCF-7 cells was 1.79 ± 0.79 nmol/min/mg protein, while in MDA-MB-231 cells, the uptake was considerably lower (0.005 ± 0.0005 nmol/min/mg protein). The elevated uptake of tested compounds in MCF-7 was accompanied by high antiproliferative activity, with compound 1 being the most active (IC(50) = 12.6 ± 1.2 µmol/L). Further studies showed that inhibition of MCF-7 growth is associated with the induction of early and late apoptosis and cell cycle arrest at the G0/G1 phase. In summary, the chemical modification of the biguanide backbone into halogenated sulfonamides leads to improved transporter-mediated cellular uptake in MCF-7 and contributes to the greater antiproliferative potency of studied compounds through apoptosis induction and cell cycle arrest. MDPI 2020-03-30 /pmc/articles/PMC7177633/ /pubmed/32235654 http://dx.doi.org/10.3390/ijms21072389 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Markowicz-Piasecka, Magdalena
Komeil, Ibrahim
Huttunen, Johanna
Sikora, Joanna
Huttunen, Kristiina M.
Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells
title Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells
title_full Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells
title_fullStr Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells
title_full_unstemmed Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells
title_short Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells
title_sort effective cellular transport of ortho-halogenated sulfonamide derivatives of metformin is related to improved antiproliferative activity and apoptosis induction in mcf-7 cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177633/
https://www.ncbi.nlm.nih.gov/pubmed/32235654
http://dx.doi.org/10.3390/ijms21072389
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