Back to Search
Start Over
Effective Cellular Transport of Ortho -Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Mar 30; Vol. 21 (7). Date of Electronic Publication: 2020 Mar 30. - Publication Year :
- 2020
-
Abstract
- 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 <subscript>50</subscript> = 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.
- Subjects :
- Antineoplastic Agents chemistry
Antineoplastic Agents pharmacokinetics
Apoptosis drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Female
Halogenation
Humans
Hypoglycemic Agents chemistry
Hypoglycemic Agents pharmacokinetics
Hypoglycemic Agents pharmacology
MCF-7 Cells
Metformin analogs & derivatives
Metformin pharmacokinetics
Sulfonamides chemistry
Sulfonamides pharmacokinetics
Antineoplastic Agents pharmacology
Breast Neoplasms drug therapy
Metformin pharmacology
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 32235654
- Full Text :
- https://doi.org/10.3390/ijms21072389