Publication: Targeting monocarboxylate transporter 1 in statin-related anti-cancer effects on mda-mb-231 cell line: in vitro and in silico studies
No Thumbnail Available
Date
2025-01
Authors
Lee, Michelle
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer due to its poor prognosis and limited targeted therapeutic options, necessitating the exploration of novel treatment strategies. This study investigates the anti-cancer effects of statins on the MDA-MB-231 cell line by targeting the functional inhibition of monocarboxylate transporter 1 (MCT1). Drug treatments with lipophilic statin (simvastatin, lactone form), hydrophilic statin (pravastatin, lactone form), AZD3965 (specific MCT1 inhibitor) and tamoxifen were tested through various assays; MTT assay was for IC50 determination, wound healing/scratch assay for cell migratory capacity assessment, and LDH activity assay for metabolic activity. In addition, molecular docking analysis was carried out to compare the binding affinities of simvastatin lactone versus simvastatin acid and simvastatin lactone versus pravastatin lactone to human MCT1. The drug treatment (24 hours) in the MDA-MB-231 cells revealed the following IC50 values: simvastatin (66.5 μM, 95% CI: 51.8 - 87.9 μM), AZD3965 (69.1 μM, 95% CI: 59.6 - 79.0 μM) and tamoxifen (28.8 μM, 95% CI: 26.1 - 32.4 μM). Compared to untreated cells, simvastatin significantly inhibited migratory capacity (P < 0.05) within the concentration range of 12.5 μM to 66 μM and increased LDH activity (P < 0.05) at 50 μM. Remarkably, simvastatin demonstrated comparable effects to AZD3965 on cell viability, migratory capacity, and LDH activity (P > 0.05), highlighting its potential as an anticancer agent Molecular docking simulations revealed that simvastatin lactone (-7.1 kcal/mol) had stronger binding affinity to MCT1 than pravastatin lactone (-6.9 kcal/mol), reflecting that lipophilicity influences affinity to MCT1. However, simvastatin acid (-6.9 kcal/mol) showed lower binding affinity than simvastatin lactone, likely due to lower lipophilicity and permeability. Overall, these findings highlight the potential significance of simvastatin-targeting MCT1 in the development of novel therapeutic approaches for TNBC
Description
Keywords
-