Glyoxalase I inhibitors targeting breast cancer-associated endothelial cells: An integrated network pharmacology and experimental investigation

Background

Angiogenesis significantly contributes to breast cancer progression. While glyoxalase I (GLO1) has been extensively studied in endothelial cells related to cardiovascular and metabolic diseases, its role in breast cancer-associated endothelial cells (BCECs) remains unclear. Moreover, Additionally, a comprehensive analysis of GLO1 inhibitors is lacking. This study aims to systematically evaluate the pharmacological profiles of GLO1 inhibitors, identify those with potential effects on BCECs, and validate these findings experimentally.

Materials and methods

Seventeen GLO1 inhibitors were analyzed using SwissADME and pkCSM for their pharmacological profiles. Target identification employed SwissTargetPrediction and SuperPred, and intersected with differentially expressed genes (DEGs) from the GSE80506 dataset to construct a BCECs-relevant target network. This network underwent enrichment analysis, expression correlation analysis, and molecular docking. Experimental validation was conducted using cellular assays and an aortic ring assay in mice.

Results

Among 515 targets associated with the 17 GLO1 inhibitors, 36 were linked to BCECs regulation. Enrichment analysis highlighted the cell cycle as a pivotal pathway, with key targets including CCNA2, CCNE1, CDC25A, CDC25B, CDK6, CHEK1, PLK1, and TTK. Molecular docking indicated that Glyoxalase I inhibitor 6 plays a significant role in regulating these targets. Experimental assays demonstrated that this inhibitor arrested cells in the G0/G1 phase by modulating CCNA2 and CCNE1, suppressed BCECs proliferation, migration, and angiogenesis, and promoted cell death.

Conclusions

GLO1 inhibitors exhibit significant regulatory effects on BCECs. Notably, Glyoxalase I inhibitor 6 effectively inhibits cell cycle progression, proliferation, migration, and angiogenesis in these cells, suggesting a promising therapeutic approach for targeting tumor-associated endothelial cells in breast cancer.