Insight into the molecular mechanism of anti-breast cancer therapeutic potential of substituted salicylidene-based compounds using cell-based assays and molecular docking studies

Abstract

Targeting oxidative stress and inflammatory signaling pathways is an effective cancer prevention and therapy approach. The mechanism of action of synthesized salicylidene-based compounds was investigated in regulating key molecular targets of breast cancer development. Compounds (1), (4), (5), and (7) were found to be more cytotoxic to MCF-7 and 4T1 cells compared to non-cancerous Chang liver cells, while these compounds were cytotoxic to MDA-MB-231 cells, but with poor selectivity. The colony formation assay indicated that bioactive compounds induced significant damage to breast cancer cells, as observed by a reduction in the number of colonies compared to control cells. By inducing a concentration and time-dependent increase of luminescence and fluorescence of phosphatidylserine, and activating the expression of caspases-3, -7, -8, -9 in breast cancer cells, (1) and (7) have shown to induce caspase-dependent apoptosis. The downregulation of NF-kB-p65 and an upregulation of TP53 expression after exposure to bioactive compounds, demonstrated the suppression of two key targets of breast cancer development. Molecular docking studies revealed that selected protein targets strongly interact with bioactive compounds, and the estimated inhibition constants (Ki) of JAK2, STAT3, COX-2, HPV31 E6, EGFR1, TP53, and PARP1 were significantly decreased compared to acetylsalicylic acid. This could be a clear indication that these protein targets are implicated with antiproliferative efficacy, thereby warranting the potential of (1) and (7) to be used as anti-breast cancer drug candidates.