Novel inhibitor against Rac1 for therapeutic approach in prevention of breast cancer progression

Abstract

Metastatic breast-cancer is one of the major causes of death, due to remaining dormant cancer cells for several years. Rac1 is upregulated with cancer and stay elevated throughout the metastatic pathway to regulate the formation of lamellipodia and filopodia. This work developed peptide FGDWS as novel inhibitor targeting Rac1-Tiam1 binding site by in-silico as it was found to be the strongest interacting peptide with Rac1 at the Tiam binding site. The binding and inhibition study of peptide with Rac1 was performed by Surface plasmon resonance and MTT assay, respectively. Cell-migration, apoptotic assay and western-blot in breast-cancer cells were performed with FGDWS and in combination with Doxorubicin (Dox). Tumor regression experiment was done with mice model. The strong binding of FGDWS with Rac1 and reduction of cell-viability were observed in breast-cancer cell-lines. The cell-migration was suppressed, and higher regression were obtained in synergy group. The apoptotic effect of FGDWS alone and with Dox were detected by annexin-V via activating caspase3/7. The tumor size was reduced by the treatment of FGDWS and more reduced in combinatorial effect. The combinatorial effect of FGDWS-Dox may enhance the treatment efficacy without side-effects.