Co-Treatment with Sulforaphane and Nano-Metformin Molecules Accelerates Apoptosis in HER2+ Breast Cancer Cells by Inhibiting Key Molecules

Abstract

Breast cancer cell lines MCF-10, MCF-7 and BT-474 expressing various levels of HER2 were examined for their response to treatment with sulforaphane (SLFN), metformin (MTFN), Nano-MTFN or combinations. Direct correlation was found between SLFN effect on cell death and HER2 levels. Bioinformatic studies suggested the possibility of additive co-effects on cell fate by SLFN-MTFN co-treatment. This co-treatment specially with SLFN + Nano-MTFN significantly affected the survival of the cells and killed more BT-474 cells than the other two. Cell sensitivity to SLFN-MTFN combination correlated with HER2 expression levels. RT-PCR showed that parallel with cell death, expression of BCL-2, SRC, WNT1, β-catenin and CD44 are diminished, whereas BAX levels are elevated significantly. Cell co-staining indicated that apoptosis percent correlates with cell death following different treatments. We also found that cell death induced by SLFN-MTFN co-treatment is in direct correlation with HER2 levels and increased cell death correlates directly with BAX levels but inversely with levels of cancer stem cell (CSC) signaling genes and CD44. In conclusion, our data indicate that SLFN and MTFN can reduce cancer cell viability via both collaborative and differential effects and suggest that MTFN increases SLFN effectiveness by targeting common molecules/pathways downstream of HER2 and key for CSC signaling.