Breast Cancer Cell Apoptosis is Synergistically Induced by Curcumin, Trastuzumab, and Glutathione Peroxidase-1 but Robustly Inhibited by Glial Cell Line-Derived Neurotrophic Factor.

We hypothesized that synergy between curcumin (CURC), trastuzumab (TZMB), and glutathione peroxidase-1 (GPX-1) accelerates breast cancer (BC) cell apoptosis which is inhibited by glial cell line-derived neurotrophic factor (GDNF). We measured survival of BC cell lines treated or cotreated with CURC and TZMB, and then with GDNF, before measuring expression levels of growth and apoptosis genes. These experiments were also repeated on SKBR3 cells transiently expressing GPX-1. CURC+TZMB cotreatment induced BC cell apoptosis more significantly than single treatment. GDNF highly inhibited CURC+TZMB toxicity and restored survival. Ectopic overexpression of GPX-1 per se induced SKBR3 cell death that was accelerated upon CURC+TZMB cotreatment. This substantial death induction was inhibited by GDNF more robustly than in single-treated cells. All these changes correlated with changes in expression levels of key molecules and were further confirmed by flow cytometry and correlation analysis. Our data indicate apoptotic induction is jointly shaped in BC cells by CURC, TZMB, and GPX-1 which correlates directly with their tripartite synergism and inversely with GDNF progrowth effects. In light of the active presence of GDNF in tumor microenvironment and necessity to overcome drug resistance, our findings can help in designing combined therapeutic strategies with implications for challenging TZMB resistance in BC.