Scheme 1

Schematic illustration of the role of autophagy in T-DM1-triggered cytotoxicity in SK-BR-3 as well as BT-474 cells. In brief, T-DM1 is internalized upon interacting with HER2 on the cellular surface, and degraded into cytotoxic metabolites by proteases in lysosomes. The toxic agent promotes Caspase-3/7 dependent apoptosis and autophagy afterwards. Mechanistically, Akt/mTOR pathway inhibition is crucial in autophagy triggered by T-DM1, and the relationship between autophagy and apoptosis is also identified. Blocking autophagy via pharmacological inhibitors partly reduced T-DM1-induced apoptotic cell death, indicating that autophagy triggered by T-DM1 therapy played a cytotoxic role which facilitated apoptosis in human HER2-overexpressed breast cancer cells