Inhibition of mitogen-activated protein kinase, kinase enhances apoptosis induced by arsenic trioxide in human breast cancer MCF-7 cells

1. Arsenic trioxide (As2O3) has recently been used to treat acute promyelocytic leukaemia and has activity in vitro against several solid tumour cell lines where the induction of differenti-ation and apoptosis are the prime effects. The mechanism of As2O3-induced cell death has yet to be clarified, especially in solid cancers. 2. In the present study, the human breast cancer cell line MCF-7 was examined as a cellular model for As2O3 treatment. The involvement of extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) was investigated in As2O3-induced cell death. 3. It was found that As2O3 activates the prosurvival mitogen-activated protein kinase kinase (MEK)/ERK pathway in MCF-7 cells, which, conversely, may compromise the efficacy of As2O3. Hence, a combination treatment of As2O3 and MEK inhibitors was investigated to determine whether this treatment could lead to enhanced growth inhibition and apoptosis in MCF-7 cells. 4. Inhibition of MEK/ERK with the pharmacological inhibitors U0126 (1