Arsenic hexoxide enhances TNF-alpha-induced anticancer effects by inhibiting NF-kappa B activity at a safe dose in MCF-7 human breast cancer cells

Abstract

Arsenic hexoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980s. Evidence suggests that the anticancer effects of As4O6 are different from those of As2O3. Tumor necrosis factor-alpha (TNF-alpha) is generally increased in advanced cancer and is closely related to cancer progression, although it has cancer-killing effects. The reason is that TNF-alpha activates nuclear factor-kappa B (NF-kappa B) that is involved in cell proliferation, invasion, drug resistance and metastasis. In the present study, we investigated the effects of As4O6 on NF-kappa B activity, NF-kappa B-mediated cellular responses, and NF-kappa B-regulated gene expressions involved in metastasis at the concentrations of As4O6 where no cytotoxicity was observed. As4O6 suppressed NF-kappa B activation in both TNF-alpha-treated and control cells, and also suppressed I kappa B phosphorylation in a time-dependent manner, suggesting the suppression of NF-kappa B results, in part, from the inhibition of I kappa B degradation. We also confirmed the anti-NF-kappa B activity of As4O6 with synergism with TNF-alpha by augmenting caspase-8 activation. As4O6 also suppressed NF-kappa B activation induced by TNF-alpha, and some of the downstream NF-kappa B-regulated proteins involved in cancer proliferation, anti-apoptosis and metastasis. In conclusion, the present study demonstrated that As4O6 has anticancer properties by inhibiting NF-kappa B activation and NF-kappa B-regulated proteins at least in part through the inhibition of I kappa B phosphorylation, especially in the conditions of advanced cancer where TNF-alpha is highly secreted.