Sulforaphane suppresses TNF-α-mediated activation of NF-κB and induces apoptosis through activation of reactive oxygen species-dependent caspase-3

Sulforaphane (SFN) is a biologically active compound extracted from cruciferous vegetables, and possessing potent anti-cancer and anti-inflammatory activities. Here, we show that tumor necrosis factor-α (TNF-α), in combination with a sub-toxic dose of SFN, significantly triggered apoptosis in TNF-α-resistant leukemia cells (THP-1, HL60, U937, and K562), which was associated with caspase activity and poly (ADP-ribose)-polymerase cleavage. We also report that SFN non-specifically inhibited TNF-α-induced NF-κB activation through the inhibition of IκBα phosphorylation, IκBα degradation, and p65 nuclear translocation. This inhibition correlated with the suppression of NF-κB-dependent genes involved in anti-apoptosis (IAP-1, IAP-2, XIAP, Bcl-2, and Bcl-xL), cell proliferation (c-Myc, COX-2, and cyclin D1), and metastasis (VEGF and MMP-9). These effects suggest that SFN inhibits TNF-α-induced NF-κB activation through the suppression of IκBα degradation, leading to reduced expression of NF-κB-regulated gene products. Combined treatment with SFN and TNF-α was also accompanied by the generation of reactive oxygen species (ROS). Pre-treatment with N-acetyl-l-cysteine significantly attenuated the combined treatment-induced ROS generation and caspase-3-dependent apoptosis, implying the involvement of ROS in this type of cell death. In conclusion, the results of the present study indicate that SFN suppresses TNF-α-induced NF-κB activity and induces apoptosis through activation of ROS-dependent caspase-3.