Blockade Of TNF-A-Induced NF-KB Signaling Pathway And Anti-Cancer Therapeutic Response Of Dihydrotanshinone â… 

The nuclear factor-KB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and angiogenesis. We identified dihydrotanshinone Ⅰ as an inhibitor of NF-κB activation through our research on Salvia miltiorrhiza Bunge. In this study, we found that dihydrotanshinone Ⅰ significantly inhibited the expression of NF-κB reporter gene induced by TNF-a in a dose-dependent manner. And dihydrotanshinone Ⅰ also inhibited TNF-a induced phosphorylation and degradation of IκBα, phosphorylation and nuclear translocation of p65. Furthermore, pretreatment of cells with this compound prevented the TNF-a-induced expression of NF-κB target genes, such as anti-apoptosis (cIAP-1 and FLIP), proliferation (COX-2), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-a, IL-6, and MCP1). In additon, we also demonstrated that dihydrotanshinone Ⅰ potentiated TNF-a-induced apoptosis. Moreover, dihydrotanshinone Ⅰ significantly impaired activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK/SAPK). In vivo studies demonstrated that dihydrotanshinone Ⅰ suppressed the growth of HeLa cells in a xenograft tumor model, which could be correlated with its modulation of TNF-a production. Taken together, dihydrotanshinone Ⅰ could be a valuable candidate for the intervention of NF-κB-dependent pathological conditions such as inflammation and cancer.