Discovery Of The Novel NF-κB Pathway Natural Product Inhibitor: Hirsutolide, And It’s Anti-tumor Activity And Mechanism Study

The nuclear factor κB (NF-κB) comprises a family of transcription factors involved in the regulation of a wide variety of biological responses. NF-κB regulates the expression of genes involved in many processes that play a key role in the development and progression of cancer such as proliferation, migration and apoptosis. Natural products are one of the most important sources of the lead compounds in drug discovery.Recently, a great number of plant-derived substances have been evaluated as possible inhibitors of the NF-κB pathway. These include a wide range of compound classess, such as lignans (manassantins, (+)-saucernetin, (-)-saucerneol methyl ether), sesquiterpenes (costunolide, parthenolide, celastrol, celaphanol A), diterpenes (excisanin, kamebakaurin), triterpenes (avicin, oleandrin), polyphenols (resveratrol, epigallocatechin gallate, quercetin), etc.The cell-based HTS assay targeting NF-κB pathway was set up.After natural products were screened several types of NF-κB inhibitor were selected,and the effects of these compounds were investigated.Hirsutolide is a sesquiterpene lactone isolated from Vernonia bockiana. Hirsutolide inhibited TNFα-induced IκBα, degradation, IKKβ, p65 phosphorylation and induced apoptotic cell death.The small molecule selectively kills some hematologic tumor cells but not solid tumor cells or normal cells.Further analysis reaveled that Hirsutolide can down-regulate c-myc gene transcription and expression. A more interesting thing is that Ramos and Raji as two cell lines of human Burkitt’s lymphoma with a high percentage of translocations involving c-myc and the immunoglobulin loci show different responses to Hirsutolide.Raji is less sensitive to Hirsutolide than Ramos while Raji has c-myc proteins with mutated Thr58 or other mutations that abolish Thr58 phosphorylation, leading to escape from ubiquitin/proteasome-mediated turnover and accumulation of c-myc protein. These studies suggest that c-myc may play a crucial role in the selective anti- hematologic tumor activities of Hirsutolide.