Abstract
Crotepoxide (a substituted cyclohexane diepoxide), isolated from Kaempferia pulchra (peacock ginger), although linked to antitumor and anti-inflammatory activities, the mechanism by which it exhibits these activities, is not yet understood. Because nuclear factor kappaB (NF-kappaB) plays a critical role in these signaling pathways, we investigated the effects of crotepoxide on NF-kappaB-mediated cellular responses in human cancer cells. We found that crotepoxide potentiated tumor necrosis factor (TNF), and chemotherapeutic agents induced apoptosis and inhibited the expression of NF-kappaB-regulated gene products involved in anti-apoptosis (Bcl-2, Bcl-xL, IAP1,(2) MCl-1, survivin, and TRAF1), apoptosis (Bax, Bid), inflammation (COX-2), proliferation (cyclin D1 and c-myc), invasion (ICAM-1 and MMP-9), and angiogenesis (VEGF). We also found that crotepoxide inhibited both inducible and constitutive NF-kappaB activation. Crotepoxide inhibition of NF-kappaB was not inducer-specific; it inhibited NF-kappaB activation induced by TNF, phorbol 12-myristate 13-acetate, lipopolysaccharide, and cigarette smoke. Crotepoxide suppression of NF-kappaB was not cell type-specific because NF-kappaB activation was inhibited in myeloid, leukemia, and epithelial cells. Furthermore, we found that crotepoxide inhibited TAK1 activation, which led to suppression of IkappaBalpha kinase, abrogation of IkappaBalpha phosphorylation and degradation, nuclear translocation of p65, and suppression of NF-kappaB-dependent reporter gene expression. Overall, our results indicate that crotepoxide sensitizes tumor cells to cytokines and chemotherapeutic agents through inhibition of NF-kappaB and NF-kappaB-regulated gene products, and this may provide the molecular basis for crotepoxide ability to suppress inflammation and carcinogenesis.
Highlights
nuclear factor B (NF-B)-regulated gene products involved in anti-apoptosis effective
We found that crotepoxide potenti- modern medicines tend to target only one gene product or ated tumor necrosis factor (TNF), and chemotherapeutic pathway at a given time
We determined its effects on the NF-B activation pathway as induced by various carcinogens and inflammatory stimuli as well as expression of NF-B-regulated gene products and apoptosis in leukemic cells
Summary
Plants including Piper kadsura (6 – 8), Monanthotaxis caffra [9], Friesodielsia obovata (Annonaceae) [10], Kaempferia angustifolia [11], and Kaempferia pulchra (peacock ginger) [12]. Nuclear factor-B (NF-B), a transcription factor that has a critical role in inflammation, is responsible for regulation of genes involved in cell survival, adhesion, differentiation, and growth. These genes include antiapoptotic (e.g. c-IAP, survivin, tumor necrosis factor receptor (TNFR)-associated factor (TRAF), cellular FLICE inhibitory protein, Bcl-2, and Bcl-xL), inflammatory (cyclooxygenase-2 (COX-2)), or invasive Crotepoxide Suppresses NF-B and Potentiates Apoptosis metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF)) and can encode adhesion molecules, chemokines, and cell-cycle regulation (e.g. cyclin D1 and c-myc) [14]. Because NF-B is known to regulate inflammation and tumorigenesis, we hypothesized that the anti-inflammatory and anticancer effects ascribed to crotepoxide may be due to its inhibition of NF-B and NF-B-regulated gene expression. We demonstrate that this crotepoxide can block NF-B pathway and potentiate the anticancer effects of various chemotherapeutic drugs
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