interleukin-8 and butein

Chronic inflammation appears to be a driving force behind cancer progression. NFκB and STAT3 activation plays a pertinent role in this process by mediating chemoresistance and the acquisition of mesenchymal features of protumorigenic cells. Epidemiological data and experimental observations suggest that Malignant Pleural Mesothelioma (MPM) is a prototype of chronic inflammation-driven cancer. Chemoresistance is a major feature of MPM. Thus, this paper explores the effect of butein (3,4,2',4'-tetrahydroxychalcone), a naturally occurring NFκB and STAT3 inhibitor, on the tumorigenic properties of MPM cells. MPM cells harbor high nuclear levels of NFκB and pSTAT3(Y(705)). Butein inhibits pSTAT3(Y(705)) phosphorylation, nuclear localization of NFκB and the physical interaction of NFκB and pSTAT3. This correlates with a downregulation of several genes involved in cancer progression (such as ICAM1, Vimentin, MMP9, Twist) of proangiogenic cytokines (VEGF) and of IL-6 and IL-8, key growth factors for MPM. Hence, butein inhibits the migration of MPM cells and strongly affects the clonogenicity of MPM cells in vitro. Finally, we show that the in vitro actions of butein translate into anticancer effects in vivo. In fact, butein treatment severely affects tumor engraftment and potentiates the anticancer effects of pemetrexed in mouse xenograft models. Butein does not significantly affect the viability of human, untransformed mesothelial cells in vitro, nor does it affect survival of tumor-free mice in vivo. The possibility of using butein as an additional treatment to current MPM therapies is discussed here.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Chalcones; Down-Regulation; Glutamates; Guanine; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Matrix Metalloproteinase 9; Mesothelioma; Mice; Mice, Nude; NF-kappa B; Pemetrexed; Phosphorylation; Pleural Neoplasms; STAT3 Transcription Factor; Transplantation, Heterologous; Twist-Related Protein 1; Vascular Endothelial Growth Factor A; Vimentin

Activation of mast cells in rheumatoid synovial tissue has often been associated with tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 production and disease pathogenesis by adjacent cell types. Butea monosperma (BM) is a well known medicinal plant in India and the tropics. The aim of this study was to examine whether a standardized extract of BM flower (BME) could inhibit inflammatory reactions in human mast cells (HMC) using activated HMC-1 cells as a model. Four previously characterized polyphenols--butrin, isobutrin, isocoreopsin, and butein--were isolated from BME by preparative thin layer chromatography, and their purity and molecular weights were determined by liquid chromatography/mass spectrometry analysis. Our results showed that butrin, isobutrin, and butein significantly reduced the phorbol 12-myristate 13-acetate and calcium ionophore A23187-induced inflammatory gene expression and production of TNF-alpha, IL-6, and IL-8 in HMC-1 cells by inhibiting the activation of NF-kappaB. In addition, isobutrin was most potent in suppressing the NF-kappaB p65 activation by inhibiting IkappaBalpha degradation, whereas butrin and butein were relatively less effective. In vitro kinase activity assay revealed that isobutrin was a potent inhibitor of IkappaB kinase complex activity. This is the first report identifying the molecular basis of the reported anti-inflammatory effects of BME and its constituents butrin, isobutrin, and butein. The novel pharmacological actions of these polyphenolic compounds indicate potential therapeutic value for the treatment of inflammatory and other diseases in which activated mast cells play a role.

Topics: Butea; Calcimycin; Chalcones; Chromatography, Thin Layer; Enzyme-Linked Immunosorbent Assay; Flavonoids; Gas Chromatography-Mass Spectrometry; Gene Expression; Humans; I-kappa B Kinase; Inflammation; Interleukin-6; Interleukin-8; Mast Cells; NF-kappa B; Plant Extracts; Plants, Medicinal; Polymerase Chain Reaction; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

In this study, we evaluated whether butein can inhibit the effects of tumor necrosis factor alpha (TNF-alpha), an inflammatory mediator, in intestinal epithelial HT-29 cells. Butein significantly inhibited TNF-alpha-induced interleukin 8 (IL-8) secretion and mRNA expression. Moreover, butein suppressed the expression of matrix metalloproteinase 7 (MMP-7) mRNA and extracellular pro-MMP-7 secretion. The signal transduction study revealed that butein significantly attenuates p38 phosphorylation and inhibits osteopontin (OPN) mediated inhibitory factor kappaBalpha (I-kappaBalpha) phosphorylation in TNF-alpha-stimulated HT-29 cells. Using specific kinase inhibitors, we also found that blocking the p38 pathway is critical for, and blocking of OPN-mediated I-kappaBalpha phosphorylation pathway is at least for, the inhibitory effect by butein on TNF-alpha-induced IL-8 and MMP-7 expression. Furthermore, using an MMP inhibitor, we showed that IL-8 lies upstream of MMP-7 in the TNF-alpha-induced signaling process in HT-29 cells. Collectively, these results suggest that butein may be an effective agent for the treatment of intestinal inflammation.

Topics: Blotting, Western; Cell Survival; Chalcones; Enzyme Inhibitors; HT29 Cells; Humans; I-kappa B Kinase; Indicators and Reagents; Interleukin-8; Matrix Metalloproteinase 7; Matrix Metalloproteinase Inhibitors; Osteopontin; p38 Mitogen-Activated Protein Kinases; Phosphodiesterase Inhibitors; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tumor Necrosis Factor-alpha