Identification of plumericin as a potent new inhibitor of the NF-κB pathway with anti-inflammatory activity in vitro and in vivo

The transcription factor NF‐κB orchestrates many pro‐inflammatory signals and its inhibition is considered a promising strategy to combat inflammation. Here we report the characterization of the natural product plumericin as a highly potent inhibitor of the NF‐κB pathway with a novel chemical scaffold, which was isolated via a bioactivity‐guided approach, from extracts of Himatanthus sucuuba, an Amazonian plant traditionally used to treat inflammation‐related disorders.

[1]  F. Luscinskas,et al.  Endothelial-Dependent Mechanisms of Leukocyte Recruitment to the Vascular Wall , 2007, Circulation research.

[2]  M Elofsson,et al.  The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. , 2001, Chemistry & biology.

[3]  C. Huck,et al.  Selected Extracts of Chinese Herbal Medicines: Their Effect on NF-κB, PPARα and PPARγ and the Respective Bioactive Compounds , 2012, Evidence-based complementary and alternative medicine : eCAM.

[4]  G. Haegeman,et al.  Cyclic AMP: a selective modulator of NF-κB action , 2011, Cellular and Molecular Life Sciences.

[5]  A. van der Eb,et al.  A new technique for the assay of infectivity of human adenovirus 5 DNA. , 1973, Virology.

[6]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[7]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[8]  Matthias Mann,et al.  IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation , 1997 .

[9]  S. Ghosh,et al.  Characterization of the Ikappa B-kinase NEMO binding domain. , 2002, The Journal of biological chemistry.

[10]  R. Hersperger,et al.  Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK. , 2006, Bioorganic & medicinal chemistry letters.

[11]  R. Scott,et al.  Inhibitory kappa B kinases as targets for pharmacological regulation , 2012, British journal of pharmacology.

[12]  Purificación Hernández-Vargas,et al.  Parthenolide Modulates the NF-&kgr;B–Mediated Inflammatory Responses in Experimental Atherosclerosis , 2006 .

[13]  J. Geng,et al.  The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a potential mechanism for thrombosis in eosinophilic inflammatory states. , 2006, Blood.

[14]  A. Amaral,et al.  Monograph of Himatanthus sucuuba, a plant of Amazonian folk medicine , 2007 .

[15]  M. Ehrich,et al.  In Vitro Methods for Detecting Cytotoxicity , 2000, Current protocols in toxicology.

[16]  M. Schmitz,et al.  Sesquiterpene lactone containing Mexican Indian medicinal plants and pure sesquiterpene lactones as potent inhibitors of transcription factor NF‐κB , 1997, FEBS letters.

[17]  C. Lugnier,et al.  NCS 613 exhibits anti-inflammatory effects on PBMCs from lupus patients by inhibiting p38 MAPK and NF-κB signalling pathways while reducing proinflammatory cytokine production. , 2013, Canadian journal of physiology and pharmacology.

[18]  Wei Chien Huang,et al.  Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel α-methylene-γ-butyrolactone derivatives , 2004 .

[19]  Â. Pinto,et al.  Anti-Inflammatory and Analgesic Activities of the Latex Containing Triterpenes from Himatanthus sucuuba , 2000, Planta medica.

[20]  M. Gerritsen,et al.  Novel Inhibitors of Cytokine-induced IκBα Phosphorylation and Endothelial Cell Adhesion Molecule Expression Show Anti-inflammatory Effects in Vivo* , 1997, The Journal of Biological Chemistry.

[21]  N. Nam Naturally occurring NF-kappaB inhibitors. , 2006, Mini reviews in medicinal chemistry.

[22]  C. Kilkenny,et al.  Guidelines for reporting experiments involving animals: the ARRIVE guidelines , 2010, British journal of pharmacology.

[23]  D. Kingston,et al.  A bioactive spirolactone iridoid and triterpenoids from Himatanthus sucuuba. , 2001, Chemical & pharmaceutical bulletin.

[24]  R. Lechler,et al.  Improved protocol for colorimetric detection of complement-mediated cytotoxicity based on the measurement of cytoplasmic lactate dehydrogenase activity. , 1996, Journal of immunological methods.

[25]  Wei‐Chien Huang,et al.  Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel alpha-methylene-gamma-butyrolactone derivatives. , 2004, Carcinogenesis.

[26]  N. Perkins,et al.  Integrating cell-signalling pathways with NF-kappaB and IKK function. , 2007, Nature reviews. Molecular cell biology.

[27]  D B Young,et al.  IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. , 1997, Science.

[28]  V. Leksa,et al.  Mannose 6-phosphate/insulin-like growth factor 2 receptor limits cell invasion by controlling alphaVbeta3 integrin expression and proteolytic processing of urokinase-type plasminogen activator receptor. , 2008, Molecular biology of the cell.

[29]  J. Rollinger,et al.  Plumeridoid C from the Amazonian traditional medicinal plant Himatanthus sucuuba. , 2011, Acta crystallographica. Section C, Crystal structure communications.

[30]  S. Noha,et al.  Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques , 2011, Bioorganic & medicinal chemistry letters.

[31]  Jingfeng Li,et al.  Parthenolide inhibits IkappaB kinase, NF-kappaB activation, and inflammatory response in cystic fibrosis cells and mice. , 2007, American journal of respiratory cell and molecular biology.

[32]  David W. Anderson,et al.  SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Jingfeng Li,et al.  Parthenolide Inhibits IκB Kinase, NF-κB Activation, and Inflammatory Response in Cystic Fibrosis Cells and Mice , 2007 .

[34]  I. Cuthill,et al.  Animal Research: Reporting In Vivo Experiments: The ARRIVE Guidelines , 2010, British journal of pharmacology.

[35]  S. Ghosh,et al.  Characterization of the IκB-kinase NEMO Binding Domain* , 2002, The Journal of Biological Chemistry.

[36]  A. Atanasov,et al.  Bioactivity-guided isolation of 1,2,3,4,6-Penta-O-galloyl-D-glucopyranose from Paeonia lactiflora roots as a PTP1B inhibitor. , 2010, Journal of natural products.

[37]  Ira Tabas,et al.  Anti-Inflammatory Therapy in Chronic Disease: Challenges and Opportunities , 2013, Science.

[38]  Michael Karin,et al.  The IKK NF-kappa B system: a treasure trove for drug development. , 2004, Nature reviews. Drug discovery.

[39]  A. Malik,et al.  cAMP targeting of p38 MAP kinase inhibits thrombin-induced NF-kappaB activation and ICAM-1 expression in endothelial cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[40]  C. Koboldt,et al.  Characterization of the Recombinant IKK1/IKK2 Heterodimer , 2000, The Journal of Biological Chemistry.

[41]  Ohad Parnes,et al.  Inflammation , 2008, The Lancet.

[42]  A. Atanasov,et al.  Ethnopharmacological in vitro studies on Austria's folk medicine—An unexplored lore in vitro anti-inflammatory activities of 71 Austrian traditional herbal drugs , 2013, Journal of ethnopharmacology.

[43]  M. Gerritsen,et al.  Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. , 1997, The Journal of biological chemistry.