Coronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-kappa B pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesis.

Abstract

Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-kappaB (NF-kappaB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-kappaB activation pathway, NF-kappaB-regulated gene products, and NF-kappaB-regulated cellular responses. The coronarin D inhibited NF-kappaB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-kappaB activity in different cell lines and inhibited IkappaBalpha kinase activation, thus leading to the suppression of IkappaBalpha phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-kappaB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-kappaB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-kappaB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis.

• Authors: Ajaikumar B Kunnumakkara, Haruyo Ichikawa, Preetha Anand, Chiramel J Mohankumar, Padmanabhan S Hema, Mangalam S Nair, Bharat B Aggarwal
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 10 Pg. 3306-17 (Oct 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18852134 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• Antineoplastic Agents
• Diterpenes
• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Neoplasm Proteins
• Nfkbia protein, mouse
• RANK Ligand
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• coronarin D
• NF-KappaB Inhibitor alpha

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Diterpenes (chemistry, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, Reporter
• Humans
• I-kappa B Proteins (metabolism)
• Mice
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Proteins (metabolism)
• Osteoclasts (cytology, drug effects)
• Phosphorylation (drug effects)
• Protein Processing, Post-Translational (drug effects)
• Protein Transport (drug effects)
• RANK Ligand (pharmacology)
• Transcription Factor RelA (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)