Christian Bailly1, Gérard Vergoten2. 1. OncoWitan, 59290, Lille (Wasquehal), France. christian.bailly@oncowitan.com. 2. Inserm, INFINITE-U1286, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Faculté de Pharmacie, University of Lille, 3 rue du Professeur Laguesse, BP-83, 59006, Lille, France.
Abstract
OBJECTIVE AND DESIGN: Japonicone A (Jap-A) is a sesquiterpene lactone (SL) dimer isolated from the plant Inula japonica Thunb. and the leading compound in the japonicone series of SL dimers which comprises 25 members (Jap-A to Jap-Y). We have analyzed the anticancer properties of Jap-A and the associated molecular targets. METHODS: All literature data on japonicones and related SL dimers, including inulanolide A (Inu-A) and lineariifolianoid A (Lin-A) have been analyzed. Molecular models of the compound/target interactions were constructed to support our analysis. RESULTS: Inulae Flos (Xuan Fu Hua) is used in traditional medicine in China and Korea to treat inflammatory diseases. The plant contains diverse japonicones and structurally related SL dimers. The interactions of Jap-A with the two main proteins, the pro-inflammatory cytokine TNF-α and the ubiquitin ligase MDM2, are at the origin of the anti-inflammatory and anticancer effects. Molecular docking analyses suggest that Inu-A is better adapted than Lin-A and Jap-A to form stable complexes with both TNF-α and MDM2. Jap-A exhibits marked capacities to inhibit cancer cell proliferation and dissemination and to trigger apoptosis, both in vitro and in vivo in several tumor models in mice. Its analogue Inu-A is more potent, functioning as a dual inhibitor of the MDM2-NFAT1 pathway. CONCLUSION: This review shed some new light on the molecular targets and potential therapeutic benefits of these SL dimers and should help the design of novel anticancer agents derived from these compounds.
OBJECTIVE AND DESIGN: Japonicone A (Jap-A) is a sesquiterpene lactone (SL) dimer isolated from the plant Inula japonica Thunb. and the leading compound in the japonicone series of SL dimers which comprises 25 members (Jap-A to Jap-Y). We have analyzed the anticancer properties of Jap-A and the associated molecular targets. METHODS: All literature data on japonicones and related SL dimers, including inulanolide A (Inu-A) and lineariifolianoid A (Lin-A) have been analyzed. Molecular models of the compound/target interactions were constructed to support our analysis. RESULTS: Inulae Flos (Xuan Fu Hua) is used in traditional medicine in China and Korea to treat inflammatory diseases. The plant contains diverse japonicones and structurally related SL dimers. The interactions of Jap-A with the two main proteins, the pro-inflammatory cytokine TNF-α and the ubiquitin ligase MDM2, are at the origin of the anti-inflammatory and anticancer effects. Molecular docking analyses suggest that Inu-A is better adapted than Lin-A and Jap-A to form stable complexes with both TNF-α and MDM2. Jap-A exhibits marked capacities to inhibit cancer cell proliferation and dissemination and to trigger apoptosis, both in vitro and in vivo in several tumor models in mice. Its analogue Inu-A is more potent, functioning as a dual inhibitor of the MDM2-NFAT1 pathway. CONCLUSION: This review shed some new light on the molecular targets and potential therapeutic benefits of these SL dimers and should help the design of novel anticancer agents derived from these compounds.
Authors: Jiang Jiang Qin; Hui Zi Jin; Jian Jun Fu; Xiao Jia Hu; Yan Wang; Shi Kai Yan; Wei Dong Zhang Journal: Bioorg Med Chem Lett Date: 2008-12-14 Impact factor: 2.823