title: DAW22, a natural sesquiterpene coumarin isolated from Ferula ferulaeoides (Steud.) Korov. that induces C6 glioma cell apoptosis and endoplasmic reticulum (ER) stress.
abstract: 2,3-Dihydro-7-hydroxy-2R*,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadienyl]-furo[3,2-c]coumarin (named DAW22), a sesquiterpene coumarin isolated from the roots of Ferula ferulaeoides (Steud.) Korov., has been reported to bear anti-proliferative activities toward different types of cancer cells. In this study, we demonstrated that DAW22 induced apoptosis in C6 glioma cells. Subsequently, we found that DAW22-induced apoptosis in C6 glioma cells occurred via the mitochondria-mediated and death-receptor pathways. Moreover, we found a massive cytoplasmic vacuolization, a dramatic change of endoplasmic reticulum (ER), up-regulation of CHOP and cleavage of caspase-12, suggesting that DAW22-induced apoptosis is involved in ER stress. In addition, we revealed that DAW22 treatment induced the activation of PERK, ATF6α and IRE1α. We further found that knockdown of CHOP affected DAW22-induced apoptosis, and DAW22-stimulated down-regulation of Bcl-2, caspase-8 activation and PARP cleavage were inhibited. Taken together, these results demonstrate that DAW22 induces apoptosis by ER stress and mitochondrial/death-receptor pathways, which may provide a new clue for exploiting this compound as a potential anti-neoplastic drug in future glioma cancer therapy.
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
authors.forename: Xupeng
authors.initials: X
authors.lastname: Tong
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: profhj@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shihezi University, Shihezi 832002, China. Electronic address: profwjh@126.com.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005309:Ferula / Q000737:chemistry*; D005910:Glioma / Q000473:pathology*; D051379:Mice; D062105:Molecular Docking Simulation; D018517:Plant Roots / Q000737:chemistry; D012717:Sesquiterpenes / Q000494:pharmacology*; D056811:Unfolded Protein Response
chemical_list: D003374:Coumarins; D012717:Sesquiterpenes; C030123:coumarin
keywords: Apoptosis; C6 glioma cell; DAW22; Endoplasmic reticulum (ER) stress; Ferula ferulaeoides (Steud.) Korov.