title: Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor subfamily with great potential in cancer therapy. Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory and anticancer activities. Here, we showed that pretreatment with Andro significantly enhances TRAIL-induced apoptosis in various human cancer cell lines, including those TRAIL-resistant cells. Such sensitization is achieved through transcriptional up-regulation of death receptor 4 (DR4), a death receptor of TRAIL. In search of the molecular mechanisms responsible for DR4 up-regulation, we found that the tumor suppressor p53 plays an essential role in DR4 transcriptional activation. Andro is capable of activating p53 via increased p53 phosphorylation and protein stabilization, a process mediated by enhanced reactive oxygen species production and subsequent c-Jun NH(2)-terminal kinase activation. Pretreatment with an antioxidant (N-acetylcysteine) or a c-Jun NH(2)-terminal kinase inhibitor (SP600125) effectively prevented Andro-induced p53 activation and DR4 up-regulation and eventually blocked the Andro-induced sensitization on TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of Andro and support its potential application in cancer therapy to overcome TRAIL resistance.
authors.affiliation: Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Lu
authors.forename: Chye-Sun
authors.initials: CS
authors.lastname: Ong
authors.forename: Choon-Nam
authors.initials: CN
authors.lastname: Ong
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D004224:Diterpenes; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D010769:Phosphothreonine; C030419:andrographolide; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases