title: Dehydroandrographolide, an iNOS inhibitor, extracted from Andrographis paniculata (Burm.f.) Nees, induces autophagy in human oral cancer cells.
abstract: Autophagy, which is constitutively executed at the basal level in all cells, promotes cellular homeostasis by regulating the turnover of organelles and proteins. Andrographolide and dehydroandrographolide (DA) are the two principle components of Andrographis paniculata (Burm.f.) Nees. and are the main contributors to its therapeutic properties. However, the pharmacological activities of dehydroandrographolide (DA) remain unclear. In this study, DA induces oral cancer cell death by activating autophagy. Treatment with autophagy inhibitors inhibited DA-induced human oral cancer cell death. In addition, DA increased LC3-II expression and reduced p53 expression in a time- and concentration-dependent manner. Furthermore, DA induced autophagy and decreased cell viability through modulation of p53 expression. DA-induced autophagy was triggered by an activation of JNK1/2 and an inhibition of Akt and p38. In conclusion, this study demonstrated that DA induced autophagy in human oral cancer cells by modulating p53 expression, activating JNK1/2, and inhibiting Akt and p38. Finally, an administration of DA effectively suppressed the tumor formation in the oral carcinoma xenograft model in vivo. This is the first study to reveal the novel function of DA in activating autophagy, suggesting that DA could serve as a new and potential chemopreventive agent for treating human oral cancer.
authors.affiliation: Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan.|School of Optometry, Chung Shan Medical University, Taichung 40201, Taiwan.|Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
authors.forename: Ming-Ju
authors.initials: MJ
authors.lastname: Hsieh
authors.affiliation: Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Chiao-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chiou
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua 500, Taiwan.
authors.forename: Mu-Kuan
authors.initials: MK
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D035685:Andrographis / Q000737:chemistry*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D004791:Enzyme Inhibitors; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D010936:Plant Extracts; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C478098:dehydroandrographolide
keywords: MAPK; autophagy; dehydroandrographolide; oral cancer; p53