title: Andrographolide induces autophagic cell death in human liver cancer cells through cyclophilin D-mediated mitochondrial permeability transition pore.
abstract: Liver cancer is the third leading cause of cancer death worldwide and about half of the patients with liver cancer require adjuvant therapy after surgical resection. Therefore, development of novel agents to eradicate cancer cells may constitute a viable approach to treat patients with liver cancer. Andrographolide, a diterpenoid lactone isolated from Andrographis paniculata, is known to possess potent antioxidant, anti-inflammatory, antineoplastic and antiviral properties. In this study, we investigated the cytotoxic effect of andrographolide on human liver cancer cells and explored the cell death mechanism. Andrographolide induced a cell death distinct from apoptosis in multiple human liver cancer cells. The death was characterized by autophagy as evidenced by the accumulation of LC3 II and autophagosomes, and the formation of puncta GFP-LC3. This autophagy as well as cytotoxicity caused by andrographolide could be effectively prevented by 3-methyladenine (a chemical inhibitor of autophagy). Mechanistic study indicated that andrographolide induced autophagic cell death by disruption of mitochondrial transmembrane potential and elevation of reactive oxygen species, which were correlated with mitochondrial permeability transition pore Inhibition of cyclophilin D (a component of MPTP) by cyclosporin A or abrogation of its expression by small interfering RNA significantly suppressed the cytotoxicity of andrographolide, suggesting that cyclophilin D may play an important role in mediating andrographolide-induced cytotoxicity. Taken together, our findings unveil a novel mechanism of drug action by andrographolide in liver cancer cells and suggest that andrographolide may represent a promising novel agent in the treatment of liver cancer.
authors.affiliation: College of Food Science and Biotechnology, Zhejiang Gongshang University Hangzhou 310035, China. zjgsuchenwei@zjgsu.edu.cn
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Lina
authors.initials: L
authors.lastname: Feng
authors.forename: Hao
authors.initials: H
authors.lastname: Nie
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000893:Anti-Inflammatory Agents; D000081406:Peptidyl-Prolyl Isomerase F; D004224:Diterpenes; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C030419:andrographolide; D021983:Cyclophilins