title: Bisdemethoxycurcumin-induced S phase arrest through the inhibition of cyclin A and E and induction of apoptosis via endoplasmic reticulum stress and mitochondria-dependent pathways in human lung cancer NCI H460 cells.
abstract: Curcuminoids are the major natural phenolic compounds found in the rhizome of many Curcuma species. Curcuminoids consist of a mixture of curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Although numerous studies have shown that curcumin induced cell apoptosis in many human cancer cells, however, mechanisms of BDMC-inhibited cell growth and -induced apoptosis in human lung cancer cells still remain unclear. Herein, we investigated the effect of BDMC on the cell death via the cell cycle arrest and induction of apoptosis in NCI H460 human lung cancer cells. Flow cytometry assay was used to measure viable cells, cell cycle distribution, the productions of reactive oxygen species (ROS) and Ca2+, mitochondrial membrane potential (ΔΨm) and caspase-3, -8 and -9 activity. DNA damage and condension were assayed by Comet assay and DAPI staining, respectively. Western blotting was used to measure the changes of cell cycle and apoptosis associated protein expressions. Results indicated that BDMC significantly induced cell death through induced S phase arrest and induced apoptosis. Moreover, DMC induced DNA damage and condension, increased ROS and Ca2+productions and decreased the levels of ΔΨmand promoted activities caspase-3, -8, and -9. Western blotting results showed that BDMC inhibited Cdc25A, cyclin A and E for causing S phase arrest, furthermore, promoted the expression of AIF, Endo G and PARP and the levels of Fas ligand (Fas L) and Fas were also up-regulated. Results also indicated that BDMC increased ER stress associated protein expression such as GRP78, GADD153, IRE1α, IRE1β, ATF-6α, ATF-6β, and caspase-4. Taken together, we suggest that BDMC induced cell apoptosis through multiple signal pathways such as extrinsic, intrinsic and ES tress pathway. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1899-1908, 2016.
authors.affiliation: Department of Radiology, China Medical University Hospital, Taichung, 404, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, 404, Taiwan.
authors.forename: Su-Tso
authors.initials: ST
authors.lastname: Yang
authors.affiliation: Department of Nursing, St. Mary's Junior College of Medicine, Nursing and Management, Yilan, 266, Taiwan.
authors.forename: An-Cheng
authors.initials: AC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Chinese Medicine, China Medical University, Taichung, 404, Taiwan.
authors.forename: Nou-Ying
authors.initials: NY
authors.lastname: Tang
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan.
authors.forename: Hsin-Chung
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Chinese Medicine, China Medical University, Taichung, 404, Taiwan.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Liao
authors.affiliation: Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan.
authors.forename: Bin-Chuan
authors.initials: BC
authors.lastname: Ji
authors.affiliation: Division of Neurosurgical Oncology, Neurological Institute, Taichung Veterans General Hospital, Taichung, 407, Taiwan.|Institute of Medical Sciences, Tzu Chi University, Hualien, 970, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Chou
authors.affiliation: Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Mei-Due
authors.initials: MD
authors.lastname: Yang
authors.affiliation: Restaurant, Hotel and Institutional Management, Fu-Jen Catholic University, Taipei, Taiwan.|Departments of Clinical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan.
authors.forename: Hsu-Feng
authors.initials: HF
authors.lastname: Lu
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan.|Department of Biotechnology, Asia University, Wu Feng, Taichung, 404, Taiwan.
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019925:Cyclin A / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D004249:DNA Damage; D036381:Diarylheptanoids; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008175:Lung Neoplasms; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; D019927:Cyclin E; D036381:Diarylheptanoids; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D017382:Reactive Oxygen Species; C034786:bisdemethoxycurcumin; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D020169:Caspases; D003474:Curcumin
keywords: ER stress; NCI H-460 cells; apoptosis; bidemethoxycurcumin; mitochondria