title: 6-Shogaol induces cell cycle arrest and apoptosis in human hepatoma cells through pleiotropic mechanisms.
abstract: Shogaols are a group of the active constituents of ginger that have been identified to have various biological activities. The aim of the current study was to investigate the antitumor activity of 6-shogaol in hepatocellular carcinoma (HCC) and the possible involvement of reactive oxygen species as a putative mechanism of action. HCC cell lines, HepG2 and Huh-7, were used to study the in vitro anti-cancer activity of 6-shogaol via the application of various molecular biology techniques. Results showed that 6-shogaol effectively inhibited the cell viability, caused cell cycle arrest at G2/M phase and induced apoptosis in HCC cells as indicated by MTT assay, DAPI nuclear staining, annexin V assay, cell cycle analysis, and activation of caspase-3. Western blot analysis revealed the ability of 6-shogaol to target cancer survival signaling pathways mediated by mitogen-activated protein kinase (MAPK), 5' AMP-activated protein kinase (AMPK) and Akt. In addition, 6-Shogaol induced alteration of cyclin proteins expression and caused cleavage of protein kinase C delta. Furthermore, 6-Shogaol was able to induce the production of reactive oxygen species and endoplasmic reticulum (ER) stress-associated proteins and the consequent activation of autophagy in HepG2 cells. Taken together, the current study highlights evidences that 6-shogaol induces apoptosis, modulates cyclins expression and targets cancer survival signaling pathways in HCC cell lines, at least in part, via the production of reactive oxygen species. These findings support 6-shogaol's clinical promise as a potential candidate for HCC therapy.
authors.affiliation: Department of Chinese Medicine, Chiayi Christian Hospital, Chiayi, Taiwan.
authors.forename: Jung-Ju
authors.initials: JJ
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt; Sharjah Institute For Medical Research, Department of Pharmacology, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
authors.forename: Hany A
authors.initials: HA
authors.lastname: Omar
authors.affiliation: Department of Medical Research, Chiayi Christian Hospital, Chiayi, Taiwan.
authors.forename: Ying-Ray
authors.initials: YR
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan.
authors.forename: Yen-Ni
authors.initials: YN
authors.lastname: Teng
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Pin-Shern
authors.initials: PS
authors.lastname: Chen
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Yu-Chung
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Chinese Medicine, Chiayi Christian Hospital, Chiayi, Taiwan.
authors.forename: Hsiao-Shan
authors.initials: HS
authors.lastname: Huang
authors.affiliation: Institute of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan; Drug Discovery and Development Center, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Kuan-Han
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan; Drug Discovery and Development Center, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. Electronic address: hung86@mail.cnu.edu.tw.
authors.forename: Jui-Hsiang
authors.initials: JH
authors.lastname: Hung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002396:Catechols / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002396:Catechols; D017382:Reactive Oxygen Species; C040115:shogaol
keywords: 6-Shogaol; Apoptosis; Autophagy; Cell cycle arrest; Endoplasmic reticulum stress; Mitogen-activated protein; Reactive oxygen species