title: Thymoquinone induces G2/M arrest, inactivates PI3K/Akt and nuclear factor-κB pathways in human cholangiocarcinomas both in vitro and in vivo.
abstract: Cholangiocarcinoma (CCA) is a notoriously lethal tumor mostly due to the de novo or acquired resistance to traditional chemotherapy besides gemcitabine and, therefore, an increasing need for effective strategies to prevent and treat the poor prognosis of this tumor is required. Thymoquinone (TQ), a hopeful natural product derived from black cumin (Nigella sativa) has shown considerable antineoplastic properties. Whether TQ exerts antitumor effects on CCA cells in vitro and in vivo remains unknown. Examinations of cell viability assay, detection of cell cycle and apoptosis, electrophoretic mobility shift assay (EMSA), western blotting and immunohistochemistry were used in the present study. We demonstrated that TQ inhibited the growth of human CCA cell lines (TFK-1 and HuCCT1) in a dose- and time-dependent manner. Firstly, our results provided evidence that TQ not only inhibits the proliferation of CCA cells, induces cell cycle arrest and prompts cell apoptotic effect in vitro, but it also exhibits inhibitory effects of tumor growth and angiogenesis in vivo. The responsible mechanism is at least partially due to TQ inhibiting the growth of CCA cell lines induced by downregulation of PI3K/Akt and NF-κB and regulated gene products, including p-AKT, p65, XIAP, Bcl-2, COX-2, VEGF. Taken together, these results provide strong evidence of our hypothesis that TQ alone presents a promising therapeutic regimen for the treatment of CCA cells with better efficiency.
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xu
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Baolei
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Yaohua
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Jizhou
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Huayang
authors.initials: H
authors.lastname: Pan
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology*; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000401:mortality; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000401:mortality; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C003466:thymoquinone