title: Lovastatin overcomes gefitinib resistance through TNF-α signaling in human cholangiocarcinomas with different LKB1 statuses in vitro and in vivo.
abstract: Gefitinib resistance has been shown to complicate cancer therapy. Lovastatin is a proteasome inhibitor that enhances gefitinib-induced antiproliferation in non-small cell lung cancer. The objective of this study is to investigate the mechanism of lovastatin-induced antiproliferation in gefitinib-resistant human cholangiocarcinoma.Two gefitinib-resistant cholangiocarcinoma cell lines, SSP-25 and HuH-28, were used in this study to determine how to compensate gefitinib resistance. The combined effect of these two drugs was examined using the MTT assay, qPCR, immunoblotting, flow cytometry, and in vivo xenograft. Results indicated that lovastatin enhanced TNF-α-induced cell death in vitro. In addition, the combination of lovastatin with gefitinib enhanced accumulation of TNF-α. Furthermore, the treatment induced a synergistic cytotoxic effect and antiproliferation through apoptosis in SSP-25 cells and cell cycle arrest in HuH-28 cells. Reproductive results were also observed in in vivo xenografts. These observations suggest that the combination of gefitinib and lovastatin might have additive antiproliferative effects against gefitinib-resistant cholangiocarcinoma cells. Based on these observations, we concluded that the combination of gefitinib and lovastatin could be used to overcome gefitinib resistance in cholangiocarcinoma cells.
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Sheng-Huei
authors.initials: SH
authors.lastname: Yang
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Institute of Translational Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Vincent H S
authors.initials: VH
authors.lastname: Chang
authors.affiliation: Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Office of Human Research, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Liu
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Jinghan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center and Beckman Research Center, Duarte, California, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Jiang
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D000077156:Gefitinib; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D008148:Lovastatin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D000077156:Gefitinib
keywords: cholangiocarcinomas; combination therapy; gefitinib; lovastatin