title: 9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11H-indeno[1, 2-c]quinolin-11-one (BPIQ), A Quinoline Derivative Inhibits Human Hepatocellular Carcinoma Cells by Inducing ER Stress and Apoptosis.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is one of the leading cancers in the world, including Taiwan. The chemoresistance of advanced HCC frequently results in the poor prognosis of patients. Previous studies demonstrated the quinoline derivative, 9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11Hindeno[ 1,2-c]quinolin-11-one (BPIQ) exerts the inhibitory potential against several cancer cells, including liver cancer cells.
  
  
  OBJECTIVE
  We further investigated the anti-HCC effects of BPIQ, including apoptosis and the modulation of ER stress.
  
  
  METHODS
  Both trypan blue exclusion assay and colony formation assay were performed to examine whether BPIQ affects the growth of HCC cell lines Ha22T and Huh7. Flow cytometry-based assay was performed for determining the cell cycle distribution and apoptosis. Western blot assay was conducted for detecting the changes in apoptosis- and endoplasmic reticulum (ER) stress-associated proteins.
  
  
  RESULTS
  BPIQ inhibits cell growth and induces the apoptosis of both Ha22T and Huh7 cell lines significantly. The level of γH2AX, an endogenous DNA damage biomarker was dramatically increased suggesting the involvement of DNA damage pathway in BPIQ-induced apoptosis. Further, BPIQ down-regulates the pro-survival proteins, survivin, XIAP and cyclin D1. BPIQ also may regulate ER stress response through modulating the levels of ER stress-related proteins Glucose-regulated protein of 78 kD (GRP78), Inositol-requiring kinase-1α (IREα), C/EBP homologous protein (Chop) and calnexin.
  
  
  CONCLUSIONS
  The anti-HCC effect of BPIQ may occur through down-regulating pro-survival proteins, and the modulation of ER stress may contribute to the BPIQ-induced apoptosis of HCC cells. The chemotherapeutic or chemopreventive applications of BPIQ for HCC treatment will be worthy of further investigation in future.
authors: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors: Wen-Tsan
authors: WT
authors: Chang
authors: Department of Thoracic Surgery, Chi-Mei Medical Center, Tainan 710, Taiwan.
authors: Yao
authors: Y
authors: Fong
authors: Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Shih-Chang
authors: SC
authors: Chuang
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Chon-Kit
authors: CK
authors: Chou
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Han-Lin
authors: HL
authors: Chou
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Chun-Feng
authors: CF
authors: Yang
authors: School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Chih-Hua
authors: CH
authors: Tseng
authors: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Yeh-Long
authors: YL
authors: Chen
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan, 100, Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan.
authors: Chien-Chih
authors: CC
authors: Chiu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000622267:9-bis(2-(pyrrolidin-1-yl)ethoxy)-6-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-11H-indeno(1,2-c)quinolin-11-one; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007192:Indenes; D011804:Quinolines
keywords: BPIQ; DNA damage; ER stress; HCC; XIAP; apoptosis; quinoline; survivin; γH2AX