title: Molecular mechanism of hepatocellular carcinoma-specific antitumor activity             of the novel thienopyridine derivative TP58.
abstract: Despite progress made in the treatment of hepatocellular carcinoma (HCC), there is no curable treatment. Novel therapies are therefore needed. In our previous study on the design and synthesis of a small molecular inhibitor targeting Aurora kinase, we discovered a novel thienopyridine derivative compound (1g, TP58) which displayed the most potent and relatively specific inhibition of the proliferation of HepG2 human hepatoma cells in vitro. However, the molecular mechanism remains to be elucidated. Herein, in vitro and in vivo studies were conducted to further verify its antitumor activity against HCC. cDNA microarray and two-dimensional protein gel electrophoresis technology were utilized to elucidate the mechanism of HCC-specific inhibition of TP58. Flow cytometry analysis displayed that TP58 can significantly induce G0/G1 arrest in HepG2 cells. Sixteen genes involved in cell cycle regulation were found to be dysregulated following TP58 treatment using microarray technology. Nine proteins whose expression was altered (corresponding to 10 spots identified as differentially expressed) were identified by proteomic analysis. Further study showed that TP58 can modulate the expression of some liver-enriched transcription factors (LETFs) and liver-specific marker genes, such as hepatic nuclear factor (HNF-4) and α-fetoprotein (AFP). These findings may help explain the mechanism of HCC-specific antitumor activity of TP58 and provide some useful insight for anti-HCC drug design and future use of thienopyridine derivatives in HCC therapy.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Huang
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Zeng
authors.forename: Ya-Qi
authors.initials: YQ
authors.lastname: Deng
authors.forename: Feng-Yun
authors.initials: FY
authors.lastname: Hu
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Tong
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Jin-Liang
authors.initials: JL
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011725:Pyridines; D013876:Thiophenes; D014157:Transcription Factors