title: Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model.
abstract: Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality and poor prognosis. Oncogenic transcription factor Late SV40 Factor (LSF) plays an important role in promoting HCC. A small molecule inhibitor of LSF, Factor Quinolinone Inhibitor 1 (FQI1), significantly inhibited human HCC xenografts in nude mice without harming normal cells. Here we evaluated the efficacy of FQI1 and another inhibitor, FQI2, in inhibiting endogenous hepatocarcinogenesis. HCC was induced in a transgenic mouse with hepatocyte-specific overexpression of c-myc (Alb/c-myc) by injecting N-nitrosodiethylamine (DEN) followed by FQI1 or FQI2 treatment after tumor development. LSF inhibitors markedly decreased tumor burden in Alb/c-myc mice with a corresponding decrease in proliferation and angiogenesis. Interestingly, in vitro treatment of human HCC cells with LSF inhibitors resulted in mitotic arrest with an accompanying increase in CyclinB1. Inhibition of CyclinB1 induction by Cycloheximide or CDK1 activity by Roscovitine significantly prevented FQI-induced mitotic arrest. A significant induction of apoptosis was also observed upon treatment with FQI. These effects of LSF inhibition, mitotic arrest and induction of apoptosis by FQI1s provide multiple avenues by which these inhibitors eliminate HCC cells. LSF inhibitors might be highly potent and effective therapeutics for HCC either alone or in combination with currently existing therapies.
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Devaraja
authors: D
authors: Rajasekaran
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Ayesha
authors: A
authors: Siddiq
authors: Department of Biology, Center for Chemical Methodology and Library Development at Boston University, Boston, MA 02215, USA.|Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors: Jennifer L S
authors: JL
authors: Willoughby
authors: Department of Chemistry, Center for Chemical Methodology and Library Development at Boston University, Boston, MA 02215, USA.
authors: Jessica M
authors: JM
authors: Biagi
authors: Department of Chemistry, Center for Chemical Methodology and Library Development at Boston University, Boston, MA 02215, USA.
authors: Lisa M
authors: LM
authors: Christadore
authors: Program in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston, MA 02215, USA.
authors: Sarah A
authors: SA
authors: Yunes
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Rachel
authors: R
authors: Gredler
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Nidhi
authors: N
authors: Jariwala
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Chadia L
authors: CL
authors: Robertson
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Maaged A
authors: MA
authors: Akiel
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Xue-Ning
authors: XN
authors: Shen
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Mark A
authors: MA
authors: Subler
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Jolene J
authors: JJ
authors: Windle
authors: Department of Chemistry, Center for Chemical Methodology and Library Development at Boston University, Boston, MA 02215, USA.
authors: Scott E
authors: SE
authors: Schaus
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.|Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.|VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Paul B
authors: PB
authors: Fisher
authors: Department of Biology, Center for Chemical Methodology and Library Development at Boston University, Boston, MA 02215, USA.|Program in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston, MA 02215, USA.
authors: Ulla
authors: U
authors: Hansen
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.|Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.|VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Devanand
authors: D
authors: Sarkar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004052:Diethylnitrosamine; D004305:Dose-Response Relationship, Drug; D016259:Genes, myc; D020022:Genetic Predisposition to Disease; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D008938:Mitosis / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic; D010641:Phenotype; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C585328:8-(2-ethoxyphenyl)-7,8-dihydro-(1,3)dioxolo(4,5-g)quinolin-6(5H)-one; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D004268:DNA-Binding Proteins; D015363:Quinolones; C501905:Tfcp2 protein, mouse; D014157:Transcription Factors; D004052:Diethylnitrosamine
keywords: FQI; HCC; LSF; apoptosis; mitotic arrest