title: Arsenic trioxide and promyelocytic leukemia protein-adenovirus synergistically inhibit in vitro and in vivo growth of a hepatoma cell line.
abstract: The present study investigated the in vitro and in vivo growth-inhibitory effects of combination therapy with arsenic trioxide (As2O3) and an adenovirus expressing promyelocytic leukemia protein (Ad-PML). Growth of HepG2 cells in culture was not inhibited by As2O3 at concentrations below 5 micromol/L (p > 0.05). However, growth was inhibited by Ad-PML alone and synergistic growth inhibition was observed following combined treatments (p < 0.05). Flow cytometry analyses demonstrated an increase in apoptosis following combined treatment with As2O3 and Ad-PML for 24 h, which was correlated with increased p53 and decreased Bcl-2 expression. To examine treatment effects on in vivo cell growth, control HepG2 cells and cells treated with As2O3, Ad-PML, or both therapies were subcutaneously injected in nude mice. After 6 weeks, tumor volumes were 0.097 +/- 0.031 and 0.083 +/- 0.005 cm3 in the control and As2O3 alone groups, respectively (p > 0.05), but were undetectable in the Ad-PML alone or Ad-PML plus As2O3 groups. Finally, established HepG2 tumors in nude mice were injected with PBS, Ad-PML, As2O3, or Ad-PML plus As2O3, the tumor volumes were measured by ultrasound, and the therapeutic effects were compared. As2O3 alone had no effect at concentrations below 5 micromol/L (p > 0.05), while Ad-PML alone at a multiplicity of infection of 20 or As2O3 plus Ad-PML significantly decreased tumor volumes (p < 0.05). Thus, the combination of As2O3 and Ad-PML has synergistic inhibitory effects on hepatocellular carcinoma (HCC), possibly resulting from regulation of apoptotic gene expression enhanced HCC apoptosis.
authors.affiliation: Department of Interventional Radiology, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Cui
authors.forename: Shide
authors.initials: S
authors.lastname: Zhang
authors.forename: Weizhe
authors.initials: W
authors.lastname: Zhang
authors.forename: Zhanliang
authors.initials: Z
authors.lastname: Hu
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Cao
authors.forename: Tao
authors.initials: T
authors.lastname: Li
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005434:Flow Cytometry; D015316:Genetic Therapy; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010087:Oxides / Q000627:therapeutic use*; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D000077237:Arsenic Trioxide