title: Low-dose 5-fluorouracil sensitizes HepG2 cells to TRAIL through TRAIL receptor DR5 and survivin-dependent mechanisms.
abstract: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer treatment due to its highly selective apoptosis-inducing action on tumour cells without harming normal cells. However, because of TRAIL resistance by some cancer cells, combined treatment with sensitizing agents is required to enhance the anticancer potential of TRAIL. In the present study, we investigated the sensitizing effect of 5-fluorouracil (5-FU) on TRAIL-induced apoptosis in TRAIL-resistant HepG2 hepatocarcinoma cells. The results show that 5-FU pretreatment could sensitize HepG2 cells to TRAIL-mediated apoptosis. The enhanced induction of cell death by the 5-FU/TRAIL combination was mediated by DR5 up-regulation and survivin down-regulation. Furthermore, this combination treatment significantly inhibited the growth of human xenografts in vivo. In conclusion, this study demonstrates that the combination of a sensitizing agent and TRAIL may be a novel and effective therapeutic regimen for treating human hepatocellular carcinoma.
authors.affiliation: a Department of Biochemistry and Molecular Biology , Shanxi Medical University , Taiyuan , China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Yang
authors.affiliation: a Department of Biochemistry and Molecular Biology , Shanxi Medical University , Taiyuan , China.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: a Department of Biochemistry and Molecular Biology , Shanxi Medical University , Taiyuan , China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zheng
authors.affiliation: a Department of Biochemistry and Molecular Biology , Shanxi Medical University , Taiyuan , China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: b Department of Clinical Cancer Prevention , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Wu
authors.affiliation: a Department of Biochemistry and Molecular Biology , Shanxi Medical University , Taiyuan , China.|c Department of Cell and Molecular Biology , University of Rhode Island , Kingston , RI , USA.
authors.forename: Gongqin
authors.initials: G
authors.lastname: Sun
authors.affiliation: a Department of Biochemistry and Molecular Biology , Shanxi Medical University , Taiyuan , China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000819:agonists / Q000378:metabolism; D011897:Random Allocation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D005472:Fluorouracil
keywords: 5-FU; Apoptosis; Chemotherapy; Hepatocarcinoma; TRAIL