title: RGD-FasL induces apoptosis in hepatocellular carcinoma.
abstract: Despite impressive results obtained in animal models, the clinical use of Fas ligand (FasL) as an anticancer drug is limited by severe toxicity. Systemic toxicity of death ligands may be prevented by using genes encoding membrane-bound death ligands and by targeted transgene expression through either targeted transduction or targeted transcription. Selective induction of tumor cell death is a promising anticancer strategy. A fusion protein is created by fusing the extracellular domain of Fas ligand (FasL) to the peptide arginine-glycine-aspartic acid (RGD) that selectively targets avbeta3-integrins on tumor endothelial cells. The purpose of this study is to evaluate the effects of RGD-FasL on tumor growth and survival in a murine hepatocellular carcinoma (HCC) tumor model. Treatment with RGD-FasL displaying an obvious suppressive effect on the HCC tumor model as compared to that with FasL (p < 0.05) and resulted in a more additive effect on tumor growth delay in this model. RGD-FasL treatment significantly enhanced mouse survival and caused no toxic effect, such as weight loss, organ failure, or other treatment-related toxicities. Apoptosis was detected by flow cytometric analysis and TUNEL assays; those results also showed that RGD-FasL is a more potent inducer of cell apoptosis for H22 and H9101 cell lines than FasL (p <0.05). In conclusion, RGD-FasL appears to be a low-toxicity selective inducer of tumor cell death, which merits further investigation in preclinical and clinical studies. Furthermore, this approach offers a versatile technology for complexing target ligands with therapeutic recombinant proteins. To distinguish the anti-tumor effects of FasL in vivo, tumor and liver tissues were harvested to examine for evidence of necrotic cells, tumor cells, or apoptotic cells by Hematoxylin and eosin (HE) staining.
authors.affiliation: Anti-Cancer Research Center, Medical College, Xiamen University, Xiamen 361005, China.
authors.forename: Zhongchen
authors.initials: Z
authors.lastname: Liu
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: Jinhua
authors.initials: J
authors.lastname: Qiu
authors.forename: Ruizhen
authors.initials: R
authors.lastname: Liu
authors.forename: Wenzhu
authors.initials: W
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Cheng
authors.forename: Caixia
authors.initials: C
authors.lastname: Chen
authors.forename: Jiakai
authors.initials: J
authors.lastname: Zhang
authors.forename: Guohong
authors.initials: G
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism; D005818:Genetic Engineering; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; C047981:arginyl-glycyl-aspartic acid