VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis.
Vascular endothelial cell growth inhibitor (VEGI) is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic potential of this gene, a secreted isoform of VEGI (VEGI-251) was inserted into a selectively replicating adenovirus with E1B 55 kDa gene deletion (ZD55) to construct ZD55-VEGI-251. We report here that secreted VEGI-251 produced from ZD55-VEGI-251-infected cancer cells potently inhibits endothelial cell proliferation, tube formation in vitro and angiogenesis of chick chorioallantoic membrane in vivo. Additionally, ZD55-VEGI-251 infection leads to a much more severe cytopathic effect than control viruses on several human cancer cell lines, including cervical cancer cell line HeLa, hepatoma cell line SMMC-7721 and colorectal cancer cell line SW620. Further study reveals that the increased cytotoxicity is a result of VEGI-251 autocrine-dependent, mitochondria-mediated apoptosis accompanied by caspase-9 activation, enhanced caspase-3 activation and PARP cleavage. Moreover, ZD55-VEGI-251-treatment of athymic nude mice bearing human cervical and colorectal tumor xenografts markedly suppressed tumor growth. Our findings indicate that the combined effect of antiangiogenesis and apoptosis-induction activity makes the VEGI-251-armed oncolytic adenovirus a promising therapeutic agent for cancer.
Xiao
Tian
T
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Fan
Jun Kai
JK
Huang
Hong Ling
HL
Gu
Jin Fa
JF
Li
Lu-Yuan
LY
Liu
Xin Yuan
XY
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics* / Q000378:metabolism
D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D053148:Caspase 3; D053453:Caspase 9