Inhibition of angiogenesis by a synthetic fusion protein VTF derived from vasostatin and tumstatin

Abstract

The inhibition of angiogenesis represents a potential strategy for antitumor therapy. A novel synthetic fusion protein VTF, composed of bioactive fragments from two different angiogenesis inhibitors, vasostatin and tumstatin with a (Gly-Ser-Gly)2 bridge, was generated using the pET-15b expression vector. The fusion protein VTF showed significantly enhanced efficacy in inhibiting human endothelial cell proliferation and tube formation and neovascularization on chick embryo chorioallantoic membrane. Moreover, VTF suppressed the growth of B16 melanoma and the formation of tumor blood vessels potently in vivo. These results indicated that the fusion protein containing the bioactive fragments of multiple angiogenesis inhibitors might be a promising therapeutic agent for tumor treatment.

Tumor angiogenesis and anti‑angiogenic gene therapy for cancer (Review)

“…In an additional experiment, gene electrotransfer of naked plasmid DNA containing the tumstatin cDNA has been adopted to investigate the anti-tumor effect of tumstatin in B16F1 melanoma-bearing mice: A marked decrease in tumor growth and an increase in mouse survival was observed, indicating that this strategy appears appealing in terms of gene delivery and tumor suppression ( 140 ). In addition, the pET-15b vector generated to express a synthetic fusion protein, VTF, which is composed of vasostatin and tumstatin with a (Gly-Ser-Gly)2 bridge, demonstrated the suppression of B16 melanoma growth and the potent inhibition of tumor blood vessels formation in vivo , when compared with a single inhibitor, the fusion proteins of different angiogenesis inhibitors targeting different pathways exhibited improved therapeutic effects ( 141 ). Additionally, as T42, which was derived from two active domains of tumstatin, has demonstrated anti-tumor efficacy, a previous study constructed two adenoviral vectors with T42 and 4xT42 peptide genes to evaluate their anti-cancer effects on breast cancer in vitro and in vivo ; the results suggested evidence that this modality may be a potential alternative for the treatment of breast cancer ( 142 ).…”

Matricryptins Network with Matricellular Receptors at the Surface of Endothelial and Tumor Cells

“…The combination of matricryptins with inhibitors of pro-angiogenic pathways, chemotherapy, or radiotherapy enhance their therapeutic efficacy. Tumstatin has been fused to another endogenous inhibitor of angiogenesis, vasostatin (Gu et al, 2014 ) and to tumor necrosis factor α, which has anti-tumoral and anti-angiogenic properties, which results in a more effective fusion protein than tumstatin alone (Luo et al, 2006 ). Endostatin has been fused to the proapoptotic domain (BH3) of the BAX protein (Chura-Chambi et al, 2014 ), to tumor necrosis factor-related apoptosis-inducing ligand (Zheng et al, 2013 ) and one of its anti-angiogenic sequences to an heptapeptide inhibitor of MMPs (Qiu et al, 2013 ).…”