1 research outputs found
Dual Function of RGD-Modified VEGI-192 for Breast Cancer Treatment
Identification of endogenous angiogenesis inhibitors
has led to
development of an increasingly attractive strategy for cancer therapy
and other angiogenesis-driven diseases. Vascular endothelial growth
inhibitor (VEGI), a potent and relatively nontoxic endogenous angiogenesis
inhibitor, has been intensively studied, and this work shed new light
on developing promising anti-angiogenic strategies. It is well-documented
that the RGD (Arg-Gly-Asp) motif exhibits high binding affinity to
integrin α<sub>v</sub>β<sub>3</sub>, which is abundantly
expressed in cancer cells and specifically associated with angiogenesis
on tumors. Here, we designed a fusion protein containing the special
RGD-4C motif sequence and VEGI-192, aimed at offering more effective
multiple targeting to tumor cells and tumor vasculature, and higher
anti-angiogenic and antitumor efficacy. Functional tests demonstrated
that the purified recombinant human RGD-VEGI-192 protein (rhRGD-VEGI-192)
potently inhibited endothelial growth in vitro and suppressed neovascularization
in chicken chorioallantoic membrane in vivo, to a higher degree as
compared with rhVEGI-192 protein. More importantly, rhRGD-VEGI-192,
but not rhVEGI-192 protein, could potentially target MDA-MB-435 breast
tumor cells, significantly inhibiting growth of MDA-MB-435 cells in
vitro, triggered apoptosis in MDA-MB-435 cells by activation of caspase-8
as well as caspase-3, which was mediated by activating the JNK signaling
associated with upregulation of pro-apoptotic protein Puma, and consequently
led to the observed significant antitumor effect in vivo against a
human breast cancer xenograft. Our study indicated that the RGD-VEGI-192
fusion protein might represent a novel anti-angiogenic and antitumor
strategy