Long-Term Local Injection of RAGE-Aptamer Suppresses the Growth of Malignant Melanoma in Nude Mice

Abstract

Accumulating evidence has suggested the pathological role of advanced glycation end products (AGEs) and their receptor RAGE axis in aging-associated disorders, including cancers. In this study, we examined the effects of local injection of RAGE-aptamer adjacent to the tumor on G361 melanoma growth in nude mice. We further investigated the effects of RAGE-aptamer on oxidative stress generation, RAGE, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1) gene expression in Nε-(carboxymethyl)lysine (CML)-exposed G361 melanoma cells in vitro. Local injection of RAGE-aptamer adjacent to the tumor dramatically decreased the growth of G361 melanoma in nude mice, which was associated with reduced expression of CML, RAGE, nitrotyrosine, VEGF, CD31, and von Willebrand factor, markers of endothelial cells in G361 tumors. Furthermore, RAGE-aptamer inhibited the binding of CML to V-domain of RAGE and blocked the CML-induced increases in oxidative stress generation, RAGE, VEGF, and MCP-1 mRNA levels in G361 melanoma cells. Our present findings suggest that long-term local injection of RAGE-aptamer adjacent to the tumor could inhibit melanoma growth in nude mice partly by suppressing tumor angiogenesis via blockade of the CML-RAGE interaction. Local injection of RAGE-aptamer may be a feasible therapeutic tool for the treatment of malignant melanoma.

Pigment epithelium‑derived factor inhibits advanced glycation end product‑induced proliferation, VEGF and MMP‑9 expression in breast cancer cells via interaction with laminin receptor

“…We have previously shown that AGEs stimulate growth and VEGF expression in both endothelial cells and malignant melanoma cells by inducing the ROS generation through the interaction with RAGE (29,43). Oxidative stress and redox-sensitive transcriptional factor are involved in VEGF and MMP-9 gene expression in various kinds of cells, including tumor cells (29,(43)(44)(45)(46). Moreover, p66ShcA has recently been shown to play a role in breast cancer metastasis, while quercetin, an anti-oxidant suppresses the mobility as well as VEGF and MMP-9 expression of breast cancer cells (47,48).…”

DNA‐Aptamer Raised against Receptor for Advanced Glycation End Products Improves Survival Rate in Septic Mice

“…In the presence of RAGE-aptamer #1, the K d value exhibited two orders of magnitude higher level [ 16 ]. Since we have reported that RAGE-aptamer clone #1 did not exert nonspecific toxic effects in both cell culture and animal model systems [ 15 , 19 ], we used RAGE-aptamer clone #1 for the following experiments.…”

“…The specimen of kidneys and livers were fixed with 4% paraformaldehyde, embedded in paraffin, sectioned at 4 μ m intervals and mounted on glass slides. The sections were left in 0.3% hydrogen peroxide for 30 minutes to block endogenous peroxidase activity and incubated overnight at 4°C with primary antibodies, and the reactions were visualized with a Histofine Simple Stain Mouse MAX PO (MULTI) kit (Cat# 424152, Nichirei Bioscience Inc., Tokyo, Japan) as described before [ 19 ]. Ten images were captured per section from individual mice in each group.…”

Association of advanced glycation end products with sarcopenia and frailty in chronic kidney disease

“…The sections were incubated with monoclonal antibody raised against AGE 62 after pretreatment with blocking agents, and the reactions were visualized with a Mouse on Mouse Basic Kit (BMK-2202; Vector Laboratories, Burlingame, CA) 63 .…”