Abstract
Epidemiological studies have suggested a link between cumulative diabetic exposure and cancer. The interaction of advanced glycation end products (AGEs) with their receptor (RAGE) may contribute to the phenomenon. We examined the effects of DNA aptamer raised against RAGE (RAGE-aptamer) on growth and liver metastasis of G361 melanoma in nude mice. Malignant melanoma cells were intradermally injected into the upper flank region of nude mice, which received continuous administration of RAGE-aptamer (38.4 pmol/day/g body weight) or vehicle intraperitoneally by an osmotic pump up to 42 d. RAGE-aptamer significantly reduced levels of 8-hydroxy-2′-deoxy-guanosine, AGEs, RAGE, proliferating nuclear antigen, cyclin D1, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), and CD31 and Mac-3, respective markers of endothelial cells and macrophages in tumors of nude mice, and suppressed proliferation and liver metastasis of malignant melanoma. Furthermore, RAGE-aptamer attenuated AGE-induced oxidative stress generation, proliferation, and VEGF and MCP-1 gene expression in both G361 melanoma cells and endothelial cells. The present findings suggest that RAGE-aptamer could attenuate melanoma growth and liver metastasis in nude mice by suppressing tumor angiogenesis and macrophage infiltration via inhibition of the AGE-RAGE system. RAGE-aptamer may be a novel therapeutic tool for the treatment of malignant melanoma.
Highlights
Diabetes and cancer are common chronic disorders observed in our aging society, both of which have been an increasing global health burden [1,2]
We have recently developed a DNA oligonucleotide aptamer directed against receptor for AGEs (RAGE) (RAGE-aptamer) and shown that it blocks the interaction of advanced glycation end products (AGEs) with RAGE and works as an antagonist for RAGE, thereby suppressing the AGEinduced inflammatory and fibrotic reactions in cultured mesangial cells [22]
We examined the effect of RAGEaptamer on tumor growth as well as tumor-associated angiogenesis and macrophage infiltration in nude mice
Summary
Diabetes and cancer are common chronic disorders observed in our aging society, both of which have been an increasing global health burden [1,2]. The positive correlation between diabetes and cancer death remained significant after additional adjustments for age, sex, socioeconomic and smoking status, and anthropometric, clinical and biochemical variables, except for glycated hemoglobin and fasting glucose levels; at fasting glucose levels above 5.5 mmol/L, the mortality risk of various cancers was increased by 5% for each 1 mmol/L increase in plasma glucose [6]. These observations indicate that, the molecular mechanism for the increased risk of cancer incidence and death in diabetic patients remains unclear, cumulative hyperglycemic exposure may partly explain the link between cancers and diabetes
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