Soluble receptor for advanced glycation endproducts (sRAGE) effectively reduces tumor growth as a single agent and in combination with doxorubicin in a spontaneous mammary tumor model

Abstract

Introduction: The receptor for advanced glycation endproducts (RAGE), a member of the immunoglobulin family interacts with distinct ligands that have been implicated in various pathophysiologic states such as diabetes, atherosclerosis, inflammation as well as tumor growth. We have previously demonstrated that blockade of RAGE in tumors raised in mice from rat C6 glioma cells or murine Lewis lung carcinoma effectively reduced tumor growth, invasion and metastases. Blockade of RAGE has also previously been shown to halt the progression of breast tumors in a murine model that spontaneously produces breast tumors. We hypothesize that the addition of RAGE antagonists to standard chemotherapeutic agents for breast cancer may enhance the effectiveness of monotherapy. Methods: Female MMTV transgenic mice (5–8 weeks) were divided into four groups: (1) Control group-no treatment, (2) doxorubicin (DOX) 2 mg/kg IP weekly x 4 weeks (3) sRAGE 20 μg IP daily x 4 weeks and (4) DOX 2 mg/kg IP weekly x 4 weeks and sRAGE 20 μg IP daily x 4 weeks. The mice were sacrificed and tumors harvested on treatment day 35 and were weighed and measured. Results: There was no difference in tumor weight between the control mice (n = 9) and DOX-treated mice (n = 4) (0.192 g v. 0.193). The administration of sRAGE (n = 7) decreased tumor weight to 0.12 g and the combination of sRAGE and DOX (n = 8) decreased tumor weight by a third (0.192 g v. 0.061 g, p = 0.11). While the mean tumor volume in the control mice was 316.7 mm3, sRAGE decreased tumor volume to 89.65 mm3 and the combination of sRAGE and DOX decreased tumor volume by 6.5 fold (316.7 mm3 vs. 48.08 mm3, p = 0.006). The mean tumor volume in the DOX treated group was 500.9 mm3. Conclusions: RAGE antagonists suppress local tumor growth in transgenic mice with spontaneously occurring cancer in an early intervention model. The addition of sRAGE, a low molecular weight RAGE antagonist, to doxorubicin enhanced the effectiveness of this standard chemotherapy agent.