Cancer Science & Therapy

Combined Angiotensin Receptor Blocker Losartan and the CXCR4 Inhibitor AMD3100 Increases the Efficacy of Radiotherapy in a Metastatic Osteosarcoma Mouse Model

Abstract

Sen Li, Wende Li, Chi-Ho Leung, Shuji Kitahara, Yujiao Liu, Sebastian Klein, Dai Fukumura, Leo E Gerweck, Jay S Loeffler, Rakesh K Jain, Dan G Duda and Peigen Huang

Objective: Osteosarcoma (OS) is highly metastatic and the most common primary malignant bone tumor. Hypoxia and CXCR4-overexpression in OS may play a role in resistance to radiotherapy. Using a metastatic OS mouse model, we investigated whether combining radiotherapy with a stroma-modifying drug (the angiotensin receptor 1 blocker losartan) and an anti-metastatic agent (the CXCR4 inhibitor AMD3100) is an effective OS treatment strategy.
Material and Methods: A highly metastatic, CXCR4-overexpressing Os-P0107 cell line was used to generate subcutaneous isografts in syngeneic C3Hf/Sed mice. When the tumors reached 6 mm in diameter, we treated the mice with either losartan (40 mg/kg body weight, gavage), AMD3100 (AMD, 5 mg/kg body weight, i.p.), or a combination of both drugs daily for 14 days, with 20 Gy local irradiation (IR) on day 7. We evaluated the tumorgrowth delay (TGD), distant metastases and host survival, as well as tumor vascular perfusion and tumor hypoxia.
Results: Treatment with IR, Losartan+IR, or AMD+IR resulted in a significant and comparable TGD (12 to 20 days) in Os-P0107 tumors versus the controls (all p<0.01). However, only the combination of Losartan+AMD+IR significantly enhanced tumor response to radiation by increasing TGD (additional 12 days, Losartan+AMD+IR vs. IR p=0.0215), decreasing distant metastasis (p=0.008), and increasing survival (p=0.025). Losartan treatment significantly increased CD31 positive tumor vascular density and decreased pimonidazole positive (hypoxic) areas (Percentage of CD31 and Pimo positive area; Losartan vs. Control, both p<0.01).
Conclusion: The combination of Losartan+AMD+IR significantly increases the efficacy of radiotherapy in a highly metastatic OS mouse model. The therapeutic effects are most likely due to the targeting both of tumor hypoxia and CXCR4 by losartan and AMD3100 with local irradiation. Our finding strongly suggests that losartan and AMD3100 with radiotherapy could be a potential new strategy for clinical metastatic OS treatment.