Metastasis of breast tumor cells to brain is suppressed by targeting RLIP alone and in combination with 2′-Hydroxyflavanone

Abstract

Brain metastasis is an important cause of morbidity and mortality in cancer-patients. Breast tumor cells frequently metastasize to brain and initiate severe therapeutic complications. In the present study, we evaluated the anti-metastatic effects of 2′-hydroxyflavanone (2HF) alone and in combination with RLIP targeted therapy in a novel murine model of breast tumor metastasis. The MDA-MB231Br (brain-seeking) breast cancer (BC) cells stably-transfected with luciferase were injected into the left-ventricle of NSG mouse heart and the migration of cells to brain was monitored using a non-invasive bioluminescent imaging system. To evaluate the tumor growth suppressive effects, mice were given 2HF (50 mg/kg, b.w., alternate days orally), RLIP-antibody (Rab; 5 mg/kg, b.w., weekly i.p.) or combination of 2HF+Rab starting day1 after intra-cardiac injection. Our results reveal that 2HF and Rab significantly prevented the metastasis of BC cells to brain. Further, mice treated with combination of 2HF+Rab exhibited no metastasis as compared to either or the single agent-treated mice. This study for the first time demonstrates the anti-metastatic effects of 2HF and RLIP-inhibition in-vivo in a novel breast tumor metastasis model and provides the rationale for further clinical investigation.