The combined use of Camellia sinensis and metronomic zoledronic acid in a breast cancer-induced osteolysis mouse model

Purpose: In previous studies, we demonstrated that green tea (Camellia sinensis, CS) water extract had potent anti-tumor and anti-metastasis effects in the 4T1 mouse breast cancer xenograft model, and the metronomic regimen (0.0125 mg/kg twice a week for 4 weeks) of zoledronic acid (ZOL) was also effective in decreasing tumor burden and metastasis when compared with the conventional regimen. This study aimed to investigate the combined use of CS water extract and metronomic ZOL against tumor metastasis and bone destruction in MDA-MB-231-TXSA human breast cancer. Methods: Female nude mice were injected with MDA-MB-231-TXSA cells into the marrow space of tibia and were treated with CS water extract and/or metronomic ZOL for 4 weeks. Tumor growth and metastasis to lungs and livers were assessed by in vivo bioluminescence imaging. Abilities of migration and invasion of MDA-MB-231-TXSA cells were also evaluated in vitro. Results: Our results demonstrated that combination of CS and ZOL had the most potent effects on tumor burden and metastasis to bone, lung and liver, while treatment with CS or ZOL alone significantly protected the bone from cancer-induced osteolysis. In vitro, the combined use of CS + ZOL significantly inhibited MDA-MB-231-TXSA cell migration and invasion. Mechanistic zymography studies showed that the enzyme activities of MMP-9 and MMP-2 were significantly suppressed by CS and CS + ZOL. Conclusions: The combination of CS plus metronomic ZOL demonstrated potent anti-tumor, anti-metastasis and anti-osteolysis effects against breast cancer, suggesting the potential clinical application against breast cancer patients.Ke-Wang Luo, Chun-Hay Ko, Grace Gar-Lee Yue, Si Gao, Julia Kin-Ming Lee, Gang Li, Kwok-Pui Fung, Ping-Chung Leung, Andreas Evdokiou, Clara Bik-San La