The combined use of Camellia sinensis and metronomic zoledronic acid in a breast cancer-induced osteolysis mouse model
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.
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.
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.
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.
KeywordsZoledronic acid Camellia sinensis Metronomic dose Breast cancer Osteolysis Metastasis
- Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A (2006) Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of principle study. Cancer Res 66:1234–1240CrossRefPubMedGoogle Scholar
- Facchini G, Caraglia M, Morabito A, Marra M, Piccirillo MC, Bochicchio AM, Striano S, Marra L, Nasti G, Ferrari E, Leopardo D, Vitale G, Gentilini D, Tortoriello A, Catalano A, Budillon A, Perrone F, Iaffaioli RV (2010) Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial. Cancer Biol Ther 10:543–548CrossRefPubMedGoogle Scholar
- Fitzgerald JB, Schoeberl B, Nielsen UB, Sorger PK (2006) Systems biology and combination therapy in the quest for clinical efficacy. Nat Chem Biol 22(3):1737–1754Google Scholar
- Martin CK, Dirksen WP, Carlton MM, Lanigan LG, Pillai SP, Werbeck JL, Simmons JK, Hildreth BE, London CA, Toribio RE, and Rosol TJ (2013) Combined zoledronic acid and meloxicam reduced bone loss and tumour growth in an orthotopic mouse model of bone-invasive oral squamous cell carcinoma. Vet Comp Oncol. doi:10.1111/vco.12037
- Okamoto S, Jiang Y, Kawamura K, Shingyoji M, Fukamachi T, Tada Y, Takiguchi Y, Tatsumi K, Shimada H, Hiroshima K, Kobayashi H, Tagawa M (2013) Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels. PLoS One 8(3):e60297CrossRefPubMedCentralPubMedGoogle Scholar
- Zhao X, Xu X, Guo L, Ragaz J, Guo H, Wu J, Shao Z, Zhu J, Guo X, Chen J, Zhu B, Wang Z, Hu X (2010) Biomarker alterations with metronomic use of low-dose zoledronic acid for breast cancer patients with bone metastases and potential clinical significance. Breast Cancer Res Treat 124:733–743CrossRefPubMedGoogle Scholar
- Zinonos I, Labrinidis A, Lee M, Liapis V, Hay S, Ponomarev V, Diamond P, Zannettino AC, Findlay DM, Evdokiou A (2009) Apomab, a fully human agonistic antibody to DR5, exhibits potent antitumor activity against primary and metastatic breast cancer. Mol Cancer Ther 8:2969–2980CrossRefPubMedGoogle Scholar