title: The combined use of Camellia sinensis and metronomic zoledronate in 4T1 mouse carcinoma against tumor growth and metastasis.
abstract: In previous studies, we demonstrated that the green tea Camellia sinensis (CS) water extract had potent antitumor and antimetastatic effects on 4T1 breast cancer. The metronomic regimen (0.0125 mg/kg twice a week for 4 weeks) of zoledronate (ZOL) was found to be effective in decreasing tumor burden and metastasis as compared with conventional regimen. The aim of the present study was to investigate the antitumor, antimetastatic and anti-osteolytic effects of the combined use of CS water extract and metronomic ZOL against 4T1 breast carcinoma in vitro and in vivo. The results demonstrated that the combination of CS+ZOL exerted a more potent effect on lung and liver by decreasing tumor burden and metastasis, when compared to CS or metronomic ZOL as monotherapies. The combination of CS+ZOL demonstrated optimal bone protection against breast cancer-induced osteolysis for the three groups of CS, ZOL and CS+ZOL. The in vitro results further demonstrated that ZOL enhanced CS-induced apoptosis in 4T1 cells as assessed by the Annexin V-FITC/PI staining and caspase-3 activity assays. In addition, the combined use of CS+ZOL significantly inhibited 4T1 cell migration. Mechanistic studies showed that the enzyme levels of matrix metalloproteinases (MMP)-2 and MMP-9 were suppressed significantly by CS+ZOL. In conclusion, to the best of our knowledge, this is the first study to investigate the novel combined application of herbal extract CS and chemotherapy ZOL in 4T1 breast cancer. The combination of CS plus metronomic ZOL demonstrated significant antitumor, antimetastatic and anti-osteolytic effects against breast cancer, and suggested potential clinical application for breast cancer patients.
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Ke-Wang
authors.initials: KW
authors.lastname: Luo
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Grace Gar-Lee
authors.initials: GG
authors.lastname: Yue
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Chun-Hay
authors.initials: CH
authors.lastname: Ko
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Si
authors.initials: S
authors.lastname: Gao
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Julia Kin-Ming
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Ping-Chung
authors.initials: PC
authors.lastname: Leung
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.
authors.forename: Clara Bik-San
authors.initials: CB
authors.lastname: Lau
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D028241:Camellia sinensis / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage* / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D010014:Osteolysis / Q000188:drug therapy* / Q000378:metabolism; D010936:Plant Extracts / Q000008:administration & dosage* / Q000494:pharmacology; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D010936:Plant Extracts; D000077211:Zoledronic Acid; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse