Journal of Cancer Research and Clinical Oncology

, Volume 141, Issue 6, pp 1025–1036 | Cite as

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

  • 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 Lau
Original Article - Cancer Research

Abstract

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.

Keywords

Zoledronic acid Camellia sinensis Metronomic dose Breast cancer Osteolysis Metastasis 

References

  1. 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
  2. Chacko SM, Thambi PT, Kuttan R, Nishigaki I (2010) Beneficial effects of green tea: a literature review. Chin Med 5:13CrossRefPubMedCentralPubMedGoogle Scholar
  3. Daubine F, Le Gall C, Gasser J, Green J, Clezardin P (2007) Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 994:322–330CrossRefGoogle Scholar
  4. Eliza WL, Fai CK, Chung LP (2012) Efficacy of Yun Zhi (Coriolus versicolor) on survival in cancer patients: systematic review and meta-analysis. Recent Pat Inflamm Allergy Drug Discov 6(1):78–87CrossRefPubMedGoogle Scholar
  5. Evdokiou A, Labrinidis A, Bouralexis S, Hay S, Findlay DM (2003) Induction of cell death of human osteogenic sarcoma cells by zoledronic acid resembles anoikis. Bone 33:216–228CrossRefPubMedGoogle Scholar
  6. 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
  7. Farabegoli F, Papi A, Orlandi M (2011) (−)-Epigallocatechin-3-gallate down-regulates EGFR, MMP-2, MMP-9 and EMMPRIN and inhibits the invasion of MCF-7 tamoxifen-resistant cells. Biosci Rep 31(2):99–108CrossRefPubMedGoogle Scholar
  8. 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
  9. Forester SC, Lambert JD (2011) The role of antioxidant versus pro-oxidant effects of green tea polyphenols in cancer prevention. Mol Nutr Food Res 55(6):844–854CrossRefPubMedCentralPubMedGoogle Scholar
  10. Gu JW, Makey KL, Tucker KB, Chinchar E, Mao X, Pei I, Thomas EY, Miele L (2013) EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression. Vasc Cell 5(1):9CrossRefPubMedCentralPubMedGoogle Scholar
  11. Hsuuw YD, Chan WH (2007) Epigallocatechin gallate dose-dependently induces apoptosis or necrosis in human MCF-7 cells. Ann N Y Acad Sci 1095:428–440CrossRefPubMedGoogle Scholar
  12. Labrinidis A, Hay S, Liapis V, Findlay DM, Evdokiou A (2010) Zoledronic acid protects against osteosarcoma-induced bone destruction but lacks efficacy against pulmonary metastases in a syngeneic rat model. Int J Cancer 127:345–354PubMedGoogle Scholar
  13. Lam YC, Cheng CW, Peng H, Law CK, Huang XZ, Bian ZX (2009) Cancer patients’ attitudes toward Traditional Chinese Medicine: a Hong Kong survey. Chinese Med 4:25CrossRefGoogle Scholar
  14. Lee JH, Jin H, Shim HE, Kim HN, Ha H, Lee ZH (2010) Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-kappaB signal. Mol Pharmacol 77(1):17–25CrossRefPubMedGoogle Scholar
  15. Lee SH, Kim BJ, Choi HJ, Cho SW, Shin CS, Park SY, Lee YS, Lee SY, Kim HH, Kim GS, Koh JM (2012) (−)-Epigallocathechin-3-gallate, an AMPK activator, decreases ovariectomy-induced bone loss by suppression of bone resorption. Calcif Tissue Int 90(5):404–410CrossRefPubMedGoogle Scholar
  16. Liang G, Tang A, Lin X, Li L, Zhang S, Huang Z, Tang H, Li QQ (2010) Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. Int J Oncol 37(1):111–123PubMedGoogle Scholar
  17. Luo KW, Ko CH, Yue GGL, Lee MY, Siu WS, Lee JK, Shum WT, Fung KP, Leung PC, Li G, Evdokiou A, Lau CBS (2013) Anti-tumor and anti-osteolysis effects of the metronomic use of zoledronic acid in primary and metastatic breast cancer mouse models. Cancer Lett 339(1):42–48CrossRefPubMedGoogle Scholar
  18. Luo KW, Ko CH, Yue GGL, Lee JKM, Lee M, Li G, Fung KP, Leung PC, Lau CBS (2014) Green tea (Camellia sinensis) extract inhibits both the metastasis and osteolytic components of mammary cancer 4T1 lesions in mice. J Nutr Biochem 25(4):395–403CrossRefPubMedGoogle Scholar
  19. 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
  20. Mazumder ME, Beale P, Chan C, Yu JQ, Huq F (2012) Epigallocatechin gallate acts synergistically in combination with cisplatin and designed trans-palladiums in ovarian cancer cells. Anticancer Res 32(11):4851–4860PubMedGoogle Scholar
  21. 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
  22. Ottewell PD, Woodward JK, Lefley DV, Evans CA, Coleman RE, Holen I (2009) Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone. Mol Cancer Ther 8:2821–2832CrossRefPubMedGoogle Scholar
  23. Pasquier E, Kavallaris M, Andre N (2011) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7:455–465CrossRefGoogle Scholar
  24. Peng L, Song XH, Shi XG, Li JX, Ye CX (2008) An improved HPLC method for simultaneous determination of phenolic compounds, purine alkaloids and theanine in Camellia species. J Food Compost Anal 21:559–563CrossRefGoogle Scholar
  25. Qiao J, Gu C, Shang W, Du J, Yin W, Zhu M, Wang W, Han M, Lu W (2011) Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro. Food Chem Toxicol 49(6):1410–1415CrossRefPubMedGoogle Scholar
  26. Rachner TD, Singh SK, Schoppet M, Benad P, Bornhauser M, Ellenrieder V, Ebert R, Jakob F, Hofbauer LC (2010) Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells. Cancer Lett 287:109–116CrossRefPubMedGoogle Scholar
  27. Ryan P, Saleh I, Stassen LF (2009) Osteonecrosis of the jaw: a rare and devastating side effect of bisphosphonates. Postgrad Med J 85:674–677CrossRefPubMedGoogle Scholar
  28. Sellmeyer DE (2010) Atypical fractures as a potential complication of long-term bisphosphonate therapy. JAMA 304(13):1480–1484CrossRefPubMedGoogle Scholar
  29. Terranova VP, Hujanen ES, Martin GR (1986) Basement membrane and the invasive activity of metastatic tumor cells. J Natl Cancer Inst 77:311–316PubMedGoogle Scholar
  30. Thangapazham RL, Passi N, Maheshwari RK (2007) Green tea polyphenol and epigallocatechin gallate induce apoptosis and inhibit invasion in human breast cancer cells. Cancer Biol Ther 6(12):1938–1943CrossRefPubMedGoogle Scholar
  31. Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, Castronovo V, Green JR (2002) Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055–1061CrossRefPubMedGoogle Scholar
  32. Yeh P, Kishony R (2007) Networks from drug–drug surfaces. Mol Syst Biol 3:85CrossRefPubMedCentralPubMedGoogle Scholar
  33. Zhang FL, Casey PJ (1996) Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65:241–269CrossRefPubMedGoogle Scholar
  34. 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
  35. Zhou F, Zhou H, Wang T, Mu Y, Wu B, Guo DL, Zhang XM, Wu Y (2012) Epigallocatechin-3-gallate inhibits proliferation and migration of human colon cancer SW620 cells in vitro. Acta Pharmacol Sin 33(1):120–126CrossRefPubMedCentralPubMedGoogle Scholar
  36. 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

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ke-Wang Luo
    • 1
    • 2
  • Chun-Hay Ko
    • 1
    • 2
  • Grace Gar-Lee Yue
    • 1
    • 2
  • Si Gao
    • 1
    • 2
  • Julia Kin-Ming Lee
    • 1
    • 2
  • Gang Li
    • 3
    • 4
  • Kwok-Pui Fung
    • 1
    • 2
    • 4
    • 5
  • Ping-Chung Leung
    • 1
    • 2
  • Andreas Evdokiou
    • 6
  • Clara Bik-San Lau
    • 1
    • 2
  1. 1.Institute of Chinese MedicineThe Chinese University of Hong KongShatinHong Kong
  2. 2.State Key Laboratory of Phytochemistry and Plant Resources in West ChinaThe Chinese University of Hong KongShatinHong Kong
  3. 3.Department of Orthopaedics and TraumatologyThe Chinese University of Hong KongShatinHong Kong
  4. 4.School of Biomedical SciencesThe Chinese University of Hong KongShatinHong Kong
  5. 5.The Chinese University of Hong Kong-Zhejiang University Joint Laboratory and Natural Products and Toxicology ResearchThe Chinese University of Hong KongShatinHong Kong
  6. 6.Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer MedicineUniversity of AdelaideAdelaideAustralia

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