Skip to main content

Bone-protective and anti-tumor effect of baicalin in osteotropic breast cancer via induction of apoptosis



Research suggested that bone is the specific target organ for breast cancer metastasis. The related tumor causes significant morbidity due to a reduction in quality of life and physical function. Increased osteoclast function is implicated in the bone microenvironment during the outgrowth of breast cancer. In the present experimental study, we examined the potential bone-protective effect of baicalin osteotropic breast Cancer and explored the possible mechanism of action.


In vitro cell viability effect of baicalin was assessed on the breast cancer cell lines (MDA-MB-231 and MCF-7). We also estimated the in vitro osteoclast and bone resorption. Further, baicalin-regulated osteoblastogenesis and osteoclastogenesis were also estimated in vitro. Finally, the role of the baicalin in the expansion of osteolytic bone disease was scrutinized in a breast cancer bone metastases model.


Baicalin significantly (p < 0.001) downregulated the viability of murine and human cancer cell lines and diminished the osteoclastogenesis of osteoclast progenitors via estimation with the help of qRT-PCR. Baicalin showed the downregulation in the mRNA expression of OCN and ALP. Baicalin reduced the TRAP-positive cells in the presence of RANKL. Baicalin considerably upregulated the cytochrome c secretion into the cytoplasm. Baicalin markedly increased the DNA fragmentation, caspase-3, caspase-8, and caspase-9. Baicalin significantly (p < 0.001) reduced the metastatic growth of MDA-MB-231 cells,preserving the bone mass in a bone metastasis model.


Collectively, we can conclude that these results highlight the bone-protective effect of baicalin, which also highlighted the anti-tumor effect; further research is needed into the likely effects on bone health in the bone metastases and osteoporosis populations, such as post-menopausal women with breast cancer.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. 1.

    Coleman R, Body JJ, Aapro M et al (2014) Bone health in cancer patients: ESMO clinical practice guidelines. Ann Oncol 25:124–137.

    Article  Google Scholar 

  2. 2.

    Sunita P, Pattanayak SP (2011) Phytoestrogens in postmenopausal indications: a theoretical perspective. Pharmacogn Rev 5:41

    CAS  Article  Google Scholar 

  3. 3.

    Nordin ML, Abdul Kadir A, Zakaria ZA et al (2018) In vitro investigation of cytotoxic and antioxidative activities of Ardisia crispa against breast cancer cell lines, MCF-7 and MDA-MB-231. BMC Complement Altern Med.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Dethlefsen C, Højfeldt G, Hojman P (2013) The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat 138:657–664

    CAS  Article  Google Scholar 

  5. 5.

    Tai KH, Foroudi F (2013) Management of bone metastases. Prostate cancer: a comprehensive perspective. Springer, London

    Google Scholar 

  6. 6.

    Christakos S, Hewison M, Gardner DG et al (2013) Vitamin D: beyond bone. Ann N Y Acad Sci.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kang Y, Siegel PM, Shu W et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell.

    Article  PubMed  Google Scholar 

  8. 8.

    Marcom PK (2017) Breast cancer. Genomic and precision medicine primary care, 3rded edn. Elsevier, Amsterdam

    Google Scholar 

  9. 9.

    Early Breast Cancer Trialists Collaborative Group (EBCTCG) (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet (London, England).

    Article  Google Scholar 

  10. 10.

    Karnoub AE, Dash AB, Vo AP et al (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature.

    Article  PubMed  Google Scholar 

  11. 11.

    Fernández Vallone VB, Hofer EL, Choi H et al (2013) Behaviour of mesenchymal stem cells from bone marrow of untreated advanced breast and lung cancer patients without bone osteolytic metastasis. Clin Exp Metastasis.

    Article  PubMed  Google Scholar 

  12. 12.

    Marino S, de Ridder D, Bishop RT et al (2019) Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice. EBioMedicine.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Brufsky AM (2008) Bone health issues in women with early-stage breast cancer receiving aromatase inhibitors. Curr Oncol Rep 10:18–26

    CAS  Article  Google Scholar 

  14. 14.

    Yin JJ, Selander K, Chirgwin JM et al (1999) TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103:197–206.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Roodman GD (2001) Biology of osteoclast activation in cancer. J Clin Oncol.

    Article  PubMed  Google Scholar 

  16. 16.

    Mundy GR, Yoneda T, Hiraga T (2001) Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. Semin Oncol.

    Article  PubMed  Google Scholar 

  17. 17.

    Pavlakis N, Schmidt RL, Stockler MR (2005) Bisphosphonates for breast cancer. Cochrane database of systematic reviews. Wiley, Chichester

    Google Scholar 

  18. 18.

    Perez EA (2006) The balance between risks and benefits: long-term use of aromatase inhibitors. Eur J Cancer.

    Article  PubMed  Google Scholar 

  19. 19.

    Marx RE, Sawatari Y, Fortin M, Broumand V (2005) Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567–1575

    Article  Google Scholar 

  20. 20.

    You L, Temiyasathit S, Lee P et al (2008) Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading. Bone.

    Article  PubMed  Google Scholar 

  21. 21.

    World Health Organisation (2017) Breast cancer: prevention and control. World Health Organisation, Geneva

    Google Scholar 

  22. 22.

    Hwang JM, Tseng TH, Tsai YY et al (2005) Protective effects of baicalein on tert-butyl hydroperoxide-induced hepatic toxicity in rat hepatocytes. J Biomed Sci 12:389–397.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Yao J, Cao X, Zhang R et al (2016) Protective effect of baicalin against experimental colitis via suppression of oxidant stress and apoptosis. Pharmacogn Mag 12:225–234.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Park BK, Zhang H, Zeng Q et al (2007) NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med.

    Article  PubMed  Google Scholar 

  25. 25.

    Tian B, Jiang T, Shao Z et al (2014) The prevention of titanium-particle-induced osteolysis by OA-14 through the suppression of the p38 signaling pathway and inhibition of osteoclastogenesis. Biomaterials.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Tang Y, Wu X, Lei W et al (2009) TGF-Β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Nolan T, Hands RE, Bustin SA (2006) Quantification of mRNA using real-time RT-PCR. Nat Protoc.

    Article  PubMed  Google Scholar 

  28. 28.

    Wang N, Feng Y, Cheung F et al (2015) A chinese medicine formula Gegen Qinlian decoction suppresses expansion of human renal carcinoma with inhibition of matrix metalloproteinase-2. Integr Cancer Ther.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Yu Y, Pei M, Li L (2015) Baicalin induces apoptosis in hepatic cancer cells in vitro and suppresses tumor growth in vivo. Int J Clin Exp Med 8:8958

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Neve RM, Chin K, Fridlyand J et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Müller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature.

    Article  PubMed  Google Scholar 

  32. 32.

    Body JJ (2006) Individualization of bisphosphonate therapy. Breast cancer and molecular medicine. Springer, Berlin

    Google Scholar 

  33. 33.

    Grav LM, Lee JS, Gerling S et al (2015) One-step generation of triple knockout CHO cell lines using CRISPR/Cas9 and fluorescent enrichment. Biotechnol J.

    Article  PubMed  Google Scholar 

  34. 34.

    Ray A, Nkhata KJ, Cleary MP (2007) Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. Int J Oncol.

    Article  PubMed  Google Scholar 

  35. 35.

    Davies MA, Kopetz S (2013) Overcoming resistance to MAPK pathway inhibitors. J Natl Cancer Inst.

    Article  PubMed  Google Scholar 

  36. 36.

    Ferlay J, Soerjomataram I, Ervik M et al (2013) Fact sheets by cancer. GLOBOCAN 2012 v1.0, Cancer Incid. Mortal. Worldw. IARC CancerBase No. 11. International Agency for Research on Cancer, Lyon

  37. 37.

    Lumachi F (2014) Malignancy-related hypercalcemia: pathophysiology and diagnosis. Anticancer res 33:6036

    Google Scholar 

  38. 38.

    Zajączkowska R, Kocot-Kępska M, Leppert W, Wordliczek J (2019) Bone pain in cancer patients: mechanisms and current treatment. Int J Mol Sci 20(23):6047

    Article  Google Scholar 

  39. 39.

    Calabrese V, Cornelius C, Cuzzocrea S et al (2011) Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Aspects Med.

    Article  PubMed  Google Scholar 

  40. 40.

    Bottini M, Magrini A, Fadeel B, Rosato N (2016) Tackling chondrocyte hypertrophy with multifunctional nanoparticles. Gene Ther.

    Article  PubMed  Google Scholar 

  41. 41.

    Tait SWG, Green DR (2012) Mitochondria and cell signalling. J Cell Sci.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Orrenius S, Gogvadze V, Zhivotovsky B (2015) Calcium and mitochondria in the regulation of cell death. Biochem Biophys Res Commun.

    Article  PubMed  Google Scholar 

  43. 43.

    Chandra D, Liu JW, Tang DG (2002) Early mitochondrial activation and cytochrome c up-regulation during apoptosis. J Biol Chem.

    Article  PubMed  Google Scholar 

  44. 44.

    Qiu JH, Asai A, Chi S et al (2000) Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. J Neurosci.

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Elmore SW, Oost TK, Park CM (2005) Inhibitors of anti-apoptotic proteins for cancer therapy. Annu Rep Med Chem 40:245–262

    CAS  Google Scholar 

  46. 46.

    Mohan S, Abdul AB, Abdelwahab SI et al (2010) Typhonium flagelliforme induces apoptosis in CEMss cells via activation of caspase-9, PARP cleavage and cytochrome c release: Its activation coupled with G0/G1 phase cell cycle arrest. J Ethnopharmacol.

    Article  PubMed  Google Scholar 

  47. 47.

    García ML, Fernández A, Solas MT (2013) Mitochondria, motor neurons and aging. J Neurol Sci.

    Article  PubMed  Google Scholar 

  48. 48.

    Li CY, Lee JS, Ko YG et al (2000) Heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation. J Biol Chem.

    Article  PubMed  Google Scholar 

  49. 49.

    Kroemer G (2001) B709 mitochondrial control of cell death. Sci World J 1:48

    Article  Google Scholar 

  50. 50.

    Berndt S, Gurevich VV, Gurevich EV (2017) Arrestins in cell death. The structural basis of arrestin functions. Springer, Cham

    Google Scholar 

  51. 51.

    Chau BN, Chen TT, Wan YY et al (2004) Tumor necrosis factor alpha-induced apoptosis requires p73 and c-ABL activation downstream of RB degradation. Mol Cell Biol.

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Kamp DW, Panduri V, Weitzman SA, Chandel N (2002) Asbestos-induced alveolar epithelial cell apoptosis: role of mitochondrial dysfunction caused by iron-derived free radicals. Mol Cell Biochem.

    Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Hong Ge.

Ethics declarations

Conflict of interest

The author states that there is no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, B., Huang, T., Fang, Q. et al. Bone-protective and anti-tumor effect of baicalin in osteotropic breast cancer via induction of apoptosis. Breast Cancer Res Treat 184, 711–721 (2020).

Download citation


  • Breast cancer
  • Baicalin
  • Bone
  • mTOR inhibition
  • Antiresorptive