Baicalin inhibits breast cancer development via inhibiting IĸB kinase activation in vitro and in vivo

  • Authors:
    • Yang Gao
    • Hui Liu
    • Hongzhi Wang
    • Hailong Hu
    • Hongjuan He
    • Ning Gu
    • Xiao Han
    • Qian Guo
    • Dong Liu
    • Shuang Cui
    • Hongjiang Shao
    • Chengjun Jin
    • Qiong Wu
  • View Affiliations

  • Published online on: October 12, 2018     https://doi.org/10.3892/ijo.2018.4594
  • Pages: 2727-2736
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Abstract

The aim of the present study was to investigate the effect and therapeutic potential of baicalin in breast cancer. Baicalin is used to treat inflammatory diseases. The effects of baicalin were assessed in breast cancer MCF-7 and MDA-MB‑231 cells, and human breast cancer xenograft mice. Cells were treated with 0, 20 or 30 µM baicalin for 48 h, while xenograft mice were treated with intraperitoneal injection of 0, 100 or 200 mg/kg baicalin for 30 days. The results demonstrated that treatment with baicalin dose-dependently suppressed breast cancer cell invasion, migration and proliferation, and also induced G1/S-phase cell cycle arrest in vitro and in vivo. Baicalin alleviated inflammation injury and inhibited the secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, thus suppressing nuclear factor (NF)-ĸB-p65 activation via inhibition of IĸB kinase. Investigation of the mechanism underlying baicalin activity indicated that it inhibited protein expression of NF-ĸB-p65, leading to NF-ĸB‑induced increased expression of CCND1, BCL2, BIRC2 and BIRC3, thus inhibiting cell proliferation, invasion and migration and suppressing anti-apoptotic factors in vitro and in vivo. In addition, baicalin did not affect non-tumorigenic normal breast epithelial cells. These results indicate that baicalin may exert therapeutic effects in breast cancer.

References

1 

Guo L, Liu S, Zhang S, Chen Q, Zhang M, Quan P, Lu J and Sun X: C-reactive protein and risk of breast cancer: A systematic review and meta-analysis. Sci Rep. 5:105082015. View Article : Google Scholar : PubMed/NCBI

2 

Zhang HY, Liang F, Wang F, Zhang JW, Wang L, Kang XG, Wang J and Duan QL: In vitro effects of HAS-2 gene silencing on the proliferation and apoptosis of the MCF-7 human breast cancer cell line. Cell Physiol Biochem. 40:807–817. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Vulcano E, Montesano M, Battista C, Carino R, Perrone G, Vincenzi B and Altomare V: Urinary complications from breast cancer metastasis: Case report and review of the literature. G Chir. 31:243–245. 2010.PubMed/NCBI

4 

Al-Sadoon MK, Abdel-Maksoud MA, Rabah DM and Badr G: Induction of apoptosis and growth arrest in human breast carcinoma cells by a snake (Walterinnesia aegyptia) venom combined with silica nanoparticles: Crosstalk between Bcl2 and caspase-3. Cell Physiol Biochem. 30:653–665. 2012. View Article : Google Scholar

5 

Naugler WE and Karin M: NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 18:19–26. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Biswas DK, Martin KJ, McAlister C, Cruz AP, Graner E, Dai SC and Pardee AB: Apoptosis caused by chemotherapeutic inhibition of nuclear factor-kappaB activation. Cancer Res. 63:290–295. 2003.PubMed/NCBI

7 

Karin M: Nuclear factor-kappaB in cancer development and progression. Nature. 441:431–436. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Gutierrez CM, Lopez-Valdez R, Subramani R, Arumugam A, Nandy S, Rajamanickam V, Ravichandran V and Lakshmanaswamy R: A breast tissue protein expression profile contributing to early parity-induced protection against breast cancer. Cell Physiol Biochem. 37:1671–1685. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Berrak Ö, Akkoç Y, Arısan ED, Çoker-Gürkan A, Obakan-Yerlikaya P and Palavan-Ünsal N: The inhibition of PI3K and NFκB promoted curcumin-induced cell cycle arrest at G2/M via altering polyamine metabolism in Bcl-2 overexpressing MCF-7 breast cancer cells. Biomed Pharmacother. 77:150–160. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Xu XF, Cai BL, Guan SM, Li Y, Wu JZ, Wang Y and Liu B: Baicalin induces human mucoepidermoid carcinoma Mc3 cells apoptosis in vitro and in vivo. Invest New Drugs. 29:637–645. 2011. View Article : Google Scholar

11 

Hou J, Wang J, Zhang P, Li D, Zhang C, Zhao H, Fu J, Wang B and Liu J: Baicalin attenuates proinflammatory cytokine production in oxygen-glucose deprived challenged rat microglial cells by inhibiting TLR4 signaling pathway. Int Immunopharmacol. 14:749–757. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Liu LL, Gong LK, Wang H, Xiao Y, Wu XF, Zhang YH, Xue X, Qi XM and Ren J: Baicalin inhibits macrophage activation by lipopolysaccharide and protects mice from endotoxin shock. Biochem Pharmacol. 75:914–922. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Yin F, Liu J, Ji X, Wang Y, Zidichouski J and Zhang J: Baicalin prevents the production of hydrogen peroxide and oxidative stress induced by Aβ aggregation in SH-SY5Y cells. Neurosci Lett. 492:76–79. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Taira Z, Yabe K, Hamaguchi Y, Hirayama K, Kishimoto M, Ishida S and Ueda Y: Effects of Sho-saiko-to extract and its components, Baicalin, baicalein, glycyrrhizin and glycyrrhetic acid, on pharmacokinetic behavior of salicylamide in carbon tetrachloride intoxicated rats. Food Chem Toxicol. 42:803–807. 2004. View Article : Google Scholar : PubMed/NCBI

15 

Xu Y, Feng Y, Li H and Gao Z: Ferric citrate CYP2E1-independently promotes alcohol-induced apoptosis in HepG2 cells via oxidative/nitrative stress which is attenuated by pretreatment with baicalin. Food Chem Toxicol. 50:3264–3272. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Cao Y, Mao X, Sun C, Zheng P, Gao J, Wang X, Min D, Sun H, Xie N and Cai J: Baicalin attenuates global cerebral ischemia/ reperfusion injury in gerbils via anti-oxidative and anti-apoptotic pathways. Brain Res Bull. 85:396–402. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Dinda B, Dinda S, DasSharma S, Banik R, Chakraborty A and Dinda M: Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. Eur J Med Chem. 131:68–80. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Wang HZ, Wang HH, Huang SS, Zhao H, Cao YG, Wang GZ, Wang D, Wang ZG and Liu YH: Inhibitory effect of baicalin on collagen-induced arthritis in rats through the nuclear factor-κB pathway. J Pharmacol Exp Ther. 350:435–443. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Yang X, Yang J and Zou H: Baicalin inhibits IL-17-mediated joint inflammation in murine adjuvant-induced arthritis. Clin Dev Immunol. 2013:2680652013. View Article : Google Scholar : PubMed/NCBI

20 

Barham W, Chen L, Tikhomirov O, Onishko H, Gleaves L, Stricker TP, Blackwell TS and Yull FE: Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ. BMC Cancer. 15:6472015. View Article : Google Scholar

21 

Kim HJ, Hawke N and Baldwin AS: NF-kappaB and IKK as therapeutic targets in cancer. Cell Death Differ. 13:738–747. 2006. View Article : Google Scholar : PubMed/NCBI

22 

Bai HY, Mogi M, Nakaoka H, Kan-No H, Tsukuda K, Wang XL, Shan BS, Kukida M, Yamauchi T, Higaki A, et al: Synergistic inhibitory effect of rosuvastatin and angiotensin II type 2 receptor agonist on vascular remodeling. J Pharmacol Exp Ther. 358:352–358. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Gibson CJ, Hossain MM, Richardson JR and Aleksunes LM: Inflammatory regulation of ATP binding cassette efflux transporter expression and function in microglia. J Pharmacol Exp Ther. 343:650–660. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Goswami S and Sharma-Walia N: Osteoprotegerin rich tumor microenvironment: Implications in breast cancer. Oncotarget. 7:42777–42791. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Lixuan Z, Jingcheng D, Wenqin Y, Jianhua H, Baojun L and Xiaotao F: Baicalin attenuates inflammation by inhibiting NF-kappaB activation in cigarette smoke induced inflammatory models. Pulm Pharmacol Ther. 23:411–419. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Guo M, Zhang N, Li D, Liang D, Liu Z, Li F, Fu Y, Cao Y, Deng X and Yang Z: Baicalin plays an anti-inflammatory role through reducing nuclear factor-κB and p38 phosphorylation in S aureus- induced mastitis. Int Immunopharmacol. 16:125–130. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Delhase M, Hayakawa M, Chen Y and Karin M: Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science. 284:309–313. 1999. View Article : Google Scholar : PubMed/NCBI

28 

Shi C, Zhang N, Feng Y, Cao J, Chen X and Liu B: Aspirin inhibits IKK-β-mediated prostate cancer cell invasion by targeting matrix metalloproteinase-9 and urokinase-type plasminogen activator. Cell Physiol Biochem. 41:1313–1324. 2017. View Article : Google Scholar

29 

Ingrassia R, Lanzillotta A, Sarnico I, Benarese M, Blasi F, Borgese L, Bilo F, Depero L, Chiarugi A, Spano PF, et al: 1B/ (-)IRE DMT1 expression during brain ischemia contributes to cell death mediated by NF-κB/RelA acetylation at Lys310. PLoS One. 7:e380192012. View Article : Google Scholar

30 

Lee-Rivera I, López E, Parrales A, Alvarez-Arce A and López-Colomé AM: Thrombin promotes the expression of Ccnd1 gene in RPE cells through the activation of converging signaling pathways. Exp Eye Res. 139:81–89. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Wang J, Wang Q, Cui Y, Liu ZY, Zhao W, Wang CL, Dong Y, Hou L, Hu G, Luo C, et al: Knockdown of cyclin D1 inhibits proliferation, induces apoptosis, and attenuates the invasive capacity of human glioblastoma cells. J Neurooncol. 106:473–484. 2012. View Article : Google Scholar

32 

Jin H, Dong YY, Zhang H, Cui Y, Xie K and Lou G: shRNA depletion of cIAP1 sensitizes human ovarian cancer cells to anticancer agent-induced apoptosis. Oncol Res. 22:167–176. 2014. View Article : Google Scholar

33 

Badr G, Al-Sadoon MK and Rabah DM: Therapeutic efficacy and molecular mechanisms of snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles in the treatment of breast cancer- and prostate cancer-bearing experimental mouse models. Free Radic Biol Med. 65:175–189. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Gyrd-Hansen M, Meier P and Ps IA: IAPs: From caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer. 10:561–574. 2010. View Article : Google Scholar : PubMed/NCBI

35 

Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, Kraut N, Beug H and Wirth T: NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 114:569–581. 2004. View Article : Google Scholar : PubMed/NCBI

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December 2018
Volume 53 Issue 6

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Copy and paste a formatted citation
APA
Gao, Y., Liu, H., Wang, H., Hu, H., He, H., Gu, N. ... Wu, Q. (2018). Baicalin inhibits breast cancer development via inhibiting IĸB kinase activation in vitro and in vivo. International Journal of Oncology, 53, 2727-2736. https://doi.org/10.3892/ijo.2018.4594
MLA
Gao, Y., Liu, H., Wang, H., Hu, H., He, H., Gu, N., Han, X., Guo, Q., Liu, D., Cui, S., Shao, H., Jin, C., Wu, Q."Baicalin inhibits breast cancer development via inhibiting IĸB kinase activation in vitro and in vivo". International Journal of Oncology 53.6 (2018): 2727-2736.
Chicago
Gao, Y., Liu, H., Wang, H., Hu, H., He, H., Gu, N., Han, X., Guo, Q., Liu, D., Cui, S., Shao, H., Jin, C., Wu, Q."Baicalin inhibits breast cancer development via inhibiting IĸB kinase activation in vitro and in vivo". International Journal of Oncology 53, no. 6 (2018): 2727-2736. https://doi.org/10.3892/ijo.2018.4594