Scutellaria baicalensis Georgi induces caspase-dependent apoptosis via mitogen activated protein kinase activation and the generation of reactive oxygen species signaling pathways in MCF-7 breast cancer cells

Park,Jin  Ryeong; Lee,Min  Cheol; Moon,Seong‑Cheol; Kim,Junghoon; Ha,Ki‑Tae; Park,Eun  Jung; Hong,Chansik; Seo,Byoung‑Do; Kim,Byung  Joo

doi:10.3892/mmr.2017.6798

Scutellaria baicalensis Georgi induces caspase-dependent apoptosis via mitogen activated protein kinase activation and the generation of reactive oxygen species signaling pathways in MCF-7 breast cancer cells

Authors:
- Jin Ryeong Park
- Min Cheol Lee
- Seong‑Cheol Moon
- Junghoon Kim
- Ki‑Tae Ha
- Eun Jung Park
- Chansik Hong
- Byoung‑Do Seo
- Byung Joo Kim
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Affiliations: Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea, Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea, Department of Physiology, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea, Department of Physiology, Chosun University College of Medicine, Gwangju 61452, Republic of Korea, Department of Physical Therapy, Kyungwoon University College of Health, Gumi 730‑739, Republic of Korea
Published online on: June 16, 2017 https://doi.org/10.3892/mmr.2017.6798
Pages: 2302-2308

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Abstract

Scutellaria baicalensis Georgi extract (SBGE) is used in traditional herbal medicine and has also been used clinically to ameliorate the symptoms of various inflammatory diseases and cancer. In women, breast cancer is one of the most common diseases and numerous women succumb to it. The present study was undertaken to investigate the mechanism responsible for the SBGE‑induced apoptosis of MCF‑7 human breast cancer cells. SBGE was administered to cells at concentrations between 100 and 500 mg/ml, and cell viabilities were identified using an MTT assay. B‑cell lymphoma 2 (Bcl-2) and Bcl-2 X‑associated protein (Bax) family members were identified by western blotting, and the mRNA expression levels of the pro‑apoptosis genes Fas, Fas ligand (FasL) and tumor necrosis factor (TNF)‑α were assessed by reverse transcription‑polymerase chain reaction. It was identified that SBGE treatment for 24 h inhibited MCF‑7 proliferation and increased the sub‑G1 phase ratio. SBGE suppressed mitochondrial membrane potentials and SBGE‑induced apoptotic cell death was identified to be associated with downregulation of Bcl‑2, but upregulation of Bax. SBGE‑activated caspases 3 and 9, and increased reactive oxygen species generation. However, SBGE had no effect on the expression levels of Fas, FasL or TNF‑α. Furthermore, mitogen‑activated protein kinase and C‑Jun N‑terminal kinase inhibitors inhibited SBGE‑induced cell death. These results suggested that SBGE be considered as an agent for the treatment of breast cancer.

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1	Weigelt B, Peterse JL and van't Veer LJ: Breast cancer metastasis: Markers and models. Nat Rev Cancer. 5:591–602. 2005. View Article : Google Scholar : PubMed/NCBI
2	Van Pham P: Breast Cancer Stem Cells & Therapy Resistance. Springer; Berlin, Germany: 2015, View Article : Google Scholar
3	Stewart B and Wild C: World Cancer Report 2014International Agency for Research on Cancer. World Health Organization; Geneva, Switzerland: 2014, View Article : Google Scholar
4	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
5	Bartsch R, Wenzel C and Steger GG: Trastuzumab in the management of early and advanced stage breast cancer. Biologics. 1:19–31. 2007.PubMed/NCBI
6	Vici P, Colucci G, Gebbia V, Amodio A, Giotta F, Belli F, Conti F, Gebbia N, Pezzella G, Valerio MR, et al: First-line treatment with epirubicin and vinorelbine in metastatic breast cancer. J Clin Oncol. 20:2689–2694. 2002. View Article : Google Scholar : PubMed/NCBI
7	Li W, Li C, Zheng H, Chen G and Hua B: Therapeutic targets of traditional Chinese medicine for colorectal cancer. J Tradit Chin Med. 36:243–249. 2016. View Article : Google Scholar : PubMed/NCBI
8	Li HL: Research progress of Scutellaria baicalensis. Chem Eng Equip. 4:100–102. 2008.
9	Zhang L, Ravipati AS, Koyyalamudi SR, Jeong SC, Reddy N, Smith PT, Bartlett J, Shanmugam K, Münch G and Wu MJ: Antioxidant and anti-inflammatory activities of selected medicinal plants containing phenolic and flavonoid compounds. J Agric Food Chem. 59:12361–12367. 2011. View Article : Google Scholar : PubMed/NCBI
10	Kim HP, Son KH, Chang HW and Kang SS: Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci. 96:229–245. 2004. View Article : Google Scholar : PubMed/NCBI
11	Choi EO, Park C, Hwang HJ, Hong SH, Kim GY, Cho EJ, Kim WJ and Choi YH: Baicalein induces apoptosis via ROS-dependent activation of caspases in human bladder cancer 5637 cells. Int J Oncol. 49:1009–1018. 2016.PubMed/NCBI
12	Choi EO, Cho EJ, Jeong JW, Park C, Hong SH, Hwang HJ, Moon SK, Son CG, Kim WJ and Choi YH: Baicalein inhibits the migration and invasion of B16F10 mouse melanoma cells through inactivation of the PI3K/Akt signaling pathway. Biomol Ther (Seoul). 25:2013–221. 2017. View Article : Google Scholar
13	Yan H, Xin S, Wang H, Ma J, Zhang H and Wei H: Baicalein inhibits MMP-2 expression in human ovarian cancer cells by suppressing the p38 MAPK-dependent NF-κB signaling pathway. Anticancer Drugs. 26:649–656. 2015.PubMed/NCBI
14	Chung H, Choi HS, Seo EK, Kang DH and Oh ES: Baicalin and baicalein inhibit transforming growth factor-β1-mediated epithelial-mesenchymal transition in human breast epithelial cells. Biochem Biophys Res Commun. 458:707–713. 2015. View Article : Google Scholar : PubMed/NCBI
15	Kim SD, Lee YJ, Baik JS, Han JY, Lee CG, Heo K, Park YS, Kim JS, Ji HD, Park SI, et al: Baicalein inhibits agonist- and tumor cell-induced platelet aggregation while suppressing pulmonary tumor metastasis via cAMP-mediated VASP phosphorylation along with impaired MAPKs and PI3K-Akt activation. Biochem Pharmacol. 92:251–265. 2014. View Article : Google Scholar : PubMed/NCBI
16	Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI
17	Saraste A and Pulkki K: Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res. 45:528–537. 2000. View Article : Google Scholar : PubMed/NCBI
18	Wong RS: Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res. 30:872011. View Article : Google Scholar : PubMed/NCBI
19	Kuno T, Tsukamoto T, Hara A and Tanaka T: Cancer chemoprevention through the induction of apoptosis by natural compounds. J Biophys Chem. 3:156–173. 2012. View Article : Google Scholar
20	Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C: A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 139:271–279. 1991. View Article : Google Scholar : PubMed/NCBI
21	Wang BJ, Won SJ, Yu ZR and Su CL: Free radical scavenging and apoptotic effects of cordycepin sinensis ractionated by supercritical carbon dioxide. Food Chem Toxicol. 43:543–552. 2005. View Article : Google Scholar : PubMed/NCBI
22	Gaire BP, Moon SK and Kim H: Scutellaria baicalensis in stroke management: Nature's blessing in traditional Eastern medicine. Chin J Integr Med. 20:712–720. 2014. View Article : Google Scholar : PubMed/NCBI
23	Chen WP, Xiong Y, Hu PF, Bao JP and Wu LD: Baicalein inhibits MMPs expression via a MAPK-dependent mechanism in chondrocytes. Cell Physiol Biochem. 36:325–333. 2015. View Article : Google Scholar : PubMed/NCBI
24	Li C, Lin G and Zuo Z: Pharmacological effects and pharmacokinetics properties of Radix Scutellariae and its bioactive flavones. Biopharm Drug Dispos. 32:427–445. 2011. View Article : Google Scholar : PubMed/NCBI
25	Lee HZ, Leung HW, Lai MY and Wu CH: Baicalein induced cell cycle arrest and apoptosis in human lung squamous carcinoma CH27 cells. Anticancer Res. 25:959–964. 2005.PubMed/NCBI
26	Kim SJ, Kim HJ, Kim HR, Lee SH, Cho SD, Choi CS, Nam JS and Jung JY: Antitumor actions of baicalein and wogonin in HT-29 human colorectal cancer cells. Mol Med Rep. 6:1443–1449. 2012.PubMed/NCBI
27	Li HL, Zhang S, Wang Y, Liang RR, Li J, An P, Wang ZM, Yang J and Li ZF: Baicalein induces apoptosis via a mitochondrial-dependent caspase activation pathway in T24 bladder cancer cells. Mol Med Rep. 7:266–270. 2013.PubMed/NCBI
28	Wang Z, Jiang C, Chen W, Zhang G, Luo D, Cao Y, Wu J, Ding Y and Liu B: Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. Biomed Res Int. 2014:7325162014.PubMed/NCBI
29	Liu-Smith F and Meyskens FL: Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma. Mol Nutr Food Res. 60:1264–1274. 2016. View Article : Google Scholar : PubMed/NCBI
30	Mu J, Liu T, Jiang L, Wu X, Cao Y, Li M, Dong Q, Liu Y and Xu H: The traditional Chinese medicine baicalein potently inhibits gastric cancer cells. J Cancer. 7:453–461. 2016. View Article : Google Scholar : PubMed/NCBI
31	Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science. 267:1456–1462. 1995. View Article : Google Scholar : PubMed/NCBI
32	Adams JM and Cory S: The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 26:1324–1337. 2007. View Article : Google Scholar : PubMed/NCBI
33	Wajant H: The Fas signaling pathway: More than a paradigm. Science. 296:1635–1636. 2002. View Article : Google Scholar : PubMed/NCBI
34	Cory S and Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
35	Moldoveanu T, Liu Q, Tocilj A, Watson M, Shore G and Gehring K: The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell. 24:677–688. 2006. View Article : Google Scholar : PubMed/NCBI
36	Suzuki M, Youle RJ and Tjandra N: Structure of Bax: Coregulation of dimer formation and intracellular localization. Cell. 103:645–654. 2000. View Article : Google Scholar : PubMed/NCBI
37	Green SR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI
38	Jeong SY and Seol DW: The role of mitochondria in apoptosis. BMB Rep. 41:11–22. 2008. View Article : Google Scholar : PubMed/NCBI
39	Spierings D, McStay G, Saleh M, Bender C, Chipuk J, Maurer U and Green DR: Connected to death: The (unexpurgated) mitochondrial pathway of apoptosis. Science. 310:66–67. 2005. View Article : Google Scholar : PubMed/NCBI
40	Earnshaw WC, Martins LM and Kaufmann SH: Mammalian caspases: Structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem. 68:383–424. 1999. View Article : Google Scholar : PubMed/NCBI
41	Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, et al: A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 10:515–527. 2006. View Article : Google Scholar : PubMed/NCBI
42	Kim HJ, Wie J, So I, Jung MH, Ha KT and Kim BJ: Menthol modulates pacemaker potentials through TRPA1 channels in cultured interstitial cells of cajal from murine small intestine. Cell Physiol Biochem. 38:1869–1882. 2016. View Article : Google Scholar : PubMed/NCBI
43	Kim BJ, Lee GS and Kim HW: Involvement of transient receptor potential melastatin type 7 channels on Poncirus fructus-induced depolarizations of pacemaking activity in interstitial cells of Cajal from murine small intestine. Integr Med Res. 2:62–69. 2013. View Article : Google Scholar : PubMed/NCBI
44	Guilbert A, Gautier M, Dhennin-Duthille I, Haren N, Sevestre H and Ouadid-Ahidouch H: Evidence that TRPM7 is required for breast cancer cell proliferation. Am J Physiol Cell Physiol. 297:C493–C502. 2009. View Article : Google Scholar : PubMed/NCBI
45	Dhillon AS, Hagan S, Rath O and Kolch W: MAP kinase signalling pathways in cancer. Oncogene. 26:3279–3290. 2007. View Article : Google Scholar : PubMed/NCBI
46	Boutros T, Chevet E and Metrakos P: Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: Roles in cell growth, death, and cancer. Pharmacol Rev. 60:261–310. 2008. View Article : Google Scholar : PubMed/NCBI
47	Sebolt-Leopold JS: Development of anticancer drugs targeting the MAP kinase pathway. Oncogene. 19:6594–6599. 2000. View Article : Google Scholar : PubMed/NCBI
48	Chakraborti S, Mandal M, Das S, Mandal A and Chakraborti T: Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem. 253:269–285. 2003. View Article : Google Scholar : PubMed/NCBI
49	Kim EK and Choi EJ: Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802:396–405. 2010. View Article : Google Scholar : PubMed/NCBI
50	Cheng YL, Chang WL, Lee SC, Liu YG, Lin HC, Chen CJ, Yen CY, Yu DS, Lin SZ and Harn HJ: Acetone extract of Bupleurum scorzonerifolium inhibits proliferation of A549 human lung cancer cells via inducing apoptosis and suppressing telomerase activity. Life Sci. 73:2383–2394. 2003. View Article : Google Scholar : PubMed/NCBI
51	Wartenberg M, Budde P, de Mareés M, Grünheck F, Tsang SY, Huang Y, Chen ZY, Hescheler J and Sauer H: Inhibition of tumor-induced angiogenesis and matrix-metalloproteinase expression in confrontation cultures of embryoid bodies and tumor spheroids by plant ingredients used in traditional chinese medicine. Lab Invest. 83:87–98. 2003. View Article : Google Scholar : PubMed/NCBI
52	Ruan WJ, Lai MD and Zhou JG: Anticancer effects of Chinese herbal medicine, science or myth? J Zhejiang Univ Sci B. 7:1006–1014. 2006. View Article : Google Scholar : PubMed/NCBI
53	Mabed M, El-Helw L and Shamaa S: Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma. Br J Cancer. 90:65–69. 2004. View Article : Google Scholar : PubMed/NCBI
54	Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, et al: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 101:5328–5335. 2004. View Article : Google Scholar : PubMed/NCBI
55	Piao BK, Wang YX, Xie GR, Mansmann U, Matthes H, Beuth J and Lin HS: Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial. Anticancer Res. 24:303–309. 2004.PubMed/NCBI
56	Yan X, Shen H, Jiang H, Hu D, Zhang C, Wang J and Wu X: External Qi of Yan Xin Qigong Induces apoptosis and inhibits migration and invasion of estrogen-independent breast cancer cells through suppression of Akt/NF-kB signaling. Cell Physiol Biochem. 25:263–270. 2010. View Article : Google Scholar : PubMed/NCBI