Journal of Shandong University (Health Sciences) ›› 2019, Vol. 57 ›› Issue (9): 74-82.doi: 10.6040/j.issn.1671-7554.0.2018.1267

Previous Articles    

Baicalein induces apoptosis of bladder cancer cells via inhibition of the PI3K/AKT/mTOR pathway

WANG Jian1,2, LI Jian1, WANG Yong2, ZHU Yaofeng2   

  1. 1. Department of Urology, Peoples Hospital of Laoling City, Laoling 253600, Shandong, China;
    2. Department of Urology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
  • Published:2022-09-27

PDF (PC)

36

Abstract: Objective To explore the effects of baicalein on bladder cancer cells and the underlying mechanism. Methods Bladder cancer cells, T24 and 5637, were treated with baicalein(the treatment group)or dimethyl sulfoxide(the control group). The rate of cell proliferation and DNA replication were examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT)assays and 5-Ethynyl-2'-deoxyuridine(EdU)incorporation assays. The migration and invasion of cancer cells were explored by Wound healing assays and transwell assay. The cell cycle and cell apoptosis were detected by flow cytometry. The protein levels of PI3K/AKT/mTOR, Bcl-2, Bax and so on were explored by Western blotting. The effects of baicalein on cell proliferation in vivo were explored by tumor formation on nude mice. Results The inhibition rate of baicalein on cell proliferation was above 80% in vitro and about 50% in vivo. Baicalein could interfere DNA replication and suppress the migration and invasion of bladder cancer cells. Baicalein could also induce G0/G1 phase arrest and apoptosis of bladder cancer cells. Treatment of baicalein down-regulated the expression of PI3K and inhibit the phosphorylation of AKT and mTOR, with an increase in Bax/Bcl-2 ratio. Conclusion Baicalein can inhibit cell proliferation, induce cell cycle arrest and apoptosis of bladder cancer cells via suppression of the PI3K/AKT/mTOR pathway.

Key words: Baicalein, Bladder cancer, B-cell lymphoma 2, PI3K/AKT/mTOR, Apoptosis

CLC Number: 

  • R737.14
[1] Morgan TM, Keegan KA, Clark PE. Bladder cancer[J]. Curr Opin Oncol, 2011, 23(3): 275-282.
[2] Schenk-Braat EA, Bangma CH. Immunotherapy for superficial bladder cancer[J]. Cancer Immunol Immunother. 2005, 54(5): 414-423.
[3] Griffiths TR, Action on Bladder Cancer. Current perspectives in bladder cancer management[J]. Int J Clin Pract, 2013, 67(5): 435-448.
[4] Fridlender M, Kapulnik Y, Koltai H. Plant derived substances with anti-cancer activity: from folklore to practice[J]. Front Plant Sci, 2015, 6: 799. doi: 10.3389/fpls.2015.00799.
[5] Cragg GM, Newman DJ. Plants as a source of anti-cancer agents[J]. J Ethnopharmacol, 2005, 100(1-2): 72-79.
[6] Li C, Lin G, Zuo Z. Pharmacological effects and pharmacokinetics properties of Radix Scutellariae and its bioactive flavones[J]. Biopharm Drug Dispos, 2011, 32(8): 427-445.
[7] Chen SF, Hsu CW, Huang WH, et al. Post-injury baicalein improves histological and functional outcomes and reduces inflammatory cytokines after experimental traumatic brain injury[J]. Br J Pharmacol, 2008, 155(8): 1279-1296.
[8] Boyle SP, Doolan PJ, Andrews CE, et al. Evaluation of quality control strategies in Scutellaria herbal medicines[J]. J Pharm Biomed Anal, 2011, 54(5): 951-957.
[9] He XL, Wang YH, Gao M, et al. Baicalein protects rat brain mitochondria against chronic cerebral hypoperfusion-induced oxidative damage[J]. Brain Res, 2009, 1249: 212-221. doi: 10.1016/j.brainres.2008.10.005.
[10] Wang L, Ling Y, Chen Y, et al. Flavonoid baicalein suppresses adhesion, migration and invasion of MDA-MB-231 human breast cancer cells[J]. Cancer Lett, 2010, 297(1): 42-48.
[11] Taniguchi H, Yoshida T, Horinaka M, et al. Baicalein overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance via two different cell-specific pathways in cancer cells but not in normal cells[J]. Cancer Res, 2008, 68(21): 8918-8927.
[12] Chen CH, Huang LL, Huang CC, et al. Baicalein, a novel apoptotic agent for hepatoma cell lines: a potential medicine for hepatoma[J]. Nutr Cancer, 2000, 38(2): 287-295.
[13] Liu H, Dong Y, Gao Y, et al. The fascinating effects of baicalein on cancer: a review[J]. Int J Mol Sci, 2016, 17(10). pii: E1681.
[14] Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132.
[15] Shen Z, Shen T, Wientjes MG, et al. Intravesical treatments of bladder cancer: review[J]. Pharm Res, 2008, 25(7): 1500-1510.
[16] Yoshida T, Okuyama H, Nakayama M, et al. High-dose chemotherapeutics of intravesical chemotherapy rapidly induce mitochondrial dysfunction in bladder cancer-derived spheroids[J]. Cancer Sci, 2015, 106(1): 69-77.
[17] Bie B, Sun J, Guo Y, et al. Baicalein: a review of its anti-cancer effects and mechanisms in Hepatocellular Carcinoma[J]. Biomed Pharmacother, 2017, 93: 1285-1291. doi: 10.1016/j.biopha.2017.07.068.
[18] Yu X, Yang Y, Li Y, et al. Baicalein inhibits cervical cancer progression via downregulating long noncoding RNA BDLNR and its downstream PI3K/Akt pathway[J]. Int J Biochem Cell Biol, 2018, 94: 107-118. doi: 10.1016/j.biocel.2017.11.009.
[19] Ma X, Yan W, Dai Z, et al. Baicalein suppresses metastasis of breast cancer cells by inhibiting EMT via downregulation of SATB1 and Wnt/beta-catenin pathway[J]. Drug Des Devel Ther, 2016, 10: 1419-1441. doi: 10.2147/DDDT.S102541.
[20] Liu P, Feng J, Sun M, et al. Synergistic effects of baicalein with gemcitabine or docetaxel on the proliferation, migration and apoptosis of pancreatic cancer cells[J]. Int J Oncol, 2017, 51(6): 1878-1886.
[21] Malaguarnera L. Implications of apoptosis regulators in tumorigenesis[J]. Cancer Metastasis Rev, 2004, 23(3-4): 367-387.
[22] Goswami A, Ranganathan P, Rangnekar VM. The phosphoinositide 3-kinase/Akt1/Par-4 axis: a cancer-selective therapeutic target[J]. Cancer Res, 2006, 66(6): 2889-2892.
[23] Chen M, Gu J, Delclos GL, et al. Genetic variations of the PI3K-AKT-mTOR pathway and clinical outcome in muscle invasive and metastatic bladder cancer patients[J]. Carcinogenesis, 2010, 31(8): 1387-1391.
[24] Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis[J]. Adv Cancer Res, 2009, 102: 19-65. doi: 10.1016/S0065-230X(09)02002-8.
[25] Hartmann W, Kuchler J, Koch A, et al. Activation of phosphatidylinositol-3'-kinase/AKT signaling is essential in hepatoblastoma survival[J]. Clin Cancer Res, 2009, 15(14): 4538-4545.
[26] Fahmy M, Mansure JJ, Brimo F, et al. Relevance of the mammalian target of rapamycin pathway in the prognosis of patients with high-risk non-muscle invasive bladder cancer[J]. Hum Pathol, 2013, 44(9): 1766-1772.
[27] Chaux A, Comperat E, Varinot J, et al. High levels of phosphatase and tensin homolog expression are associated with tumor progression, tumor recurrence, and systemic metastases in pT1 urothelial carcinoma of the bladder: a tissue microarray study of 156 patients treated by transurethral resection[J]. Urology, 2013, 81(1): 116-122.
[28] Gonzalez-Roibon ND, Chaux A, Al-Hussain T, et al. Dysregulation of mammalian target of rapamycin pathway in plasmacytoid variant of urothelial carcinoma of the urinary bladder[J]. Hum Pathol, 2013, 44(4): 612-622.
[29] Schultz L, Chaux A, Albadine R, et al. Immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas[J]. Am J Surg Pathol, 2011, 35(10): 1549-1556.
[30] Danial NN. BCL-2 family proteins: critical checkpoints of apoptotic cell death[J]. Clin Cancer Res, 2007, 13(24): 7254-7263.
[31] Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked[J]. Science, 1997, 275(5303): 1129-1132
[32] Skommer J, Brittain T, Raychaudhuri S. Bcl-2 inhibits apoptosis by increasing the time-to-death and intrinsic cell-to-cell variations in the mitochondrial pathway of cell death[J]. Apoptosis, 2010, 15(10): 1223-1233.
[33] Zhao Y, Zhang CL, Zeng BF, et al. Enhanced chemosensitivity of drug-resistant osteosarcoma cells by lentivirus-mediated Bcl-2 silencing[J]. Biochem Biophys Res Commun, 2009, 390(3): 642-627.
[34] Reagan-Shaw S, Nihal M, Ahsan H, et al. Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio[J]. Prostate, 2008, 68(15): 1624-1634.
[35] Katiyar SK, Roy AM, Baliga MS. Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation[J]. Mol Cancer Ther, 2005, 4(2): 207-216.
[1] LU Xiang-Dong, YANG Wei, XU Guang-Meng, QU Yuan-Ming. Expression and role of PPAR-γin meningiomas and troglitazone induced meningiomas cell apoptosis in vitro [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2209, 47(6): 65-.
[2] ZHAO Ge, ZOU Cunhua, SONG Dongdong, ZHAO Shuping. Effects of tanshinone IIA on the proliferation and apoptosis of endometrial carcinoma cells [J]. Journal of Shandong University (Health Sciences), 2022, 60(9): 53-58.
[3] LIU Min, ZHANG Yuchao, MA Xiaoli, LIU Xinyu, SUN Lu, ZUO Dan, LIU Yuantao. Effects of orphan nuclear receptor NR4A1 on H2O2 induced injury of mouse renal podocytes [J]. Journal of Shandong University (Health Sciences), 2022, 60(5): 16-21.
[4] LI Hui, JIANG Chaoyang, LIU Yan, ZHANG Man. Effects and mechanism of histone deacetylase SIRT1 controlled macrophage apoptosis induced by oxidized low density lipoprotein [J]. Journal of Shandong University (Health Sciences), 2022, 60(1): 6-12.
[5] ZHANG Qian, QIN Mingming, HE Xuejia, CAI Qiujing, ZHANG Yamin, LI Qingsu, ZHU Weiwei. Effects of calcitriol on EMT induced by TGF-β1 in asthma [J]. Journal of Shandong University (Health Sciences), 2021, 59(7): 10-18.
[6] MI Qi, SHI Shuang, LI Juan, LI Peilong, DU Lutao, WANG Chuanxin. Construction of circRNA-mediated ceRNA network and prognostic assessment model for bladder cancer [J]. Journal of Shandong University (Health Sciences), 2021, 59(6): 94-102.
[7] LU You, QIE Di, WU Jinhui, YANG Fan. Effects of the intervention of Sonic Hedgehog signaling pathway on learning and memory ability in rats with intrauterine growth restriction [J]. Journal of Shandong University (Health Sciences), 2021, 59(5): 82-89.
[8] NAN Li, YANG Kaizhuan, ZHANG Yifan. Effects of domestic white light-emitting diodes exposure on rat retina [J]. Journal of Shandong University (Health Sciences), 2021, 59(4): 56-62.
[9] LIU Shudan, ZHANG Feiyan, GUO Songlin, LIANG Xueyun, CHEN Dongmei. Oxymatrine ameliorates oxidative stress injury of HaCaT cells induced by hypoxia ischemia [J]. Journal of Shandong University (Health Sciences), 2021, 59(3): 26-34.
[10] GAO Jinmei, ZHANG Xianglian, LIU Tieju. Correlation between plasma D-dimer and metastasis in 109 cases of bladder cancer [J]. Journal of Shandong University (Health Sciences), 2021, 59(3): 98-102.
[11] XUE Yuan, LIN Xueyan, XU Ge, TIAN Yongjie. Expression of hypoxia-inducible factor-1α in the serum of patients with endometriosis and its effect on epithelial mesenchymal transition of eutopic endometrial stromal cells [J]. Journal of Shandong University (Health Sciences), 2021, 59(2): 41-47.
[12] LIANG Li, SUN Bin, ZHANG Hongzhan, YE Fangzhi, FENG Xianguang, ZHANG Kai. Analysis of clinical characteristics of 48 cases of gallbladder adenoma based on different pathological grades [J]. Journal of Shandong University (Health Sciences), 2021, 59(1): 59-63.
[13] ZHANG Xiaolu, WANG Lili, CHEN Kaiming, LOU Xianzhi, ZHANG Man. Mechanism of histone deacetylase SIRT1 inhibiting macrophages apoptosis via TLR4 signaling pathway [J]. Journal of Shandong University (Health Sciences), 2020, 58(12): 8-14.
[14] SHI Li, MA Jing, ZHAO Xiwa, GUAN Yingxia, ZHAO Lianmei, SHAN Baoen. Expression and function of miR-25-3p in endometrial cancer [J]. Journal of Shandong University (Health Sciences), 2020, 58(12): 86-91.
[15] LUO Mengying, WU Bei, WANG Ye, LUO Heng, CAO Yu. Effect of ar-turmerone on poliferation, migration and invasion of cervical squamous cancer cell line SiHa [J]. Journal of Shandong University (Health Sciences), 2019, 57(6): 68-74.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd