Costunolide induces mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells
Tóm tắt
Costunolide, a sesquiterpene lactone extracted from Radix Aucklandiae, has the activity against multiple cancers. However, the effect of costunolide on gastric cancer (GC) have remained to be ambiguous. In this study, we investigated the underlying mechanisms of apoptosis induced by costunolide in human gastric adenocarcinoma BGC-823 cells in vitro and in vivo. The viability of BGC-823 cells was detected by MTT assay. The apoptosis and mitochondrial membrane potential (ΔΨm) of BGC-823 cells induced by costunolide were analyzed by flow cytometry. The inhibiton of costunolide on human gastric adenocarcinoma was estimated in xenografts in nude mice. Apoptosis related proteins and genes were detected by Western blot and Q-PCR. Costunolide inhibited the viability of BGC-823 cells in a time and concentration dependent manner. Costunolide induced the apoptosis and lowered the ΔΨm of BGC-823 cells significantly. Costunolide increased the expression of Bax, cleaved caspase 9, cleaved caspase 7, cleaved caspase 3 and cleaved poly ADP ribose polymerase (PARP) proteins and decreased the expression of Bcl-2, pro-caspase 9, pro-caspase 7, pro-caspase 3 and PARP proteins. Costunolide upregulated the expression of puma, Bak1 and Bax mRNA and downregulated the expression of Bcl-2 mRNA. In addition, we demonstrated that costunolide inhibited the growth and induced apoptosis of BGC-823 cells xenografted in athymic nude mice. Costunolide increased the expression of cleaved caspase 9, cleaved caspase 3 and Bax proteins and decreased the expression of Bcl-2 protein in xenografted tumor. Costunolide upregulated the expression of puma and Bax mRNA and decreased the expression of Bcl-2 mRNA in xenografted tumor. Collectively, our results suggested that costunolide induced mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells and could be the candidate drug against GC in clinical practice.
Tài liệu tham khảo
Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 2014;23(5):700–13.
Shimizu T, Marusawa H, Watanabe N, Chiba T. Molecular pathogenesis of helicobacter pylori-related gastric Cancer. Gastroenterol Clin N Am. 2015;44(3):625–38.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.
Yoo C, Park YS. Companion diagnostics for the targeted therapy of gastric cancer. World J Gastroenterol. 2015;21(39):10948–55.
Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D'Orazi G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging. 2016;8(4):603–19.
Hassan M, Watari H, AbuAlmaaty A, Ohba Y, Sakuragi N. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int. 2014;2014:150845.
Lin X, Peng Z, Su C. Potential anti-cancer activities and mechanisms of costunolide and dehydrocostuslactone. Int J Mol Sci. 2015;16(5):10888–906.
Zhang J, Hu X, Gao W, Qu Z, Guo H, Liu Z, Liu C. Pharmacokinetic study on costunolide and dehydrocostuslactone after oral administration of traditional medicine Aucklandia lappa Decne. By LC/MS/MS. J Ethnopharmacol. 2014;151(1):191–7.
Cheong CU, Yeh CS, Hsieh YW, Lee YR, Lin MY, Chen CY, Lee CH. Protective effects of Costunolide against hydrogen peroxide-induced injury in PC12 cells. Molecules (Basel, Switzerland). 2016;21(7):898.
Dong GZ, Shim AR, Hyeon JS, Lee HJ, Ryu JH. Inhibition of Wnt/beta-catenin pathway by Dehydrocostus lactone and Costunolide in Colon Cancer cells. Phytotherapy research : PTR. 2015;29(5):680–6.
Hsu JL, Pan SL, Ho YF, Hwang TL, Kung FL, Guh JH. Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer. J Urol. 2011;185(5):1967–74.
Hua P, Zhang G, Zhang Y, Sun M, Cui R, Li X, Li B, Zhang X. Costunolide induces G1/S phase arrest and activates mitochondrial-mediated apoptotic pathways in SK-MES 1 human lung squamous carcinoma cells. Oncol Lett. 2016;11(4):2780–6.
Liu CY, Chang HS, Chen IS, Chen CJ, Hsu ML, Fu SL, Chen YJ. Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells. Radiation Oncol (London, England). 2011;6:56.
Rasul A, Bao R, Malhi M, Zhao B, Tsuji I, Li J, Li X. Induction of apoptosis by costunolide in bladder cancer cells is mediated through ROS generation and mitochondrial dysfunction. Molecules (Basel, Switzerland). 2013;18(2):1418–33.
Roy A, Manikkam R. Cytotoxic impact of Costunolide isolated from Costus speciosus on breast Cancer via differential regulation of cell cycle-an in-vitro and in-silico approach. Phytother Res. 2015;29(10):1532–9.
Wang Z, Zhao X, Gong X. Costunolide induces lung adenocarcinoma cell line A549 cells apoptosis through ROS (reactive oxygen species)-mediated endoplasmic reticulum stress. Cell Biol Int. 2016;40(3):289–97.
Yang YI, Kim JH, Lee KT, Choi JH. Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species. Gynecol Oncol. 2011;123(3):588–96.
Perry SW, Norman JP, Barbieri J, Brown EB, Gelbard HA. Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. BioTechniques. 2011;50(2):98–115.
Peng Z, Wang Y, Fan J, Lin X, Liu C, Xu Y, Ji W, Yan C, Su C. Costunolide and dehydrocostuslactone combination treatment inhibit breast cancer by inducing cell cycle arrest and apoptosis through c-Myc/p53 and AKT/14-3-3 pathway. Sci Rep. 2017;7:41254.
Lopez J, Tait SW. Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer. 2015;112(6):957–62.
Mao J, Yi M, Tao Y, Huang Y, Chen M. Costunolide isolated from Vladimiria souliei inhibits the proliferation and induces the apoptosis of HepG2 cells. Mol Med Rep. 2019;19(2):1372–9.
Zhuge W, Chen R, Vladimir K, Dong X, Zia K, Sun X, Dai X, Bao M, Shen X, Liang G. Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer. Cancer Lett. 2018;412:46–58.
Chen J, Chen B, Zou Z, Li W, Zhang Y, Xie J, Liu C. Costunolide enhances doxorubicin-induced apoptosis in prostate cancer cells via activated mitogen-activated protein kinases and generation of reactive oxygen species. Oncotarget. 2017;8(64):107701–15.