Alantolactone induces gastric cancer BGC‑823 cell apoptosis by regulating reactive oxygen species generation and the AKT signaling pathway

Zhang,Xin; Zhang,Hong‑Ming

doi:10.3892/ol.2019.10172

Alantolactone induces gastric cancer BGC‑823 cell apoptosis by regulating reactive oxygen species generation and the AKT signaling pathway

Authors:
- Xin Zhang
- Hong‑Ming Zhang
View Affiliations

Affiliations: Department of Gastroenterology, People's Hospital, Chongqing 401120, P.R. China, Department of Blood Transfusion, General Hospital of Xinjiang Military Area Command for the People's Liberation Army, Urumqi, Xinjiang Uygur Autonomous Region 830000, P.R. China
Published online on: March 19, 2019 https://doi.org/10.3892/ol.2019.10172
Pages: 4795-4802
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Alantolactone (ALT), a natural sesquiterpene lactone, has been suggested to exert anti‑cancer activities in various cancer cell lines. However, the effects and mechanisms of action of ALT in human gastric cancer remains to be elucidated. In the present study, the effects of ALT on BGC‑823 cells were examined and the underlying molecular mechanisms associated with these effects were investigated. Cell viability was detected by using an MTT assay. Cell cycle, cell apoptosis and the level of reactive oxygen species (ROS) were assessed by flow cytometry, and the expression levels of proteins of interest were analyzed by western blot assay. The results demonstrated that ALT triggered apoptosis and induced G0/G1 phase arrest in a dose‑dependent manner. Furthermore, the expression level of the anti‑apoptosis protein Bcl‑2 was downregulated, and expression of the pro‑apoptosis proteins Bax and cleaved PARP were significantly upregulated. The cell cycle‑associated proteins cyclin‑dependent kinase inhibitor 1 and cyclin‑dependent kinase inhibitor 1B were also increased, while cyclin D1 was deceased. In addition, ALT induced apoptosis via the inhibition of RAC‑alpha serine/threonine‑protein kinase (AKT) signaling and ROS generation, which was effectively inhibited by the ROS scavenger, N‑acetyl cysteine. Therefore, the results from the present study indicated that the ROS‑mediated inhibition of the AKT signaling pathway serves an important role in ALT‑induced apoptosis in BGC‑823 cells. In conclusion, the results demonstrated that ALT exerted significant anti‑cancer effects against gastric cancer cells in vitro.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Theuer CP, Kurosaki T, Ziogas A, Butler J and Anton-Culver H: Asian patients with gastric carcinoma in the United States exhibit unique clinical features and superior overall and cancer specific survival rates. Cancer. 89:1883–1892. 2000. View Article : Google Scholar : PubMed/NCBI
3	Lemjabbar-Alaoui H, Hassan OU, Yang YW and Buchanan P: Lung cancer: Biology and treatment options. Biochim Biophys Acta. 1856:189–210. 2015.PubMed/NCBI
4	Dikken JL, van de Velde CJ, Coit DG, Shah MA, Verheij M and Cats A: Treatment of resectable gastric cancer. Therap Adv Gastroenterol. 5:49–69. 2012. View Article : Google Scholar : PubMed/NCBI
5	Ueno T, Iida M, Yoshino S, Takeda S, Kubota H, Higashida M, Oka Y, Tsuruta A, Matsumoto H and Nagano H: East versus west: Differences in surgical management in asia compared with Europe and North America. Surg Clin North Am. 97:453–466. 2017. View Article : Google Scholar : PubMed/NCBI
6	Kubatka P, Kapinova A, Kruzliak P, Kello M, Výbohová D, Kajo K, Novák M, Chripková M, Adamkov M, Péč M, et al: Antineoplastic effects of Chlorella pyrenoidosa in the breast cancer model. Nutrition. 31:560–569. 2015. View Article : Google Scholar : PubMed/NCBI
7	Pan J, Miao D and Chen L: Germacrone reverses adriamycin resistance in human chronic myelogenous leukemia K562/ADM cells by suppressing MDR1 gene/P-glycoprotein expression. Chem Biol Interact. 288:32–37. 2018. View Article : Google Scholar : PubMed/NCBI
8	Zhang X, Lan D, Ning S and Ruan L: Anticancer action of lactucopicrin in SKMEL-5 human skin cancer cells is mediated via apoptosis induction, G2/M cell cycle arrest and downregulation of m=TOR/PI3K/AKT signalling pathway. J BUON. 23:224–228. 2018.PubMed/NCBI
9	Khan M, Yi F, Rasul A, Li T, Wang N, Gao H, Gao R and Ma T: Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction. IUBMB Life. 64:783–794. 2012. View Article : Google Scholar : PubMed/NCBI
10	Ding Y, Wang H, Niu J, Luo M, Gou Y, Miao L, Zou Z and Cheng Y: Induction of ROS overload by alantolactone prompts oxidative DNA damage and apoptosis in colorectal cancer cells. Int J Mol Sci. 17:5582016. View Article : Google Scholar : PubMed/NCBI
11	Lei JC, Yu JQ, Yin Y, Liu YW and Zou GL: Alantolactone induces activation of apoptosis in human hepatoma cells. Food Chem Toxicol. 50:3313–3319. 2012. View Article : Google Scholar : PubMed/NCBI
12	Khan M, Li T, Ahmad Khan MK, Rasul A, Nawaz F, Sun M, Zheng Y and Ma T: Alantolactone induces apoptosis in HepG2 cells through GSH depletion, inhibition of STAT3 activation, and mitochondrial dysfunction. Biomed Res Int. 2013:7198582013. View Article : Google Scholar : PubMed/NCBI
13	Yang C, Yang J, Sun M, Yan J, Meng X and Ma T: Alantolactone inhibits growth of K562/adriamycin cells by downregulating Bcr/Abl and P-glycoprotein expression. IUBMB Life. 65:435–444. 2013. View Article : Google Scholar : PubMed/NCBI
14	Cui L, Bu W, Song J, Feng L, Xu T, Liu D, Ding W, Wang J, Li C, Ma B, et al: Apoptosis induction by alantolactone in breast cancer MDA-MB-231 cells through reactive oxygen species-mediated mitochondrion-dependent pathway. Arch Pharm Res. 41:299–313. 2018. View Article : Google Scholar : PubMed/NCBI
15	Lee SS, Jeong HE, Liu KH, Ryu JY, Moon T, Yoon CN, Oh SJ, Yun CH and Shin JG: Identification and functional characterization of novel CYP2J2 variants: G312R variant causes loss of enzyme catalytic activity. Pharmacogenet Genomics. 15:105–113. 2005. View Article : Google Scholar : PubMed/NCBI
16	Gaedigk A, Baker DW, Totah RA, Gaedigk R, Pearce RE, Vyhlidal CA, Zeldin DC and Leeder JS: Variability of CYP2J2 expression in human fetal tissues. J Pharmacol Exp Ther. 319:523–532. 2006. View Article : Google Scholar : PubMed/NCBI
17	Jiang Y, Xu H and Wang J: Alantolactone induces apoptosis of human cervical cancer cells via reactive oxygen species generation, glutathione depletion and inhibition of the Bcl-2/Bax signaling pathway. Oncol Lett. 11:4203–4207. 2016. View Article : Google Scholar : PubMed/NCBI
18	Zhang J, Li Y, Duan D, Yao J, Gao K and Fang J: Inhibition of thioredoxin reductase by alantolactone prompts oxidative stress-mediated apoptosis of HeLa cells. Biochem Pharmacol. 102:34–44. 2016. View Article : Google Scholar : PubMed/NCBI
19	Liu YR, Cai QY, Gao YG, Luan X, Guan YY, Lu Q, Sun P, Zhao M and Fang C: Alantolactone, a sesquiterpene lactone, inhibits breast cancer growth by antiangiogenic activity via blocking VEGFR2 signaling. Phytother Res. 32:643–650. 2018. View Article : Google Scholar : PubMed/NCBI
20	Maryam A, Mehmood T, Zhang H, Li Y, Khan M and Ma T: Alantolactone induces apoptosis, promotes STAT3 glutathionylation and enhances chemosensitivity of A549 lung adenocarcinoma cells to doxorubicin via oxidative stress. Sci Rep. 7:62422017. View Article : Google Scholar : PubMed/NCBI
21	Yu ZY, Wang Z, Lee KY, Yuan P and Ding J: Effect of silencing colon cancer-associated transcript 2 on the proliferation, apoptosis and autophagy of gastric cancer BGC-823 cells. Oncol Lett. 15:3127–3132. 2018.PubMed/NCBI
22	Wen W, Lowe G, Roberts CM, Finlay J, Han ES, Glackin CA and Dellinger TH: Pterostilbene Suppresses ovarian cancer growth via induction of apoptosis and blockade of cell cycle progression involving inhibition of the STAT3 pathway. Int J Mol Sci. 19(pii): E19832018. View Article : Google Scholar : PubMed/NCBI
23	Ling Z, Guan H, You Z, Wang C, Hu L, Zhang L, Wang Y, Chen S, Xu B and Chen M: Aloperine executes antitumor effects through the induction of apoptosis and cell cycle arrest in prostate cancer in vitro and in vivo. Onco Targets Ther. 11:2735–2743. 2018. View Article : Google Scholar : PubMed/NCBI
24	Cho HD, Lee JH, Moon KD, Park KH, Lee MK and Seo KI: Auriculasin-induced ROS causes prostate cancer cell death via induction of apoptosis. Food Chem Toxicol. 111:660–669. 2018. View Article : Google Scholar : PubMed/NCBI
25	Lai ZQ, Ip SP, Liao HJ, Lu Z, Xie JH, Su ZR, Chen YL, Xian YF, Leung PS, Lin ZX and Brucein D: a naturally occurring tetracyclic triterpene quassinoid, induces apoptosis in pancreatic cancer through ROS-associated PI3K/Akt signaling pathway. Front Pharmacol. 8:9362017. View Article : Google Scholar : PubMed/NCBI
26	Xia S, Miao Y and Liu S: Withaferin A induces apoptosis by ROS-dependent mitochondrial dysfunction in human colorectal cancer cells. Biochem Biophys Res Commun. 503:2363–2369. 2018. View Article : Google Scholar : PubMed/NCBI
27	Xu Y, Tong Y, Ying J, Lei Z, Wan L, Zhu X, Ye F, Mao P, Wu X, Pan R, et al: Chrysin induces cell growth arrest, apoptosis, and ER stress and inhibits the activation of STAT3 through the generation of ROS in bladder cancer cells. Oncol Lett. 15:9117–9125. 2018.PubMed/NCBI
28	Sun Q, Lu NN and Feng L: Apigetrin inhibits gastric cancer progression through inducing apoptosis and regulating ROS-modulated STAT3/JAK2 pathway. Biochem Biophys Res Commun. 498:164–170. 2018. View Article : Google Scholar : PubMed/NCBI
29	Sathe A and Nawroth R: Targeting the PI3K/AKT/mTOR Pathway in Bladder Cancer. Methods Mol Biol. 1655:335–350. 2018. View Article : Google Scholar : PubMed/NCBI
30	Costa RLB, Han HS and Gradishar WJ: Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: A review. Breast Cancer Res Treat. 169:397–406. 2018. View Article : Google Scholar : PubMed/NCBI
31	Wang B, Zhou TY, Nie CH, Wan DL and Zheng SS: Bigelovin, a sesquiterpene lactone, suppresses tumor growth through inducing apoptosis and autophagy via the inhibition of mTOR pathway regulated by ROS generation in liver cancer. Biochem Biophys Res Commun. 499:156–163. 2018. View Article : Google Scholar : PubMed/NCBI
32	Zhao P, Pan Z, Luo Y, Zhang L, Li X, Zhang G, Zhang Y, Cui R, Sun M and Zhang X: Alantolactone induces apoptosis and cell cycle arrest on lung squamous cancer SK-MES-1 cells. J Biochem Mol Toxicol. 29:199–206. 2015. View Article : Google Scholar : PubMed/NCBI
33	Zhang Y, Bao YL, Wu Y, Yu CL, Huang YX, Sun Y, Zheng LH and Li YX: Alantolactone induces apoptosis in RKO cells through the generation of reactive oxygen species and the mitochondrial pathway. Mol Med Rep. 8:967–972. 2013. View Article : Google Scholar : PubMed/NCBI
34	King KL and Cidlowski JA: Cell cycle regulation and apoptosis. Annu Rev Physiol. 60:601–617. 1998. View Article : Google Scholar : PubMed/NCBI
35	Sithara T, Dhanya BP, Arun KB, Sini S, Dan M, Kokkuvayil Vasu R and Nisha P: Zerumbone, a cyclic sesquiterpene from Zingiber zerumbet induces apoptosis, cell cycle arrest, and antimigratory effects in SW480 colorectal cancer cells. J Agric Food Chem. 66:602–612. 2018. View Article : Google Scholar : PubMed/NCBI
36	Wang J, Li XM, Bai Z, Chi BX, Wei Y and Chen X: Curcumol induces cell cycle arrest in colon cancer cells via reactive oxygen species and Akt/GSK3β/cyclin D1 pathway. J Ethnopharmacol. 210:1–9. 2018. View Article : Google Scholar : PubMed/NCBI
37	Sikander M, Hafeez BB, Malik S, Alsayari A, Halaweish FT, Yallapu MM, Chauhan SC and Jaggi M: Cucurbitacin D exhibits potent anti-cancer activity in cervical cancer. Sci Rep. 6:365942016. View Article : Google Scholar : PubMed/NCBI
38	Cicenas J, Kalyan K, Sorokinas A, Jatulyte A, Valiunas D, Kaupinis A and Valius M: Highlights of the latest advances in research on CDK inhibitors. Cancers (Basel). 6:2224–2242. 2014. View Article : Google Scholar : PubMed/NCBI
39	Sithara T, Arun KB, Syama HP, Reshmitha TR and Nisha P: Morin inhibits proliferation of SW480 colorectal cancer cells by inducing apoptosis mediated by reactive oxygen species formation and uncoupling of warburg effect. Front Pharmacol. 8:6402017. View Article : Google Scholar : PubMed/NCBI
40	Choi AY, Choi JH, Yoon H, Hwang KY, Noh MH, Choe W, Yoon KS, Ha J, Yeo EJ and Kang I: Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. Eur J Pharmacol. 668:115–126. 2011. View Article : Google Scholar : PubMed/NCBI
41	Shahali A, Ghanadian M, Jafari SM and Aghaei M: Mitochondrial and caspase pathways are involved in the induction of apoptosis by nardosinen in MCF-7 breast cancer cell line. Res Pharm Sci. 13:12–21. 2018. View Article : Google Scholar : PubMed/NCBI
42	Park J, Ko YS, Yoon J, Kim MA, Park JW, Kim WH, Choi Y, Kim JH, Cheon Y and Lee BL: The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway. Gastric Cancer. 17:423–430. 2014. View Article : Google Scholar : PubMed/NCBI
43	Zheng QS and Zheng RL: Effects of ascorbic acid and sodium selenite on growth and redifferentiation in human hepatoma cells and its mechanisms. Pharmazie. 57:265–269. 2002.PubMed/NCBI
44	Balaban RS, Nemoto S and Finkel T: Mitochondria, oxidants, and aging. Cell. 120:483–495. 2005. View Article : Google Scholar : PubMed/NCBI
45	Chetram MA, Bethea DA, Odero-Marah VA, Don-Salu-Hewage AS, Jones KJ and Hinton CV: ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells. Mol Cell Biochem. 376:63–71. 2013. View Article : Google Scholar : PubMed/NCBI
46	Pavithra PS, Mehta A and Verma RS: Aromadendrene oxide 2, induces apoptosis in skin epidermoid cancer cells through ROS mediated mitochondrial pathway. Life Sci. 197:19–29. 2018. View Article : Google Scholar : PubMed/NCBI
47	Cui YQ, Liu YJ and Zhang F: The suppressive effects of Britannin (Bri) on human liver cancer through inducing apoptosis and autophagy via AMPK activation regulated by ROS. Biochem Biophys Res Commun. 497:916–923. 2018. View Article : Google Scholar : PubMed/NCBI
48	Zhong WF, Wang XH, Pan B, Li F, Kuang L and Su ZX: Eupatilin induces human renal cancer cell apoptosis via ROS-mediated MAPK and PI3K/AKT signaling pathways. Oncol Lett. 12:2894–2899. 2016. View Article : Google Scholar : PubMed/NCBI
49	Xu H, Li X, Ding W, Zeng X, Kong H, Wang H and Xie W: Deguelin induces the apoptosis of lung cancer cells through regulating a ROS driven Akt pathway. Cancer Cell Int. 15:252015. View Article : Google Scholar : PubMed/NCBI