Anticancer effect of salidroside on A549 lung cancer cells through inhibition of oxidative stress and phospho‑p38 expression

Wang,Jun; Li,Jian‑Zhe; Lu,Ai‑Xia; Zhang,Ke‑Fen; Li,Bao‑Jiang

doi:10.3892/ol.2014.1863

Anticancer effect of salidroside on A549 lung cancer cells through inhibition of oxidative stress and phospho‑p38 expression

Authors:
- Jun Wang
- Jian‑Zhe Li
- Ai‑Xia Lu
- Ke‑Fen Zhang
- Bao‑Jiang Li
View Affiliations

Affiliations: Department of Oncology, The Central Hospital of Taian, Taian, Shandong 271000, P.R. China, Department of Medical Laboratory, Taishan Sanatorium, Taian, Shandong 271000, P.R. China, Department of Breast Surgery, The Central Hospital of Taian, Taian, Shandong 271000, P.R. China
Published online on: February 10, 2014 https://doi.org/10.3892/ol.2014.1863
Pages: 1159-1164

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

Oxidative stress is important in carcinogenesis and metastasis. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., shows potent antioxidant properties. The aim of the present study was to investigate the roles of salidroside in cell proliferation, the cell cycle, apoptosis, invasion and epithelial‑mesenchymal transition (EMT) in A549 cells. The human alveolar adenocarcinoma cell line, A549, was incubated with various concentrations of salidroside (0, 1, 5, 10 and 20 µg/ml) and cell proliferation was detected by 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay. Propidium iodide (PI) staining was used to determine the cell cycle by flow cytometry. Cell apoptosis was detected by Annexin V‑fluorescein isothiocyanate and PI double‑staining, and tumor invasion was detected by Boyden chamber invasion assay. Western blot analysis was performed to detect the expression of EMT markers, Snail and phospho‑p38. The results showed that salidroside significantly reduced the proliferation of A549 cells, inhibited cell cycle arrest in the G0/G1 phase and induced apoptosis. Salidroside inhibited transforming growth factor‑β‑induced tumor invasion and suppressed the protein expression of Snail. As an antioxidant, salidroside inhibited the intracellular reactive oxygen species (ROS) formation in a dose‑dependent manner in A549 cells, and depletion of intracellular ROS by vitamin C suppressed apoptosis by salidroside treatment. Salidroside was also found to inhibit the expression of phospho‑p38 in A549 cells. In conclusion, salidroside inhibits cell proliferation, the cell cycle and metastasis and induces apoptosis, which may be due to its interference in the intracellular ROS generation, thereby, downregulating the ROS‑phospho‑p38 signaling pathway.

View Figures

View References

1	Han SW and Roman J: Targeting apoptotic signaling pathways in human lung cancer. Curr Cancer Drug Targets. 10:566–574. 2010. View Article : Google Scholar : PubMed/NCBI
2	Azad N, Iyer A, Vallyathan V, Wang L, Castranova V, Stehlik C and Rojanasakul Y: Role of oxidative/nitrosative stress-mediated Bcl-2 regulation in apoptosis and malignant transformation. Ann N Y Acad Sci. 1203:1–6. 2010. View Article : Google Scholar : PubMed/NCBI
3	Scatena R: Mitochondria and cancer: a growing role in apoptosis, cancer cell metabolism and dedifferentiation. Adv Exp Med Biol. 942:287–308. 2012. View Article : Google Scholar : PubMed/NCBI
4	Hu ML: Dietary polyphenols as antioxidants and anticancer agents: more questions than answers. Chang Gung Med J. 34:449–460. 2011.
5	Di Domenico F, Foppoli C, Coccia R and Perluigi M: Antioxidants in cervical cancer: chemopreventive and chemotherapeutic effects of polyphenols. Biochim Biophys Acta. 1822:737–747. 2012.PubMed/NCBI
6	Panossian A and Wagner H: Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration. Phytother Res. 19:819–838. 2005. View Article : Google Scholar
7	Yu S, Liu M, Gu X and Ding F: Neuroprotective effects of salidroside in the PC12 cell model exposed to hypoglycemia and serum limitation. Cell Mol Neurobiol. 28:1067–1078. 2008. View Article : Google Scholar
8	Wu YL, Piao DM, Han XH and Nan JX: Protective effects of salidroside against acetaminophen-induced toxicity in mice. Biol Pharm Bull. 31:1523–1529. 2008. View Article : Google Scholar : PubMed/NCBI
9	Li HB, Ge YK, Zheng XX and Zhang L: Salidroside stimulated glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase. Eur J Pharmacol. 588:165–169. 2008. View Article : Google Scholar : PubMed/NCBI
10	Schriner SE, Abrahamyan A, Avanessian A, et al: Decreased mitochondrial superoxide levels and enhanced protection against paraquat in Drosophila melanogaster supplemented with Rhodiola rosea. Free Radic Res. 43:836–843. 2009. View Article : Google Scholar
11	Hu X, Lin S, Yu D, Qiu S, Zhang X and Mei R: A preliminary study: the anti-proliferation effect of salidroside on different human cancer cell lines. Cell Biol Toxicol. 26:499–507. 2010. View Article : Google Scholar : PubMed/NCBI
12	Liu Z, Li X, Simoneau AR, Jafari M and Zi X: Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy. Mol Carcinog. 51:257–267. 2012. View Article : Google Scholar
13	Hu X, Zhang X, Qiu S, Yu D and Lin S: Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells. Biochem Biophys Res Commun. 398:62–67. 2010. View Article : Google Scholar : PubMed/NCBI
14	Carver EA, Jiang R, Lan Y, Oram KF and Gridley T: The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol. 21:8184–8188. 2001. View Article : Google Scholar : PubMed/NCBI
15	Sato A, Okada M, Shibuya K, et al: Pivotal role for ROS activation of p38 MAPK in the control of differentiation and tumor-initiating capacity of glioma-initiating cells. Stem Cell Res. 12:119–131. 2013. View Article : Google Scholar : PubMed/NCBI
16	Qu ZQ, Zhou Y, Zeng YS, Lin YK, Li Y, Zhong ZQ and Chan WY: Protective Effects of a Rhodiola Crenulata Extract and Salidroside on Hippocampal Neurogenesis against Streptozotocin-Induced Neural Injury in the Rat. PLoS One. 7:e296412012. View Article : Google Scholar
17	Zhong H, Xin H, Wu LX and Zhu YZ: Salidroside attenuates apoptosis in ischemic cardiomyocytes: a mechanism through a mitochondria-dependent pathway. J Pharmacol Sci. 114:399–408. 2010. View Article : Google Scholar
18	Tan CB, Gao M, Xu WR, Yang XY, Zhu XM and Du GH: Protective effects of salidroside on endothelial cell apoptosis induced by cobalt chloride. Biol Pharm Bull. 32:1359–1363. 2009. View Article : Google Scholar : PubMed/NCBI
19	Jančinová V, Perečko T, Harmatha J, Nosál’ R and Drábiková K: Decreased activity and accelerated apoptosis of neutrophils in the presence of natural polyphenols. Interdiscip Toxicol. 5:59–64. 2012.PubMed/NCBI
20	Park HS, Park KI, Lee DH, et al: Polyphenolic extract isolated from Korean Lonicera japonica Thunb. induce G2/M cell cycle arrest and apoptosis in HepG2 cells: involvements of PI3K/Akt and MAPKs. Food Chem Toxicol. 50:2407–2416. 2012.
21	Castillo-Pichardo L and Dharmawardhane SF: Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer. Nutr Cancer. 64:1058–1069. 2012. View Article : Google Scholar
22	Shang D, Liu Y, Yang P, Chen Y and Tian Y: TGFBI-promoted adhesion, migration and invasion of human renal cell carcfinoma depends on inactivation of von Hippel-Lindau tumor suppressor. Urology. 79:966.e1–e7. 2012. View Article : Google Scholar : PubMed/NCBI
23	Sun C, Wang Z, Zheng Q and Zhang H: Salidroside inhibits migration and invasion of human fibrosarcoma HT1080 cells. Phytomedicine. 19:355–363. 2012. View Article : Google Scholar : PubMed/NCBI
24	Micalizzi DS, Farabaugh SM and Ford HL: Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 15:117–134. 2010. View Article : Google Scholar
25	Yin D, Yao W, Chen S, Hu R and Gao X: Salidroside, the main active compound of Rhodiola plants, inhibits high glucose-induced mesangial cell proliferation. Planta Med. 75:1191–1195. 2009. View Article : Google Scholar : PubMed/NCBI
26	Ouyang J, Gao Z, Ren Z, Hong D, Qiao H and Chen Y: Synergistic effects of rMSCs and salidroside on the experimental hepatic fibrosis. Pharmazie. 65:607–613. 2010.PubMed/NCBI
27	Yang LH, Ho YJ, Lin JF, Yeh CW, Kao SH and Hsu LS: Butein inhibits the proliferation of breast cancer cells through generation of reactive oxygen species and modulation of ERK and p38 activities. Mol Med Rep. 6:1126–1132. 2012.PubMed/NCBI
28	Chye SM, Tiong YL, Yip WK, et al: Apoptosis induced by para-phenylenediamine involves formation of ROS and activation of p38 and JNK in chang liver cells. Environ Toxicol. 2012 Nov 22;(Epub ahead of print).
29	Giovannini C and Masella R: Role of polyphenols in cell death control. Nutr Neurosci. 15:134–149. 2012. View Article : Google Scholar : PubMed/NCBI
30	del Barco Barrantes I and Nebreda AR: Roles of p38 MAPKs in invasion and metastasis. Biochem Soc Trans. 40:79–84. 2012.PubMed/NCBI
31	Lv ZM, Wang Q, Wan Q, Lin JG, Hu MS, Liu YX and Wang R: The role of the p38 MAPK signaling pathway in high glucose-induced epithelial-mesenchymal transition of cultured human renal tubular epithelial cells. PLoS One. 6:e228062011. View Article : Google Scholar