Abstract
Background
β-Elemene is a natural anticancer compound extracted from the Chinese medicinal herb Curcuma Wenyujin. This study was done to determine the effect of β-elemene on the apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and associated molecular mechanisms.
Methods
RA-FLS were treated for 72 h with β-elemene at 10–200 μg/ml and cell viability and apoptotic changes were examined. The involvement of reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) was checked.
Results
We found that β-elemene significantly inhibited the viability and promoted apoptosis of RA-FLS in a concentration-dependent fashion. β-Elemene-treated FLS showed a significant decline in mitochondrial membrane potential, an accumulation of cytochrome c in the cytosol, and increased activities of caspase-9 and caspase-3. β-Elemene treatment caused an enhancement of p38 MAPK phosphorylation and ROS production. The pro-apoptotic activity of β-elemene was significantly reversed by pretreatment with the p38 inhibitor SB203580 or ROS inhibitor N-acetyl-l-cysteine.
Conclusions
Taken together, β-elemene is effective in inducing mitochondrial apoptosis of RA-FLS, which is mediated through induction of ROS formation and p38 MAPK activation. β-Elemene may thus have therapeutic benefits for RA.
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References
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;365(23):2205–19.
Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol 2013;9(1):24–33.
Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2010;233(1):233–55.
Pope RM. Apoptosis as a therapeutic tool in rheumatoid arthritis. Nat Rev Immunol 2002;2(7):527–35.
Baier A, Meineckel I, Gay S, Pap T. Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol 2003;15(3):274–9.
Li H, Wan A. Apoptosis of rheumatoid arthritis fibroblast-like synoviocytes: possible roles of nitric oxide and the thioredoxin 1. Mediators Inflamm 2013;2013:953462.
Laothong U, Hiraku Y, Oikawa S, Intuyod K, Murata M, Pinlaor S. Melatonin induces apoptosis in cholangiocarcinoma cell lines by activating the reactive oxygen species-mediated mitochondrial pathway. Oncol Rep 2015. http://dx.doi.org/10.3892/or.2015.3738.
Oyinloye BE, Adenowo AF, Kappo AP. Reactive oxygen species, apoptosis, antimicrobial peptides and human inflammatory diseases. Pharmaceuticals (Basel) 2015;8(2):151–75.
Shin GC, Kim C, Lee JM, Cho WS, Lee SG, Jeong M, et al. Apigenin-induced apoptosis is mediated by reactive oxygen species and activation of ERK1/2 in rheumatoid fibroblast-like synoviocytes. Chem Biol Interact 2009;182(1): 29–36.
Olavarría VH, Recabarren P, Fredericksen F, Villalba M, Yáñez A. ISAV infection promotes apoptosis of SHK-1 cells through a ROS/p38 MAPK/Bad signaling pathway. Mol Immunol 2015;64(1):1–8.
Chen X, Wang Y, Luo H, Luo Z, Zhang T, Yang N, et al. β-Elemene acts as an antitumor factor and downregulates the expression of survivin, Bcl-xL and Mta-1. Mol Med Rep 2012;6(5):989–95.
Lee RX, Li QQ, Reed E. β-Elemene effectively suppresses the growth and survival of both platinum-sensitive and -resistant ovarian tumor cells. Anti-cancer Res 2012;32(8):3103–13.
Li QQ, Wang G, Huang F, Banda M, Reed E. Antineoplastic effect of beta-elemene on prostate cancer cells and other types of solid tumour cells. J Pharm Pharmacol 2010;62(8):1018–27.
Yao CC, Tu YR, Jiang J, Ye SF, Du HX, Zhang Y. β-elemene reverses the drug resistance of lung cancer A549/DDP cells via the mitochondrial apoptosis pathway. Oncol Rep 2014;31(5):2131–8.
Yao YQ, Ding X, Jia YC, Huang CX, Wang YZ, Xu YH. Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. Cancer Lett 2008;264(1):127–34.
Glasow A, Prodromou N, Xu K, von Lindern M, Zelent A. Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways. Blood 2005;105(1):341–9.
Liu LB, Xie H, Xue YX, Liu YH, Li Z, Wang P. Endothelial-monocyte-activating polypeptide II induces rat C6 glioma cell apoptosis via the mitochondrial pathway. Biochem Biophys Res Commun 2015;457(4):595–601.
Hua P, Sun M, Zhang G, Zhang Y, Tian X, Li X, et al. Cepharanthine induces apoptosis through reactive oxygen species and mitochondrial dysfunction in human non-small-cell lung cancer cells. Biochem Biophys Res Commun 2015. pii: S0006–291X(15)00378-2.
Guan C, Liu W, Yue Y, Jin H, Wang X, Wang XJ. Inhibitory effect of β-elemene on human breast cancer cells. Int J Clin Exp Pathol 2014;7(7):3948–56.
Hu Z, Wu H, Li Y, Hou Q, Wang Y, Li S, et al. β-Elemene inhibits the proliferation of esophageal squamous cell carcinoma by regulating long noncoding RNA-mediated inhibition of hTERT expression. Anticancer Drugs 2015;26(5):531–9.
Li X, Wang G, Zhao J, Ding H, Cunningham C, Chen F, et al. Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase. Cell Mol Life Sci 2005;62(7–8):894–904.
Caroppi P, Sinibaldi F, Fiorucci L, Santucci R. Apoptosis and human diseases: mitochondrion damage and lethal role of released cytochrome C as proapoptotic protein. Curr Med Chem 2009;16(31):4058–65.
Kong LR, Chua KN, Sim WJ, Ng HC, Bi C, Ho J, et al. MEK inhibition overcomes cisplatin resistance conferred by SOS/MAPK pathway activation in squamous cell carcinoma. Mol Cancer Ther 2015. pii: molcanther.0062.2015.
Hao W, Yuan X, Yu L, Gao C, Sun X, Wang D, et al. Licochalcone A-induced human gastric cancer BGC-823 cells apoptosis by regulating ROS-mediated MAPKs and PI3K/AKT signaling pathways. Sci Rep 2015;5:10336.
Liagre B, Leger DY, Vergne-Salle P, Beneytout JL. MAP kinase subtypes and Akt regulate diosgenin-induced apoptosis of rheumatoid synovial cells in association with COX-2 expression and prostanoid production. Int J Mol Med 2007;19(1):113–22.
Liagre B, Vergne-Salle P, Leger DY, Beneytout JL. Inhibition of human rheumatoid arthritis synovial cell survival by hecogenin and tigogenin is associated with increased apoptosis, p38 mitogen-activated protein kinase activity and upregulation of cyclooxygenase-2. Int J Mol Med 2007;20(4):451–60.
Zhang Q, Wu J, Cao Q, Xiao L, Wang L, He D, et al. A critical role of Cyr61 in interleukin-17-dependent proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum 2009;60(12):3602–12.
Zhou H, Shen T, Shang C, Luo Y, Liu L, Yan J, et al. Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway. Oncotarget 2014;5(20):10140–50.
Yu Z, Wang R, Xu L, Xie S, Dong J, Jing Y. β-Elemene piperazine derivatives induce apoptosis in human leukemia cells through downregulation of c-FLIP and generation of ROS. PLoS ONE 2011;6(1):e15843.
Hu F, Yang S, Zhao D, Zhu S, Wang Y, Li J. Moderate extracellular acidification inhibits capsaicin-induced cell death through regulating calcium mobilization, NF-κB translocation and ROS production in synoviocytes. Biochem Biophys Res Commun 2012;424(1):196–200.
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Zou, S., Wang, C., Cui, Z. et al. β-Elemene induces apoptosis of human rheumatoid arthritis fibroblast-like synoviocytes via reactive oxygen species-dependent activation of p38 mitogen-activated protein kinase. Pharmacol. Rep 68, 7–11 (2016). https://doi.org/10.1016/j.pharep.2015.06.004
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DOI: https://doi.org/10.1016/j.pharep.2015.06.004