Cryptotanshinone induces reactive oxygen species‑mediated apoptosis in human rheumatoid arthritis fibroblast‑like synoviocytes

Sun,Hu‑Nan; Luo,Ying‑Hua; Meng,Ling‑Qi; Piao,Xian‑Ji; Wang,Yue; Wang,Jia‑Ru; Wang,Hao; Zhang,Yi; Li,Jin‑Qian; Xu,Wan‑Ting; Liu,Yang; Zhang,Yu; Zhang,Tong; Han,Ying‑Hao; Jin,Mei‑Hua; Shen,Gui‑Nan; Zang,Yan‑Qing; Cao,Long‑Kui; Zhang,Dong‑Jie; Jin,Cheng‑Hao

doi:10.3892/ijmm.2018.4012

Cryptotanshinone induces reactive oxygen species‑mediated apoptosis in human rheumatoid arthritis fibroblast‑like synoviocytes

Authors:
- Hu‑Nan Sun
- Ying‑Hua Luo
- Ling‑Qi Meng
- Xian‑Ji Piao
- Yue Wang
- Jia‑Ru Wang
- Hao Wang
- Yi Zhang
- Jin‑Qian Li
- Wan‑Ting Xu
- Yang Liu
- Yu Zhang
- Tong Zhang
- Ying‑Hao Han
- Mei‑Hua Jin
- Gui‑Nan Shen
- Yan‑Qing Zang
- Long‑Kui Cao
- Dong‑Jie Zhang
- Cheng‑Hao Jin
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Affiliations: Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China, Department of Grass Science, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China, Department of Gynaecology and Obstetrics, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang 163316, P.R. China, Department of Food Science and Engineering, College of Food Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
Published online on: December 3, 2018 https://doi.org/10.3892/ijmm.2018.4012
Pages: 1067-1075

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Abstract

The present study investigated the mechanisms of apoptosis induced by cryptotanshinone (CT) in human rheumatoid arthritis fibroblast‑like synoviocytes (RA‑FLSs). Cell Counting kit‑8 assay was performed to determine the cytotoxic effects of CT in human RA‑FLSs, including primary RA‑FLS, HFLS‑RA and MH7A cells, and in HFLS cells derived from normal synovial tissue. Annexin V‑FITC/PI staining was used to detect the apoptotic effects of CT in HFLS‑RA and MH7A cells. Flow cytometry was performed to detect the apoptotic and reactive oxygen species (ROS) levels induced by CT in HFLS‑RA cells. Western blotting was used to assess the expression levels of proteins associated with apoptosis and with the mitogen‑activated protein kinase (MAPK), protein kinase B (Akt), and signal transducer and activator of transcription‑3 (STAT3) signaling pathways. The results demonstrated that CT treatment significantly suppressed HFLS‑RA and MH7A cell growth, whereas no clear inhibitory effect was observed in normal HFLS cells. CT exposure downregulated the expression levels of B‑cell lymphoma 2 (Bcl‑2), p‑Akt, p‑extracellular signal‑related kinase and p‑STAT3, while it upregulated the expression levels of Bcl‑2‑associated death promoter (Bad), caspase‑3, poly (ADP‑ribose) polymerase (PARP), p‑p38 and p‑c‑Jun N‑terminal kinase. Following ROS scavenging, the CT‑induced apoptosis and altered expression levels of Bcl‑2, Bad, cleaved caspase‑3 and cleaved PARP were restored. Furthermore, the Akt, MAPK and STAT3 signaling pathways were regulated by intracellular ROS. These results suggest that ROS‑mediated Akt, MAPK and STAT3 signaling pathways serve important roles in the CT‑induced apoptosis of RA‑FLSs.

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1	Xu H, He Y, Yang X, Liang L, Zhan Z, Ye Y, Yang X, Lian F and Sun L: Anti-malarial agent artesunate inhibits TNF-alpha- induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology (Oxford). 46:920–926. 2007. View Article : Google Scholar
2	Muthana M, Hawtree S, Wilshaw A, Linehan E, Roberts H, Khetan S, Adeleke G, Wright F, Akil M, Fearon U, et al: C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis. Proc Natl Acad Sci USA. 112:11618–11623. 2015. View Article : Google Scholar : PubMed/NCBI
3	Taylor JS: Thrombotic Thrombocytopenic Purpura. Pediatric Surgery. Springer International Publishing; Cham, Switzerland: pp. 303–304. 2014
4	Firth J: Rheumatoid arthritis: Diagnosis and multidisciplinary management. Br J Nurs. 20:1179–1180. 2011. View Article : Google Scholar
5	Ota F, Maeshima A, Yamashita S, Ikeuchi H, Kaneko Y, Kuroiwa T, Hiromura K, Ueki K, Kojima I and Nojima Y: Activin A induces cell proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum. 48:2442–2449. 2003. View Article : Google Scholar
6	Kalkan A, Hallert E, Carlsson P, Roback K and Sjöwall C: Individual variations in treatment decisions by Swedish rheumatologists regarding biological drugs for rheumatoid arthritis. Scand J Rheumatol. 44:265–270. 2015.
7	Puppo F, Murdaca G, Ghio M and Indiveri F: Emerging biologic drugs for the treatment of rheumatoid arthritis. Autoimmun Rev. 4:537–541. 2005. View Article : Google Scholar
8	Messori A, Fadda V, Maratea D, Trippoli S, Gatto R, De Rosa M and Marinai C: Biological drugs for the treatment of rheumatoid arthritis by the subcutaneous route: Interpreting efficacy data to assess statistical equivalence. Ther Adv Musculoskelet Dis. 6:207–214. 2014. View Article : Google Scholar
9	Tian J, Chen JW, Gao JS, Li L and Xie X: Resveratrol inhibits TNF-α-induced IL-1β, MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway. Rheumatol Int. 33:1829–1835. 2013. View Article : Google Scholar
10	Westra J and Limburg PC: p38 mitogen-activated protein kinase (MAPK) in rheumatoid arthritis. Mini Rev Med Chem. 6:867–874. 2006. View Article : Google Scholar
11	Hammaker DR, Boyle DL, Inoue T and Firestein GS: Regulation of the JNK pathway by TGF-β activated kinase 1 in rheumatoid arthritis synoviocytes. Arthritis Res Ther. 9:R572007. View Article : Google Scholar
12	Valère A, Garnotel R, Villena I, Guenounou M, Pinon JM and Aubert D: Activation of the cellular mitogen-activated protein kinase pathways ERK, P38 and JNK during Toxoplasma gondii invasion. Parasite. 10:59–64. 2003. View Article : Google Scholar
13	Reynolds G, Cooles FA, Isaacs JD and Hilkens CM: Emerging immunotherapies for rheumatoid arthritis. Hum Vaccin Immunother. 10:822–837. 2014. View Article : Google Scholar
14	Migita K, Izumi Y, Torigoshi T, Satomura K, Izumi M, Nishino Y, Jiuchi Y, Nakamura M, Kozuru H, Nonaka F, et al: Inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in rheumatoid synovial fibroblasts using small molecule compounds. Clin Exp Immunol. 174:356–363. 2013. View Article : Google Scholar : PubMed/NCBI
15	Ahmad SF, Ansari MA, Zoheir KM, Bakheet SA, Korashy HM, Nadeem A, Ashour AE and Attia SM: Regulation of TNF-α and NF-κB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation. Immunobiology. 220:889–898. 2015. View Article : Google Scholar
16	Bugatti S, Manzo A, Caporali R and Montecucco C: Inflammatory lesions in the bone marrow of rheumatoid arthritis patients: A morphological perspective. Arthritis Res Ther. 14:2292012. View Article : Google Scholar
17	Rahman N, Jeon M, Song HY and Kim YS: Cryptotanshinone, a compound of Salvia miltiorrhiza inhibits pre-adipocytes differentiation by regulation of adipogenesis-related genes expression via STAT3 signaling. Phytomedicine. 23:58–67. 2016. View Article : Google Scholar
18	Rahman T, Hosen I, Islam MM and Shekhar HU: Oxidative stress and human health. Adv Biosci Biotechnol. 3:997–1019. 2012. View Article : Google Scholar
19	Domej W, Oettl K and Renner W: Oxidative stress and free radicals in COPD-implications and relevance for treatment. Int J Chron Obstruct Pulmon Dis. 9:1207–1224. 2014. View Article : Google Scholar
20	Mateen S, Moin S, Khan AQ, Zafar A and Fatima N: Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS One. 11:e01529252016. View Article : Google Scholar
21	Griendling KK, Touyz RM, Zweier JL, Dikalov S, Chilian W, Chen YR, Harrison DG and Bhatnagar A; American Heart Association Council on Basic Cardiovascular Sciences: Measurement of reactive oxygen species, reactive nitrogen species, and redox-dependent signaling in the cardiovascular system: A scientific statement from the american heart association. Circ Res. 119:e39–e75. 2016. View Article : Google Scholar : PubMed/NCBI
22	Chen L, Wang HJ, Xie W, Yao Y, Zhang YS and Wang H: Cryptotanshinone inhibits lung tumorigenesis and induces apoptosis in cancer cells in vitro and in vivo. Mol Med Rep. 9:2447–2452. 2014. View Article : Google Scholar
23	Wu CF, Klauck SM and Efferth T: Anticancer activity of cryptotanshinone on acute lymphoblastic leukemia cells. Arch Toxicol. 90:2275–2286. 2016. View Article : Google Scholar
24	Chen W, Pan Y, Wang S, Liu Y, Chen G, Zhou L, Ni W, Wang A and Lu Y: Cryptotanshinone activates AMPK-TSC2 axis leading to inhibition of mTORC1 signaling in cancer cells. BMC Cancer. 17:342017. View Article : Google Scholar :
25	Chen W, Lu Y, Chen G and Huang S: Molecular evidence of cryptotanshinone for treatment and prevention of human cancer. Anticancer Agents Med Chem. 13:979–987. 2013. View Article : Google Scholar :
26	Li XH, Yang XM and Wu XK: Effects of cryptotanshinone in lowering androgens synthesis for the prenatally androgenized male rats. Zhongguo Zhong Xi Yi Jie He Za Zhi. 28:1001–1004. 2008.In Chinese.
27	Cha JD, Lee JH, Choi KM, Choi SM and Park JH: Synergistic effect between cryptotanshinone and antibiotics against clinic methicillin and vancomycin-resistant staphylococcus aureus. Evid Based Complement Alternat Med. 2014:4505722014. View Article : Google Scholar
28	Li W, Saud SM, Young MR, Colburn NH and Hua B: Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro. Mol Cell Biochem. 406:63–73. 2015. View Article : Google Scholar : PubMed/NCBI
29	Lin L, Wang D, Li L, Ding X and Ma H: Dehydroepiandrosterone inhibits cell proliferation and improves viability by regulating S phase and mitochondrial permeability in primary rat leydig cells. Mol Med Rep. 14:705–714. 2016. View Article : Google Scholar
30	Ye T, Zhu S, Zhu Y, Feng Q, He B, Xiong Y, Zhao L, Zhang Y, Yu L and Yang L: Cryptotanshinone induces melanoma cancer cells apoptosis via, ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion. Biomed Pharmacother. 82:319–326. 2016. View Article : Google Scholar : PubMed/NCBI
31	Du J, Chen C, Sun Y, Zheng L and Wang W: Ponicidin suppresses HT29 cell growth via the induction of G1 cell cycle arrest and apoptosis. Mol Med Rep. 12:5816–5820. 2015. View Article : Google Scholar
32	Zhou L, Luan H, Dong X and Li Y: Activation of the PI3K/Akt and MAPK signaling pathways antagonizes adriamycin-induced HL-60 leukemia cell apoptosis. Mol Med Rep. 3:641–644. 2010. View Article : Google Scholar
33	Li S, Chen JW, Xie X, Tian J, Deng C, Wang J, Gan HN and Li F: Autophagy inhibitor regulates apoptosis and proliferation of synovial fibroblasts through the inhibition of PI3K/AKT pathway in collagen-induced arthritis rat model. Am J Transl Res. 9:2065–2076. 2017.
34	Zhai H, Hu S, Liu T, Wang F, Wang X, Wu G, Zhang Y, Sui M, Liu H and Jiang L: Nitidine chloride inhibits proliferation and induces apoptosis in colorectal cancer cells by suppressing the ERK signaling pathway. Mol Med Rep. 13:2536–2542. 2016. View Article : Google Scholar
35	Hao W, Zhang X, Zhao W, Zhu H, Liu ZY, Lu J and Chen X: Cryptotanshinone induces pro-death autophagy through JNK signaling mediated by reactive oxygen species generation in lung cancer cells. Anticancer Agents Med Chem. 16:593–600. 2016. View Article : Google Scholar
36	Park KR, Yun HM, Quang TH, Oh H, Lee DS, Auh QS and Kim EC: 4-Methoxydalbergione suppresses growth and induces apoptosis in human osteosarcoma cells in vitro and in vivo xenograft model through down-regulation of the JAK2/STAT3 pathway. Oncotarget. 7:6960–6971. 2016.PubMed/NCBI
37	Cheng G, Gao F, Sun X, Bi H and Zhu Y: Paris saponin VII suppresses osteosarcoma cell migration and invasion by inhibiting MMP-2/9 production via the p38 MAPK signaling pathway. Med Rep. 14:3199–3205. 2016. View Article : Google Scholar
38	Miao D and Zhang L: Leptin modulates the expression of catabolic genes in rat nucleus pulposus cells through the mitogen-activated protein kinase and Janus kinase 2/signal transducer and activator of transcription 3 pathways. Mol Med Rep. 12:1761–1768. 2015. View Article : Google Scholar
39	Yang Y, Dong Q and Li R: Matrine induces the apoptosis of fibroblast-like synoviocytes derived from rats with collagen- induced arthritis by suppressing the activation of the JAK/STAT signaling pathway. Int J Mol Med. 39:307–316. 2017. View Article : Google Scholar
40	Zheng R, You Z, Jia J, Lin S, Han S, Liu A, Long H and Wang S: Curcumin enhances the antitumor effect of ABT-737 via activation of the ROS-ASK1-JNK pathway in hepatocellular carcinoma cells. Mol Med Rep. 13:1570–1576. 2016. View Article : Google Scholar