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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

A Network Pharmacology Guided Mechanism of Action Study on Oldenlandia diffusa Against Osteosarcoma

Author(s): Jun Zhao, Liang Dong, Jun Wang, Boyu Pan and Yun Yang*

Volume 20, Issue 8, 2023

Published on: 06 October, 2022

Page: [1123 - 1134] Pages: 12

DOI: 10.2174/1570180819666220919101605

Price: $65

Abstract

Background: Osteosarcoma (OS) is the most prevalent primary bone sarcoma in the global child and young adult population, and the current mainstream treatment regimens are not very effective. The unique efficacy of traditional Chinese medicine (TCM) for cancers has recently received increasing attention. Oldenlandia diffusa (OD) is commonly used as adjuvant therapy for various cancers in Chinese herb medicine (CHM) with its unique pharmacological activities, but its therapeutic effect as well as the underlying mechanism against OS has yet to be systematically investigated.

Objective: This study aims to find the underlying active mechanism of OD against OS.

Methods: The candidate ingredients as well as drug targets of OD were obtained from the Traditional Chinese Medicine System Pharmacology (TCMSP) database, respectively. Meanwhile, the OS diseaserelated targets were acquired from GeneCards and MalaCards online databases. Then, by using Venny 2.1, the common key targets were imported into the STRING database to acquire their interaction relationship, and imported this PPI network file (.csv) into Cytoscape 3.6.0 software and merged to obtain PPI network intersections. Meanwhile, the MCODE plugin of Cytoscape was also used to further trim the core therapeutic targets. GO and KEGG enrichment and molecular docking analyses were performed to predict the underlying mechanism of OD against OS. Furthermore, in silico analysis results were validated by a series of cellular functional and molecular biological assays.

Results: A total of 131 putative targets were identified to be involved in the anti-OS activity of OD. The PPI network, GO as well as KEGG analyses revealed that the 18 core targets were closely related to cell proliferation, apoptosis. Importantly, the subsequent in vitro assays verified that the suppressive effect of OD on OS cell growth indeed resulted from disrupted apoptosis and cell proliferation via Akt and ERK signaling pathways. Furthermore, our results showed that quercetin, beta-sitosterol and 2-methoxy-3- methyl-9,10-anthraquinone were the key ingredients, while PTGS2, CASP3 and JUN were the key targets in delivering the pharmacological activities of OD against OS, thus providing an insight into the anti-OS action of OD from a holistic perspective.

Conclusion: In summary, our results indicate that OD has good prospects in the treatment of OS.

Keywords: Oldenlandia diffusa (OD), osteosarcoma (OS), network pharmacology, molecular docking, Tradition Chinese Medicine (TCM), Chinese herb medicine (CHM)

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[1]
Moore, D.D.; Luu, H.H. Osteosarcoma. Cancer Treat. Res., 2014, 162, 65-92.
[http://dx.doi.org/10.1007/978-3-319-07323-1_4] [PMID: 25070231]
[2]
Zhou, W.; Hao, M.; Du, X.; Chen, K.; Wang, G.; Yang, J. Advances in targeted therapy for osteosarcoma. Discov. Med., 2014, 17(96), 301-307.
[PMID: 24979249]
[3]
Gupta, S.C.; Prasad, S.; Sethumadhavan, D.R.; Nair, M.S.; Mo, Y.Y.; Aggarwal, B.B. Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer xenografts by suppressing the proinflammatory microenvironment. Clin. Cancer Res., 2013, 19(16), 4465-4476.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0080] [PMID: 23766363]
[4]
Liu, X.; Wu, J.; Zhang, D.; Wang, K.; Duan, X.; Zhang, X. A network pharmacology approach to uncover the multiple mechanisms of Hedyotis diffusa Willd on colorectal cancer. Evid. Based Complement. Alternat. Med., 2018, 2018, 6517034.
[http://dx.doi.org/10.1155/2018/7802639] [PMID: 29619072]
[5]
Zhang, Y.F.; Huang, Y.; Ni, Y.H.; Xu, Z.M. Systematic elucidation of the mechanism of geraniol via network pharmacology. Drug Des. Devel. Ther., 2019, 13, 1069-1075.
[http://dx.doi.org/10.2147/DDDT.S189088] [PMID: 31040644]
[6]
Yu, G.; Wang, W.; Wang, X.; Xu, M.; Zhang, L.; Ding, L.; Guo, R.; Shi, Y. Network pharmacology-based strategy to investigate pharmacological mechanisms of Zuojinwan for treatment of gastritis. BMC Complement. Altern. Med., 2018, 18(1), 292.
[http://dx.doi.org/10.1186/s12906-018-2356-9] [PMID: 30382864]
[7]
Bi, Y.H.; Zhang, L.; Chen, S.; Ling, Q. Antitumor mechanisms of Curcumae Rhizoma based on network pharmacology. Evid. Based Complement. Alternat. Med., 2018, 2018, 1-9.
[http://dx.doi.org/10.1155/2018/4509892] [PMID: 29636777]
[8]
Liu, X.; Wu, J.; Zhang, D.; Wang, K.; Duan, X.; Meng, Z.; Zhang, X. Network pharmacology-based approach to investigate the mechanisms of hedyotis diffusa willd. in the treatment of gastric cancer. Evid. Based Complement. Alternat. Med., 2018, 2018, 1-17.
[http://dx.doi.org/10.1155/2018/7802639] [PMID: 29853970]
[9]
Sadava, D.; Ahn, J.; Zhan, M.; Pang, M.L.; Ding, J.; Kane, S. Effects of four Chinese herbal extracts on drug-sensitive and multidrug-resistant small-cell lung carcinoma cells. Cancer Chemother. Pharmacol., 2002, 49(4), 261-266.
[http://dx.doi.org/10.1007/s00280-002-0427-5] [PMID: 11914903]
[10]
Ting, C.T.; Kuo, C.J.; Hu, H.Y.; Lee, Y.L.; Tsai, T.H. Prescription frequency and patterns of Chinese herbal medicine for liver cancer patients in Taiwan: A cross-sectional analysis of the National Health Insurance Research Database. BMC Complement. Altern. Med., 2017, 17(1), 118.
[http://dx.doi.org/10.1186/s12906-017-1628-0] [PMID: 28219357]
[11]
Lu, P.H.; Chen, M.B.; Ji, C.; Li, W.T.; Wei, M.X.; Wu, M.H. Aqueous Oldenlandia diffusa extracts inhibits colorectal cancer cells via activating AMP-activated protein kinase signalings. Oncotarget, 2016, 7(29), 45889-45900.
[http://dx.doi.org/10.18632/oncotarget.9969] [PMID: 27322552]
[12]
Willimott, S.; Barker, J.; Jones, L.A.; Opara, E.I. Apoptotic effect of Oldenlandia diffusa on the leukaemic cell line HL60 and human lymphocytes. J. Ethnopharmacol., 2007, 114(3), 290-299.
[http://dx.doi.org/10.1016/j.jep.2007.08.030] [PMID: 17936528]
[13]
Song, Y.H.; Jeong, S.J.; Kwon, H.Y.; Kim, B.; Kim, S.H.; Yoo, D.Y. Ursolic acid from Oldenlandia diffusa induces apoptosis via activation of caspases and phosphorylation of glycogen synthase kinase 3 beta in SK-OV-3 ovarian cancer cells. Biol. Pharm. Bull., 2012, 35(7), 1022-1028.
[http://dx.doi.org/10.1248/bpb.b110660] [PMID: 22791147]
[14]
Chung, T.W.; Choi, H.; Lee, J.M.; Ha, S.H.; Kwak, C.H.; Abekura, F.; Park, J.Y.; Chang, Y.C.; Ha, K.T.; Cho, S.H.; Chang, H.W.; Lee, Y.C.; Kim, C.H. Oldenlandia diffusa suppresses metastatic potential through inhibiting matrix metalloproteinase-9 and intercellular adhesion molecule-1 expression via p38 and ERK1/2 MAPK pathways and induces apoptosis in human breast cancer MCF-7 cells. J. Ethnopharmacol., 2017, 195, 309-317.
[http://dx.doi.org/10.1016/j.jep.2016.11.036] [PMID: 27876502]
[15]
Gu, G.; Barone, I.; Gelsomino, L.; Giordano, C.; Bonofiglio, D.; Statti, G.; Menichini, F.; Catalano, S.; Andò, S. Oldenlandia diffusa extracts exert antiproliferative and apoptotic effects on human breast cancer cells through ERα/Sp1-mediated p53 activation. J. Cell. Physiol., 2012, 227(10), 3363-3372.
[http://dx.doi.org/10.1002/jcp.24035] [PMID: 22213398]
[16]
Sunwoo, Y.Y.; Lee, J.H.; Jung, H.Y.; Jung, Y.J.; Park, M.S.; Chung, Y.A.; Maeng, L.S.; Han, Y.M.; Shin, H.S.; Lee, J.; Park, S.I. Oldenlandia diffusa promotes antiproliferative and apoptotic effects in a rat hepatocellular carcinoma with liver cirrhosis. Evid. Based Complement. Alternat. Med., 2015, 2015, 1-11.
[http://dx.doi.org/10.1155/2015/501508] [PMID: 25852766]
[17]
Kim, S.J.; Chung, W.S.; Kim, S.S.; Ko, S.G.; Um, J.Y. Antiinflammatory effect of Oldenlandia diffusa and its constituent, hentriacontane, through suppression of caspase-1 activation in mouse peritoneal macrophages. Phytother. Res., 2011, 25(10), 1537-1546.
[http://dx.doi.org/10.1002/ptr.3443] [PMID: 21394806]
[18]
Wong, B.Y.Y.; Lau, B.H.S.; Jia, T.Y.; Wan, C.P. Oldenlandia diffusa and Scutellaria barbata augment macrophage oxidative burst and inhibit tumor growth. Cancer Biother. Radiopharm., 1996, 11(1), 51-56.
[http://dx.doi.org/10.1089/cbr.1996.11.51] [PMID: 10851520]
[19]
Pu, F.; Chen, F.; Lin, S.; Chen, S.; Zhang, Z.; Wang, B.; Shao, Z. The synergistic anticancer effect of cisplatin combined with Oldenlandia diffusa in osteosarcoma MG-63 cell line in vitro. OncoTargets Ther., 2016, 9, 255-263.
[PMID: 26834484]
[20]
Ward, A.B.; Mir, H.; Kapur, N.; Gales, D.N.; Carriere, P.P.; Singh, S. Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways. World J. Surg. Oncol., 2018, 16(1), 108.
[http://dx.doi.org/10.1186/s12957-018-1400-z] [PMID: 29898731]
[21]
Pagliacci, M.C.; Smacchia, M.; Migliorati, G.; Grignani, F.; Riccardi, C.; Nicoletti, I. Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur. J. Cancer, 1994, 30(11), 1675-1682.
[http://dx.doi.org/10.1016/0959-8049(94)00262-4] [PMID: 7833143]
[22]
Maclatchy, D.L.; Vanderkraak, G.J. The phytoestrogen beta-sitosterol alters the reproductive endocrine status of goldfish. Toxicol. Appl. Pharmacol., 1995, 134(2), 305-312.
[http://dx.doi.org/10.1006/taap.1995.1196] [PMID: 7570607]
[23]
Awad, A.B.; Roy, R.; Fink, C.S. Beta-sitosterol, a plant sterol, induces apoptosis and activates key caspases in MDA-MB-231 human breast cancer cells. Oncol. Rep., 2003, 10(2), 497-500.
[PMID: 12579296]
[24]
Vundru, S.S.; Kale, R.K.; Singh, R.P. β-sitosterol induces G1 arrest and causes depolarization of mitochondrial membrane potential in breast carcinoma MDA-MB-231 cells. BMC Complement. Altern. Med., 2013, 13(1), 280.
[http://dx.doi.org/10.1186/1472-6882-13-280] [PMID: 24160369]
[25]
Li, S.; Pei, Y.; Wang, W.; Liu, F.; Zheng, K.; Zhang, X. Quercetin suppresses the proliferation and metastasis of metastatic osteosarcoma cells by inhibiting parathyroid hormone receptor 1. Biomed. Pharmacother., 2019, 114, 108839.
[http://dx.doi.org/10.1016/j.biopha.2019.108839] [PMID: 30978523]
[26]
Malakoti, F.; Majidinia, M.; Ahmadi, Y.; Yousefi, B.; Shanebandi, D. Quercetin augments cisplatin-induced apoptosis, DNA damage response, and MiR-22 expression while it prevents DNA repair in osteosarcoma cells. Drug Res. (Stuttg.), 2022.
[http://dx.doi.org/10.1055/a-1800-6030] [PMID: 35724673]
[27]
Kunzmann, A.T.; Murray, L.J.; Cardwell, C.R.; McShane, C.M.; McMenamin, Ú.C.; Cantwell, M.M. PTGS2 (Cyclooxygenase-2) expression and survival among colorectal cancer patients: A systematic review. Cancer Epidemiol. Biomarkers Prev., 2013, 22(9), 1490-1497.
[http://dx.doi.org/10.1158/1055-9965.EPI-13-0263] [PMID: 23810915]
[28]
Fang, Y.; Zhang, Z.; Wang, Q.; Zhao, J. Expression and clinical significance of cyclooxygenase-2 and microRNA-143 in osteosarcoma. Exp. Ther. Med., 2015, 9(6), 2374-2378.
[http://dx.doi.org/10.3892/etm.2015.2420] [PMID: 26136990]
[29]
Li, Y.S.; Deng, Z.H.; Zeng, C.; Lei, G.H. JNK pathway in osteosarcoma: Pathogenesis and therapeutics. J. Recept. Signal Transduct. Res., 2016, 36(5), 465-470.
[http://dx.doi.org/10.3109/10799893.2015.1122045] [PMID: 26669256]
[30]
Zhaorigetu; Farrag, I.M.; Belal, A.; Badawi, M.H.A.; Abdelhady, A.A.; Galala, F.M.A.A.; El-Sharkawy, A.; El-Dahshan, A.A.; Mehany, A.B.M. Antiproliferative, apoptotic effects and suppression of oxidative stress of quercetin against induced toxicity in lung cancer cells of rats: In vitro and in vivo study. J. Cancer, 2021, 12, 5249-5259.
[31]
Vo, T.K.; Ta, Q.T.H.; Chu, Q.T.; Nguyen, T.T.; Vo, V.G. Anti-hepatocellular-cancer activity exerted by β-sitosterol and β-sitosterol-glucoside from Indigofera zollingeriana miq. Molecules, 2020, 25(13), 3021.
[http://dx.doi.org/10.3390/molecules25133021] [PMID: 32630623]
[32]
Srivastava, N.S.; Srivastava, R.A.K. Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin signaling and apoptotic pathways in A375 cells. Phytomedicine, 2019, 52, 117-128.
[http://dx.doi.org/10.1016/j.phymed.2018.09.224] [PMID: 30599890]
[33]
Cao, B.; Lin, J.; Wu, Z.; Liu, H.; Zhang, D.; Xu, H.; Xu, R.; Han, L. Mechanisms exploration of Xiaojin Pills on lung cancer based on metabolomics and network pharmacology. J. Pharm. Pharmacol., 2021, 73(8), 1071-1079.
[http://dx.doi.org/10.1093/jpp/rgab050] [PMID: 33864464]
[34]
Sook, S.H.; Lee, H.J.; Kim, J.H.; Sohn, E.J.; Jung, J.H.; Kim, B.; Kim, J.H.; Jeong, S.J.; Kim, S.H. Reactive oxygen species-mediated activation of AMP-activated protein kinase and c-Jun N-terminal kinase plays a critical role in beta-sitosterol-induced apoptosis in multiple myeloma U266 cells. Phytother. Res., 2014, 28(3), 387-394.
[http://dx.doi.org/10.1002/ptr.4999] [PMID: 23640957]

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