Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synergistic Antitumor Effect of 5-Fluorouracil Combined with Constituents from Pleurospermum lindleyanum in Hepatocellular Carcinoma SMMC-7721 Cells

Author(s): Xiao-Feng Zhu, Xiao-Jin Li, Zhong-Lian Cao, Xiu-Jie Liu, Ping Yang, Dianwen Ju and Qing Mu*

Volume 21, Issue 4, 2021

Published on: 24 August, 2020

Page: [508 - 522] Pages: 15

DOI: 10.2174/1871520620666200824094624

Price: $65

Abstract

Background: A Chinese folk medicine plant Pleurospermum lindleyanum possesses pharmacological activities of heat-clearing, detoxifying and preventing from hepatopathy, coronary heart disease, hypertension, and high altitude sickness. We isolated and characterized its constituents to investigate its synergistic effects against human hepatoma SMMC-7721 cells.

Objective: The aim of this study was to explore the synergistic anti-cancer activities of isolates from P. lindleyanum with 5-FU on hepatoma SMMC-7721 cells in vitro and their primary mechanisms.

Methods: Sequential chromatographic techniques were conducted for the isolation studies. The isolate's structures were established by spectroscopic analysis as well as X-ray crystallographic diffraction. Growth inhibition was detected by MTT assay. The isobologram method was used to assess the effect of drug combinations. Flow cytometry and western blot were used to examine apoptosis and protein expression.

Results: A new coumarin (16), along with sixteen known compounds, were isolated from the whole plant of P. lindleyanum and their structures were elucidated by spectroscopic methods. Four coumarins (2, 3, 5, and 16), two flavonoids (8 and 9) and three phytosterols and triterpenes (12-14) were found to synergistically enhance the inhibitory effect of 5-FU against SMMC-7721 cells. Among them, compounds 3 and 16 exhibited the best synergistic effects with IC50 of 5-FU reduced by 16-fold and 22-fold possessing the minimum Combination Index (CI) 0.34 and 0.27. The mechanism of action of combinations might be through synergistic arresting for the cell cycle at G1 phases and the induction of apoptosis. Moreover, western blotting and molecular docking revealed that compounds 3 or 5 might promote 5-FU-induced apoptosis by regulating the expression of Caspase 9 and PARP.

Conclusion: Constituents from P. lindleyanum may improve the treatment effectiveness of 5-FU against hepatocellular carcinoma cells.

Keywords: Pleurospermum lindleyanum, coumarin, 5-fluorouracil, synergism, hepatoma cell SMMC-7721, apoptosis.

« Previous Next »
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Chen, W.; Sun, K.; Zheng, R.; Zeng, H.; Zhang, S.; Xia, C.; Yang, Z.; Li, H.; Zou, X.; He, J. Cancer incidence and mortality in China, 2014. Chin. J. Cancer Res., 2018, 30(1), 1-12.
[http://dx.doi.org/10.21147/j.issn.1000-9604.2018.01.01] [PMID: 29545714]
[3]
Liver, E.A.S. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol., 2018, 69(1), 182-236.
[http://dx.doi.org/10.1016/j.jhep.2018.03.019] [PMID: 29628281]
[4]
Longley, D.B.; Harkin, D.P.; Johnston, P.G. 5-fluorouracil: Mechanisms of action and clinical strategies. Nat. Rev. Cancer, 2003, 3(5), 330-338.
[http://dx.doi.org/10.1038/nrc1074] [PMID: 12724731]
[5]
Douillard, J.Y.; Cunningham, D.; Roth, A.D.; Navarro, M.; James, R.D.; Karasek, P.; Jandik, P.; Iveson, T.; Carmichael, J.; Alakl, M.; Gruia, G.; Awad, L.; Rougier, P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet, 2000, 355(9209), 1041-1047.
[http://dx.doi.org/10.1016/S0140-6736(00)02034-1] [PMID: 10744089]
[6]
Noordhuis, P.; Holwerda, U.; Van der Wilt, C.L.; Van Groeningen, C.J.; Smid, K.; Meijer, S.; Pinedo, H.M.; Peters, G.J. 5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers. Ann. Oncol., 2004, 15(7), 1025-1032.
[http://dx.doi.org/10.1093/annonc/mdh264] [PMID: 15205195]
[7]
Jin, J.; Huang, M.; Wei, H.L.; Liu, G.T. Mechanism of 5-fluorouracil required resistance in human hepatocellular carcinoma cell line Bel(7402). World J. Gastroenterol., 2002, 8(6), 1029-1034.
[http://dx.doi.org/10.3748/wjg.v8.i6.1029] [PMID: 12439919]
[8]
Roosild, T.P.; Castronovo, S.; Fabbiani, M.; Pizzorno, G. Implications of the structure of human uridine phosphorylase 1 on the development of novel inhibitors for improving the therapeutic window of fluoropyrimidine chemotherapy. BMC Struct. Biol., 2009, 9(1), 14-22.
[http://dx.doi.org/10.1186/1472-6807-9-14] [PMID: 19291308]
[9]
Klampfer, L.; Swaby, L.A.; Huang, J.; Sasazuki, T.; Shirasawa, S.; Augenlicht, L. Oncogenic Ras increases sensitivity of colon cancer cells to 5-FU-induced apoptosis. Oncogene, 2005, 24(24), 3932-3941.
[http://dx.doi.org/10.1038/sj.onc.1208552] [PMID: 15856030]
[10]
Pourcel, L.; Routaboul, J.M.; Cheynier, V.; Lepiniec, L.; Debeaujon, I. Flavonoid oxidation in plants: From biochemical properties to physiological functions. Trends Plant Sci., 2007, 12(1), 29-36.
[http://dx.doi.org/10.1016/j.tplants.2006.11.006] [PMID: 17161643]
[11]
Fishbein, A.B.; Wang, C.Z.; Li, X.L.; Mehendale, S.R.; Sun, S.; Aung, H.H.; Yuan, C.S. Asian ginseng enhances the anti-proliferative effect of 5-fluorouracil on human colorectal cancer: comparison between white and red ginseng. Arch. Pharm. Res., 2009, 32(4), 505-513.
[http://dx.doi.org/10.1007/s12272-009-1405-9] [PMID: 19407967]
[12]
Yang, L.; Wu, D.; Luo, K.; Wu, S.; Wu, P. Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrial pathway involving p53 participation in hepatocellular carcinoma (SMMC-7721) cells. Cancer Lett., 2009, 276(2), 180-188.
[http://dx.doi.org/10.1016/j.canlet.2008.11.015] [PMID: 19097688]
[13]
Xinjiang Traditional Chinese Medicine Resources Survey Office. Chinese Medicine Resources Survey Atlas in Xinjiang Uygur autonomous region; Chinese: Urumqi, 1988, p. 19.
[14]
Chen, J.; Li, F.G.; Fang, S.D. Chemical constituents reaserch of Pleurospermum lindleyanum. Chin. Tradit. Herbal Drugs, 1987, 18, 290-293.
[15]
Tajik Autonomous County’s Chronicles Compiling Committee. Tajik Autonomous County’s Chronicle in Tashkurgan Region (Chinese); Xinjiang People's Publishing House: Urumqi, 2009, p. 86.
[16]
Chen, J.; Fang, S.D. Chemical constituents reaserch of Pleurospermum lindleyanum II. Chin. Tradit. Herbal Drugs, 1989, 20, 98-99.
[17]
Tan, J.J.; Tan, C.H.; Wang, Y.Q.; Jiang, S.H.; Zhu, D.Y. Lindleyanin and bergapten-8-yl sulfate from Pleurospermum lindleyanum. Helv. Chim. Acta, 2006, 89(1), 117-121.
[http://dx.doi.org/10.1002/hlca.200690002]
[18]
Tian, Y.Q.; Zhang, Z.X.; Xu, H.H. Laboratory and field evaluations on insecticidal activity of Cicuta virosa L. var. latisecta Celak. Ind. Crops Prod., 2013, 41, 90-93.
[http://dx.doi.org/10.1016/j.indcrop.2012.04.015]
[19]
Wang, D.; Du, N.; Wen, L.; Zhu, H.; Liu, F.; Wang, X.; Du, J.; Li, S. An efficient method for the preparative isolation and purification of flavonoid glycosides and caffeoylquinic acid derivatives from leaves of Lonicera japonica Thunb. using High Speed Counter-Current Chromatography (HSCCC) and Prep-HPLC guided by DPPH-HPLC experiments. Molecules, 2017, 22(2), 229-242.
[http://dx.doi.org/10.3390/molecules22020229] [PMID: 28157166]
[20]
Bai, Y.; Li, D.H.; Zhou, T.T.; Qin, N.B.; Li, Z.L.; Yu, Z.G.; Hua, H.M. Coumarins from the roots of Angelica dahurica with antioxidant and antiproliferative activities. J. Funct. Foods, 2016, 20, 453-462.
[http://dx.doi.org/10.1016/j.jff.2015.11.018]
[21]
Chou, T.C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res., 2010, 70(2), 440-446.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1947] [PMID: 20068163]
[22]
Bergendorff, O.; Dekermendjian, K.; Nielsen, M.; Shan, R.; Witt, R.; Ai, J.; Sterner, O. Furanocoumarins with affinity to brain benzodiazepine receptors in vitro. Phytochemistry, 1997, 44(6), 1121-1124.
[http://dx.doi.org/10.1016/S0031-9422(96)00703-0] [PMID: 9055449]
[23]
Mi, C.; Shi, H.; Li, F.; Qiao, B.; Wang, C. Chemical study of root of Angelica polymorpha Maxim. (II). Nat. Prod. Res. Dvpt., 1997, 9(1), 43-45.
[24]
Harkar, S.; Razdan, T.K.; Waight, E.S. Steroids, chromone and coumarins from Angelica officinalis.Phytochemistry, 1984, 23(2),419-426.,
[http://dx.doi.org/10.1016/S0031-9422(00)80344-1]
[25]
Atkinson, E.; Boyd, D.R.; Grundon, M.F. Coumarins of Skimmia-japonica. Phytochemistry, 1974, 13(5), 853-855.
[http://dx.doi.org/10.1016/S0031-9422(00)91150-6]
[26]
Guilhon, G.M.S.P.; Baetas, A.C.S.; Maia, J.G.S.; Conserva, L.M. 2-alkyl-4-quinolone alkaloids and cinnamic acid-derivatives from Esenbeckia-almawillia. Phytochemistry, 1994, 37(4), 1193-1195.
[http://dx.doi.org/10.1016/S0031-9422(00)89556-4]
[27]
Franke, K.; Porzel, A.; Masaoud, M.; Adam, G.; Schmidt, J. Furanocoumarins from Dorstenia gigas. Phytochemistry, 2001, 56(6), 611-621.
[http://dx.doi.org/10.1016/S0031-9422(00)00419-2] [PMID: 11281139]
[28]
Youssef, D.; Frahm, A.W. Constituents of the Egyptian Centaurea scoparia. III. Phenolic constituents of the aerial parts. Planta Med., 1995, 61(6), 570-573.
[http://dx.doi.org/10.1055/s-2006-959378] [PMID: 17238113]
[29]
Li, Y.M.; Jiang, S.H.; Gao, W.Y.; Zhu, D.Y. Phenylpropanoid glycosides from Scrophularia ningpoensis. Phytochemistry, 2000, 54(8), 923-925.
[http://dx.doi.org/10.1016/S0031-9422(00)00171-0] [PMID: 11014290]
[30]
Chaturvedula, V.; Prakash, I. Isolation of stigmasterol and β-sitosterol from the dichloromethane extract of Rubus suavissimus. Int. Curr. Pharm. J., 2012, 9(1), 239-242.
[http://dx.doi.org/10.3329/icpj.v1i9.11613]
[31]
Kim, H.J.; Le, Q.K.; Lee, M.H.; Kim, T.S.; Lee, H.K.; Kim, Y.H.; Bae, K.; Lee, I.S. A cytotoxic secocycloartenoid from Abies koreana. Arch. Pharm. Res., 2001, 24(6), 527-531.
[http://dx.doi.org/10.1007/BF02975159] [PMID: 11794529]
[32]
Pereda, R.; Delgado, G.; Romo, A. New triterpenoids from Salvia nicolsoniana. J. Nat. Prod., 1986, 49(2), 225-230.,
[http://dx.doi.org/10.1021/np50044a005]
[33]
Iwase, Y.; Takahashi, M.; Tada, T.; Takemura, Y.; Juichi, M.; Ito, C.; Furukawa, H.; Hashimoto, T.; Takaoka, S.; Asakawa, Y.; Yano, M. A novel dimeric coumarin from Citrus lumia.Heterocycles,2000, 53(2), 441-446.,
[http://dx.doi.org/10.3987/COM-99-8782]
[34]
Ragasa, C.Y.; Ganzon, J.; Hofileña, J.; Tamboong, B.; Rideout, J.A. A new furanoid diterpene from Caesalpinia pulcherrima. Chem. Pharm. Bull. (Tokyo), 2003, 51(10), 1208-1210.
[http://dx.doi.org/10.1248/cpb.51.1208] [PMID: 14519933]
[35]
Ngadjui, B.T.; Ayafor, J.F.; Sondengam, B.L.; Connolly, J.D. Prenylated coumarins from the leaves of Clausena anisata. J. Nat. Prod., 1989, 52(2), 243-247.
[http://dx.doi.org/10.1021/np50062a003]

Rights & Permissions Print Cite
Article Metrics
23
1
© 2024 Bentham Science Publishers | Privacy Policy