[an error occurred while processing this directive]

Journal of Chinese Integrative Medicine ›› 2008, Vol. 6 ›› Issue (1): 51-59.doi: 10.3736/jcim20080111

• Original Experimental Research • Previous Articles     Next Articles

Antitumor activities of kushen flavonoids in vivo and in vitro

Ming-yu Sun1(), Jian Zuo2, Ji-feng Duan2, Jun Han3, Shi-ming Fan2, Wei Zhang2, Li-fang Zhu2, Ming-hui Yao4   

  1. 1. Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
    2. Department of Pharmacology, Hutchison Medipharma Ltd, Zhangjiang Hi-Technology Park, Shanghai 201203, China
    3. Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
    4. Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai 200032, China
  • Online:2008-01-20 Published:2008-01-15
  • Contact: SUN Ming-yu E-mail:mysun248@hotmail.com

RichHTML

2

PDF (PC)

112

Like

Objective:To explore the antitumor activities of kushen (Sophora flavescens) flavonoids (KS-Fs) in vivo and in vitro.

Methods:Cell proliferation was assayed by using methyl thiazolyl tetrazolium (MTT) method. H22 hepatocellular carcinoma and S180 sarcoma were induced in ICR mice. Lewis lung carcinoma was induced in C57BL/6 mice. H460 and Eca-109 tumor were induced in Balb/c nude mice by injecting 5×10 5 or 5×10 6 tumor cells in the right flank, respectively. 

Results:KS-Fs could inhibit the growth of a variety of human tumor cell lines (A549, SPC-A-1, NCI-H460, etc.) in vitro. The antitumor efficacies were confirmed in the mice models of H22, S180 and Lewis lung tumors and the nude mice models of human H460 and Eca-109 xenografted tumors. The oral or intravenous maximum tolerated dose of KS-Fs was more than 2.8 g/kg or 750 mg/kg respectively, far more than the oral medial lethal dose of kushen alkaloids (≤1.18 g/kg). No adverse reactions were observed.

Conclusion:These results suggest that KS-Fs or kurarinone may be developed as a novel antitumor agent.

Key words: Sophora flavescens, flavones, antineoplastic agents, mice

CLC Number: 

  • R286.91

Figure 1

High-performance liquid chromatograms and chemical structures of compounds in KS-Fs"

Figure 2

Cytotoxicity of marketed preparation of kushen alkaloids and KS-Fs in vitro **P<0.01, vs KS-Fs-treated group."

Table 1

Effects of KS-Fs on tumor and body weights in H22 hepatoma mice ($\bar{x}$±$s_{\bar{x}}$)"

Group n Body weight after tumor excision (g) Tumor weight (g) Inhibition rate (%)
Vehicle control 19 32.04±0.12 2.47±0.03 -
CTX-treated 10 32.23±0.23 0.47±0.02** 81.00
20 mg/kg KS-Fs-treated 10 32.88±0.22 1.40±0.08** 43.40
100 mg/kg KS-Fs-treated 10 32.69±0.18 0.83±0.05** 66.45
500 mg/kg KS-Fs-treated 10 33.77±0.10 0.52±0.02** 78.98

Figure 3

Effects of different doses of KS-Fs on the tumor of H22 hepatoma and S180 sarcoma in mice A: H22 hepatoma; B: S180 sarcoma."

Table 2

Effects of KS-Fs on tumor and body weights in S180 sarcoma mice ($\bar{x}$±$s_{\bar{x}}$)"

Group n Body weight after tumor excision (g) Tumor weight (g) Inhibition rate (%)
Vehicle control 10 29.65±0.51 2.91±0.11 -
CTX-treated 10 27.51±0.14 0.43±0.02** 85.11
60 mg/kg KS-Fs-treated 10 31.73±0.42 0.80±0.08** 72.52
200 mg/kg KS-Fs-treated 10 34.41±0.29* 0.52±0.05** 82.14

Table 3

Effects of KS-Fs on tumor and body weights in Lewis mice with lung carcinoma ($\bar{x}$±$s_{\bar{x}}$)"

Group n Body weight after tumor excision (g) Tumor weight (g) Inhibition rate (%)
Vehicle control 6 19.58±0.19 2.57±0.09 -
CTX-treated 6 18.38±0.07* 0.28±0.01** 88.96
60 mg/kg KS-Fs-treated 6 19.23±0.13 1.53±0.05** 40.26
200 mg/kg KS-Fs-treated 6 19.70±0.15 1.03±0.06** 59.74

Table 4

Effects of KS-Fs on the tumor weight of H460 in xenografted nude mice on the 25th day ($\bar{x}$±$s_{\bar{x}}$)"

Group n RTV Tumor weight (g) Inhibition rate (%)
Vehicle control 8 36.04±4.59 3.19±0.18 -
Cisplatin-treated 5 16.78±1.94** 1.69±0.06* 47.10
200 mg/kg KS-Fs-treated 8 19.24±1.03** 1.70±0.21* 46.80

Figure 4

Effects of KS-Fs or Kur on the relative tumor volume and relative body weight of H460 and Eca-109 xenografted tumors in nude mice *P<0.05, **P<0.01, vs vehicle control group; △P<0.05, △△P<0.01, vs cisplatin-treated group."

Table 5

Effects of KS-Fs or Kur on the tumor weight of Eca-109 in xenografted nude mice on the 22nd day ($\bar{x}$±$s_{\bar{x}}$)"

Group n RTV Tumor weight (g) Inhibition rate (%)
Vehicle control 6 9.08±1.06 0.53±0.04 -
Cisplatin-treated 6 5.25±0.63** 0.27±0.02** 49.81
200 mg/kg Kur-treated 6 5.21±0.63* 0.31±0.02** 41.29
50 mg/kg Kur-treated 6 6.59±0.60 0.50±0.08 4.92
200 mg/kg KS-Fs-treated 6 4.80±0.79* 0.30±0.02* 42.71
[1] State Administration of Traditional Chinese Medicine. Chinese herbal medicine. Shanghai: Shanghai Scientific and Technical Publishers. 1999: 634-643. Chinese.
国家中医药管理局.中华本草.上海科学技术出版社. 1999: 634-643.
[2] Kyogoku K, Hatayama K, Komatsu M . Constituents of Chinese crude drug "Kushen"( the root of Sophora flavescens Ait. ). Isolation of five new flavonoids and formononetin. Chem Pharm Bull. 1973 ; 21(12) : 2733-2738.
doi: 10.1248/cpb.21.2733
[3] Zhao YY j Wang B, Lei LM , et al. Constituents of the flavonoids from the roots of Sophora flavescens. Zhi WuXueBao. 1993; 35(4):304-306.
赵玉英, 王邠, 雷黎明 , 等. 苦参黄酮类成分的研究. 植物学报. 1993; 35(4):304-306.
[4] Ryu SY, Kim SK , No et al. A novel flavonoid from Sophora flavescens. Planta Med. 1996; 62(4):361-363.
doi: 10.1055/s-2006-957906 pmid: 17252471
[5] Woo ER, Kwak JH, Kim HJ , et al. A new prenylated flavonol from the roots of Sophora flavescens. J Nat Prod. 1998; 61(12):1552-1554.
doi: 10.1080/14786419.2012.761622
[6] Kuroyanagi M, Arakawa T, Hirayama Y , et al. Antibacterial and antiandrogen flavonoids from Sophora flavescens.[J] Nat Prod. 1999; 62(12):1595-1599.
doi: 10.1021/np990051d
[7] Kang TH, Jeong SJ, Ko WG , et al. Cytotoxic lavandu- lyl flavanones from Sophora flavescens.[J] Nat Prod. 2000; 63(5):680-681.
doi: 10.1021/np990567x
[8] Ko WG, Kang TH, Kim NY , et al. Lavandulyl flavonoids :a new class of in vitro apoptogenic agents from Sophora flavescens. Toxicol In Vitro. 2000; 14(5):429-433.
doi: 10.1016/S0887-2333(00)00041-2 pmid: 10963959
[9] Ding PL, Chen DF, Bastow KF , et al. Cytotoxic iso- prenylated flavonoids from the roots of Sophora flavescens. Helvetica Chimica Acta. 2004; 87(10):2574-2580.
doi: 10.1002/chin.200512244
[10] Kim YK, Min BS, Bae KH . A cytotoxic constituent from Sophora flavescens. Arch Pharm Res. 1997 ; 20(4):342-345.
doi: 10.1007/BF02976197 pmid: 18975176
[11] De Naeyer A, Vanden Berghe W, Pocock V , et al. Estrogenic and anticarcinogenic properties of kurarinone, a lavandulyl flavanone from the roots of Sophora flavescens. J Nat Prod. 2004; 67(11):1829-1832.
[12] Ha TJ, Yang SY, Jang DS , et al. Inhibitory activities of flavanone derivatives isolated from Sophora flavescens for melanogenesis. Bull Korean Chem Soc. 2001; 22(1):97-99.
[13] Kang SS, Kim JS , Xu YN, et al. Isolation of a new cer- ebroside from the root bark of aralia elata. J Nat Prod. 1999; 62(7):1059-106.
doi: 10.1021/np990018r pmid: 10425144
[14] Chung MY, Rho MC, Ko JS , et al. In vitro inhibition of diacylglycerol acyltransferase by prenylflavonoids irom Sophora flavescens. Planta Med. 2004; 70(3):258-260.
doi: 10.1055/s-2004-815545
[15] Carmichael J, Mitchell JB , DeGraff WG, et al. Chemo- sensitivity testing of human lung cancer cell lines using the MTT assay. Br J Cancer. 1988; 57(6):540-547.
doi: 10.1038/bjc.1988.125 pmid: 2841961
[16] Bissery MC, Guenard D, Gueritte-Voegelein F , et al. Experimental antitumor activity of Taxotere( RP 56976,NSC 628503),a Taxol analogue. Cancer Res. 1991; 51(18):4845-4852.
pmid: 1680023
[17] Xu SY, Bian RL, Chen X. Pharmacological experimental methods. 3rd ed. People ' s Medical Publishing House. 2002: 1762. Chinese.
徐叔云, 卞如廉, 陈修 .药理实验方法学.第三版.人民卫生出版社. 2002: 1762.
[18] Sanceau J, Poupon MF, Delattre O , et al. Strong inhibition of Ewing tumor xenograft growth by combination of human interferon-alpha or interferon-beta with ifosf- amid. Oncogene. 2002; 21(50):7700-7709.
doi: 10.1038/sj.onc.1205881
[19] Hoi SU, Kim KH, Choi EJ , et al. P-glycoprotein (Pgp) does not affect the cytotoxicity of flavonoids from Sophora flavescens, which also have no effects on Pgp action. Anticancer Res. 1999; 19(3):2035-2040.
[20] Zhang LP , Jiang JK. Study of matrine on proliferation and differentiation of K562 cell line. Zhonghua Xue Ye XueZaZhi. 1999; 20(6):315-316. Chinese.
doi: 10.3760/j:issn:0253-2727.1999.06.010
张莉萍, 蒋纪恺 . 苦参碱对K562细胞增殖与分化作用的机制研究.中华血液学杂志. 1999; 20(6):315-316.
doi: 10.3760/j:issn:0253-2727.1999.06.010
[21] Zhou BG, Sun JZ, Su G , et al. Apoptosis of human breast cancer MCF-7 cells induced by oxymatrine. Zhonghua Shi Yan Wai Ke Za Zhi. 2002; 18(6):689-691. Chinese with abstract in English.
周炳刚, 孙靖中, 苏刚 , 等. 氧化苦参碱诱导人乳腺癌细胞MCF-7凋亡的实验研究.中华实验外科杂志. 2002; 18(6):689-691.
[22] Li LJ, Chen ZQ, Zheng YY , et al. Effects of oxymatrine on human ovarian cancer cell SKOV-3 in vitro. Shi Yong Zhong Liu Xue Za Zhi. 2003; 17(2):100-101. Chinese.
doi: 10.3969/j.issn.1002-3070.2003.02.009
李龙江, 陈志琼, 郑元义 , 等. 氧化苦参碱对人卵巢癌细胞SKOV-3体外活性的影响.实用肿瘤学杂志. 2003; 17(2):100-101.
doi: 10.3969/j.issn.1002-3070.2003.02.009
[23] Wang YS. Chinese herbal drug pharmacology and application. Beijing: People's Medical Publishing House. 1983: 638. Chinese.
王浴生 . 中药药理与应用.北京: 人民卫生出版社. 1983: 638.
[24] Li XR. Effects of 7 alkaloids from Kudouzi on immune function in mice. Zhong Cao Yao. 1987; 18(5):22-23. Chinese.
黎雪如 . 苦豆子的7种生物碱对小鼠免疫功能的影响. 中草药. 1987; 18(5):22-23.
[1] Avijit Paul, Kausik Bishayee, Samrat Ghosh, Avinaba Mukherjee, Sourav Sikdar, Debrup Chakraborty, Naoual Boujedaini, Anisur Rahman Khuda-Bukhsh. Chelidonine isolated from ethanolic extract of Chelidonium majus promotes apoptosis in HeLa cells through p38-p53 and PI3K/AKT signalling pathways. Journal of Chinese Integrative Medicine, 2012, 10(9): 1025-1038.
[2] Yi-tao Zhao , Xin-guang Zhang , Li Bai , Li-qing Li , Jian-er Yu . Effects of Chinese herbal medicine Pingchuan Formula on airway inflammation, interferon-γ and interleukin-4 in mice with asthma. Journal of Chinese Integrative Medicine, 2012, 10(7): 807-813.
[3] Mei-jiao Mao, Jun-ping Hu, Cong Wang, Yi-yi Zhang, Ping Liu. Effects of Chinese herbal medicine Guanxinkang on expression of PPARγ-LXRα-ABCA1 pathway in ApoE-knockout mice with atherosclerosis. Journal of Chinese Integrative Medicine, 2012, 10(7): 814-820.
[4] Lin Wang, Guan-liang Wang, Jia-han Liu, Di Li, De-zeng Zhu, Liang-neng Wu . Effects of ursolic acid in ameliorating insulin resistance in liver of KKAy mice via peroxisome proliferator-activated receptors α and γ. Journal of Chinese Integrative Medicine, 2012, 10(7): 793-799.
[5] Dong-mei Zhang, Li-xia Lou, Ai-ming Wu, Xi-ying Lü, Zhao-juan Hu, Yan-hong Zhang, Hong-fang Liu. Effects of Astragalus membranaceus and Potentilla discolor mixture on insulin resistance and its related mRNA expressions in KKAy mice with type 2 diabetes. Journal of Chinese Integrative Medicine, 2012, 10(7): 821-826.
[6] Yogesh Bendale, Vineeta Bendale, Saili Paul, Soumya Sundar Bhattacharyya. Green synthesis, characterization and anticancer potential of platinum nanoparticles Bioplatin. Journal of Chinese Integrative Medicine, 2012, 10(6): 681-689.
[7] Surendra Kr. Sharma, Naveen Goyal. Protective effect of Heliotropium eichwaldi against cisplatin-induced nephrotoxicity in mice. Journal of Chinese Integrative Medicine, 2012, 10(5): 555-560.
[8] Jing Guo, Ju-yong Wang, Zhan Zheng, Qing Wang, Chang-sheng Dong . Effects of Chinese herbal medicine Feiyanning Decoction on the ratio of CD4+CD25+ regulatory T cells and expression of transcription factor Foxp3 in mice bearing Lewis lung carcinoma. Journal of Chinese Integrative Medicine, 2012, 10(5): 584-590.
[9] Zhan gheng, Ju-yong Wang, Qing Wang, Ling Xu, Zhen-ye Xu. Effects of Chinese herbal medicine Feiyanning decoction on expressions of nucleosome conformation-regulating factors H3-K56, Rtt109, Asf1 and E2F1 in Lewis-bearing mice. Journal of Chinese Integrative Medicine, 2012, 10(4): 448-453.
[10] Mahmoudian Alireza, Rajaei Ziba, Haghir Hossein, Banihashemian Shahaboldin, Hami Javad. Effects of valerian consumption during pregnancy on cortical volume and the levels of zinc and copper in the brain tissue of mouse fetus. Journal of Chinese Integrative Medicine, 2012, 10(4): 424-429.
[11] Gang Guo, Jian-hua Xu, Jian-hong Han, Fang Liang, Yong Zhang, Qiang Zhang, Jue Sun, Zhong-ze Fan . Chinese herbal decoction Shiquan Dabu Tang inhibits tumor growth and angiogenesis of metastasis after primary tumor surgical removal in mice. Journal of Chinese Integrative Medicine, 2012, 10(4): 436-447.
[12] Meenakshi Sundaram, Satyajit Patra, Gunasingham Maniarasu. Antitumor activity of ethanol extract of Gracilaria edulis (Gmelin) Silva on Ehrlich ascites carcinoma-bearing mice. Journal of Chinese Integrative Medicine, 2012, 10(4): 430-435.
[13] Gao Shan, Wang Xing-hui, Huang Ling-ling, Yu Ting-ting, Du Su-ming, Guo Yan-wei, Jia Yuan, Wang Jian. Effects of a compound Chinese medicine Xinji’erkang on isoproterenol-induced ventricular remodeling in mice. Journal of Chinese Integrative Medicine, 2012, 10(3): 330-336.
[14] Rahmatullah Mohammed, Kanij Hasan Sumaiyah, Ali Zulfiquar, Rahman Shahnaz, Jahan Rownak. Antihyperglycemic and antinociceptive activities of methanolic extract of Euphorbia thymifolia L. whole plants. Journal of Chinese Integrative Medicine, 2012, 10(2): 228-232.
[15] Arul Raj Chinthamony, Sophia Dominic, Ragavendran Paramasivam, Starlin Thangarajan, Ahalliya Rathi Muthian, Kanniappan Gopalakrishnan Velliyur. Leaf extract of Alpinia purpurata (Vieill.) K. Schum screened for its phytochemical constituents and antibacterial and anticancer activities. Journal of Chinese Integrative Medicine, 2012, 10(12): 1460-1464.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] Dong Yang, Yong-ping Du, Qing Shen, Wei Chen, Yan Yu, Guang-lei Chen. Expression of alpha-smooth muscle actin in renal tubulointerstitium in patients with kidney collateral stasis. Journal of Chinese Integrative Medicine, 2008, 6(1): 41-44
[2] Hai-feng Wei, Bai-liu Ya, Ling Zhao, Cui-fei Ye, Li Zhang, Lin Li. Evaluation of tongue manifestation of blood stasis syndrome and its relationship with blood rheological disorder in a rat model of transient brain ischemia. Journal of Chinese Integrative Medicine, 2008, 6(1): 73-76
[3] Xi Lin, Jian-ping Liu. Herbal medicines for viral myocarditis. Journal of Chinese Integrative Medicine, 2008, 6(1): 76
[4] Xi Lin, Jian-ping Liu. Tai chi for treating rheumatoid arthritis. Journal of Chinese Integrative Medicine, 2008, 6(1): 82
[5] Liang-ping Hu, Hui Gao. Discrimination of errors in statistical analysis of medical papers published in the first issue of 2006 in Journal of Chinese Integrative Medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 98-106
[6] Yan-bo Zhu , Qi Wang, Cheng-yu Wu, Guo-ming Pang, Jian-xiong Zhao, Shi-lin Shen, Zhong-yuan Xia , Xue Yan . Logistic regression analysis on relationships between traditional Chinese medicine constitutional types and overweight or obesity. Journal of Chinese Integrative Medicine, 2010, 8(11): 1023-1035
[7] Wei Xu, Meng Shi, Jian-gang Liu, Cheng-long Wang . Collagen protein expressions in ischemic myocardium of rats with acute myocardial infarction and effects of qi-tonifying, yin-tonifying and blood-activating herbs and detoxifying and blood-activating herbs. Journal of Chinese Integrative Medicine, 2010, 8(11): 1041-1047
[8] Tao Wang , Feng Qin. Effects of Chinese herbal medicine Xiaoyao Powder on monoamine neurotransmitters in hippocampus of rats with postpartum depression. Journal of Chinese Integrative Medicine, 2010, 8(11): 1075-1079
[9] Ying Xu , Chang-chun Zeng , Xiu-yu Cai , Rong-ping Guo , Guang Nie , Ying Jin. Chromaticity and optical spectrum colorimetry of the tongue color in different syndromes of primary hepatic carcinoma. Journal of Chinese Integrative Medicine, 2012, 10(11): 1263-1271
[10] Xiang-ying Mao , Qin Bian , Zi-yin Shen. Analysis of the osteogenetic effects exerted on mesenchymal stem cell strain C3H10T1/2 by icariin via MAPK signaling pathway in vitro. Journal of Chinese Integrative Medicine, 2012, 10(11): 1272-1278
[an error occurred while processing this directive]