Full Text:   <1515>

CLC number: R735

On-line Access: 

Received: 2009-05-22

Revision Accepted: 2009-08-17

Crosschecked: 2009-08-17

Cited: 45

Clicked: 3950

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2009 Vol.10 No.9 P.668~674


Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway

Author(s):  Jian-zhen SHAN, Yan-yan XUAN, Shu ZHENG, Qi DONG, Su-zhan ZHANG

Affiliation(s):  Department of Traditional Chinese Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; more

Corresponding email(s):   zhang1873@gmail.com, zrsj@zju.edu.cn

Key Words:  Colon cancer, Ursolic acid, Epidermal growth factor receptor (EGFR), Mitogen-activated protein kinase (MAPK), Apoptosis

Jian-zhen SHAN, Yan-yan XUAN, Shu ZHENG, Qi DONG, Su-zhan ZHANG. Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway[J]. Journal of Zhejiang University Science B, 2009, 10(9): 668~674.

@article{title="Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway",
author="Jian-zhen SHAN, Yan-yan XUAN, Shu ZHENG, Qi DONG, Su-zhan ZHANG",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway
%A Jian-zhen SHAN
%A Yan-yan XUAN
%A Su-zhan ZHANG
%J Journal of Zhejiang University SCIENCE B
%V 10
%N 9
%P 668~674
%@ 1673-1581
%D 2009
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B0920149

T1 - Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway
A1 - Jian-zhen SHAN
A1 - Yan-yan XUAN
A1 - Shu ZHENG
A1 - Qi DONG
A1 - Su-zhan ZHANG
J0 - Journal of Zhejiang University Science B
VL - 10
IS - 9
SP - 668
EP - 674
%@ 1673-1581
Y1 - 2009
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B0920149

Objective: To investigate the effects of ursolic acid on the proliferation and apoptosis of human HT-29 colon cancer cells. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays were performed to evaluate the effects of ursolic acid on the growth and apoptosis of HT-29 cells. Western blot analysis was applied to investigate the inhibitory effects of ursolic acid on the phosphorylation of the epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK), and the activity of B cell leukemia-2 (Bcl-2), B cell leukemia-xL (Bcl-xL), caspase-3, and caspase-9. Results: ursolic acid inhibited the growth of HT-29 cells in dose- and time-dependent manners. The median inhibition concentration (IC50) values for 24, 48, and 72 h treatment were 26, 20, and 18 μmol/L, respectively. The apoptotic rates of 10, 20, and 40 μmol/L ursolic acid treatments for 24 h were 5.74%, 14.49%, and 33.05%, and for 48 h were 9%, 21.39%, and 40.49%, respectively. ursolic acid suppressed the phosphorylation of EGFR, ERK1/2, p38 MAPK, and JNK, which is well correlated with its growth inhibitory effect. 10, 20, and 40 μmol/L ursolic acid significantly inhibited the proliferation of EGF-stimulated HT-29 cells (P<0.05). Cell proliferation was most significantly inhibited when treated with 10 and 20 μmol/L ursolic acid combined with 200 nmol/L AG 1478 or 10 μmol/L U0126 (P<0.01). Besides, it also down-regulated the expression of Bcl-2 and Bcl-xL and activated caspase-3 and caspase-9. Conclusion: ursolic acid induces apoptosis in HT-29 cells by suppressing the EGFR/MAPK pathway, suggesting that it may be a potent agent for the treatment of colorectal cancer.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1] Andersson, D., Liu, J.J., Nilsson, A., Duan, R.D., 2003. Ursolic acid inhibits proliferation and stimulates apoptosis in HT29 cells following activation of alkaline sphingomyelinase. Anticancer Res., 23(4):3317-3322.

[2] Andersson, D., Cheng, Y., Duan, R.D., 2008. Ursolic acid inhibits the formation of aberrant crypt foci and affects colonic sphingomyelin hydrolyzing enzymes in azoxymethane-treated rats. J. Cancer Res. Clin. Oncol., 134(1): 101-107.

[3] Cao, K.J., Fan, Q.Y., Liu, Y.L., Huang, R., Yin, C.Z., Ma, G.S., Liu, Z.Q., Wan, D.S., Zeng, Y.X., 2008. Cancer incidence and mortality in Guangzhou City from 2000 to 2002. Chin. J. Cancer, 27(3):225-230 (in Chinese).

[4] Cha, H.J., Bae, S.K., Lee, H.Y., Lee, O.H., Sato, H., Seiki, M., Park, B.C., Kim, K.W., 1996. Anti-invasive activity of ursolic acid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT1080 human fibrosarcoma cells. Cancer Res., 56(10):2281-2284.

[5] Denizot, F., Lang, R., 1986. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods., 89(2):271-277.

[6] Dougherty, U., Sehdev, A., Cerda, S., Mustafi, R., Little, N., Yuan, W., agadeeswaran, S., Chumsangsri, A., Delgado, J., Tretiakova, M., et al., 2008. Epidermal growth factor receptor controls flat dysplastic aberrant crypt foci development and colon cancer progression in the rat azoxymethane model. Clin. Cancer Res., 14(8):2253-2262.

[7] Fang, J.Y., Richardson, B.C., 2005. The MAPK signalling pathways and colorectal cancer. Lancet Oncol., 6(5): 322-327.

[8] Grandis, J.R., Sok, J.C., 2004. Signaling through the epidermal growth factor receptor during the development of malignancy. Pharmacol. Ther., 102(1):37-46.

[9] Hsu, Y.L., Kuo, P.L., Lin, C.C., 2004. Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. Life Sci., 75(19):2303-2316.

[10] Huang, M.T., Ho, C.T., Wang, Z.Y., Ferraro, T., Lou, Y.R., Stauber, K., Ma, W., Georgiadis, C., Laskin, J.D., Conney, A.H., 1994. Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer Res., 54(2):701-708.

[11] Ikeda, Y., Murakami, A., Ohigashi, H., 2008. Ursolic acid: an anti- and pro-inflammatory triterpenoid. Mol. Nutr. Food Res., 52(1):26-42.

[12] Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., Thun, M.J., 2008. Cancer statistics, 2008. CA Cancer J. Clin., 58(2):71-96.

[13] Kroemer, G., 1997. The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat. Med., 3(6):614-620.

[14] Li, F.Y., Lai, M.D., 2009. Colorectal cancer, one entity or three. J. Zhejiang Univ. Sci. B, 10(3):219-229.

[15] Manu, K.A., Kuttan, G., 2008. Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of Bcl-2 in B16F-10 melanoma cells. Int. Immunopharmacol., 8(7): 974-981.

[16] Pathak, A.K., Bhutani, M., Nair, A.S., Ahn, K.S., Chakraborty, A., Kadara, H., Guha, S., Sethi, G., Aggarwal, B.B., 2007. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol. Cancer Res., 5(9): 943-955.

[17] Roberts, P.J., Der, C.J., 2007. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26(22):3291-3310.

[18] Saltz, L., 2008. Colorectal cancer treatment: what’s next? (or: is there life after EGFR and VEGF?). Gastrointest. Cancer Res., 2(4 Suppl.):20-22.

[19] Schwartsmann, G., Di Leone, L.P., Dal Pizzol, F., Roesler, R., 2005. MAPK pathway activation in colorectal cancer: a therapeutic opportunity for GRP receptor antagonists. Lancet Oncol., 6(7):444-445.

[20] Shishodia, S., Majumdar, S., Banerjee, S., Aggarwal, B.B., 2003. Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res., 63(15): 4375-4383.

[21] Subbaramaiah, K., Michaluart, P., Sporn, M.B., Dannenberg, A.J., 2000. Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Res., 60(9):2399-2404.

[22] Sung, J.J., Lau, J.Y., Goh, K.L., Leung, W.K., 2005. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol., 6(11):871-876.

[23] Tan, J., Shen, Z.X., Gen, W., 2006. Ursolic acid induces apoptosis in colon cancer HT-29 cells. Chin. J. Oncog., 28(2):99-102 (in Chinese).

[24] Xavier, C.P., Lima, C.F., Preto, A., Seruca, R., Fernandes-Ferreira, M, Pereira-Wilson, C., 2009. Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells. Cancer Lett., 281(2):162-170.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - Journal of Zhejiang University-SCIENCE