Full Text:   <733>

Summary:  <368>

CLC number: R735.3+5

On-line Access: 2016-09-07

Received: 2016-06-10

Revision Accepted: 2016-08-08

Crosschecked: 2016-08-11

Cited: 2

Clicked: 1805

Citations:  Bibtex RefMan EndNote GB/T7714


Jian-zhen Shan


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2016 Vol.17 No.9 P.672-682


Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

Author(s):  Jian-zhen Shan, Yan-yan Xuan, Qi Zhang, Jian-jin Huang

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

Corresponding email(s):   huangjianjin18@163.com

Key Words:  Ursolic acid, Colon cancer, Hypoxia-inducible factor-1α, (HIF-1α, ), Multidrug resistance gene 1 (MDR1), Drug resistance

Jian-zhen Shan, Yan-yan Xuan, Qi Zhang, Jian-jin Huang. Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α[J]. Journal of Zhejiang University Science B, 2016, 17(9): 672-682.

@article{title="Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α",
author="Jian-zhen Shan, Yan-yan Xuan, Qi Zhang, Jian-jin Huang",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α
%A Jian-zhen Shan
%A Yan-yan Xuan
%A Qi Zhang
%A Jian-jin Huang
%J Journal of Zhejiang University SCIENCE B
%V 17
%N 9
%P 672-682
%@ 1673-1581
%D 2016
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1600266

T1 - Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α
A1 - Jian-zhen Shan
A1 - Yan-yan Xuan
A1 - Qi Zhang
A1 - Jian-jin Huang
J0 - Journal of Zhejiang University Science B
VL - 17
IS - 9
SP - 672
EP - 682
%@ 1673-1581
Y1 - 2016
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1600266

Objective: To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. Methods: Three colon cancer cell lines (RKO, LoVo, and SW480) were used as in vitro models. 5-Fluorouracil (5-FU) and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and expression levels of hypoxia-inducible factor-1α; (HIF-1α;), multidrug resistance gene 1 (MDR1), and vascular endothelial growth factors (VEGF) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis. Results: We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-1α. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis. Conclusions: ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-1α accumulation and the subsequent expression of the MDR1 and VEGF.




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


[1]Bai, X.L., Zhang, Q., Ye, L.Y., et al., 2014. Inhibition of protein phosphatase 2A enhances cytotoxicity and accessibility of chemotherapeutic drugs to hepatocellular carcinomas. Mol. Cancer Ther., 13(8):2062-2072.

[2]Bellamy, W.T., 1996. P-glycoproteins and multidrug resistance. Annu. Rev. Pharmacol. Toxicol., 36:161-183.

[3]Cao, Y., Eble, J.M., Moon, E., et al., 2013. Tumor cells upregulate normoxic HIF-1α in response to doxorubicin. Cancer Res., 73(20):6230-6242.

[4]Chen, J., Ding, Z., Peng, Y., 2014. HIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-glycoprotein. PLOS ONE, 9(6):e98882.

[5]Chen, W., Zheng, R., Baade, P.D., 2016. Cancer statistics in China, 2015. CA: Cancer J. Clin., 66(2):115-132.

[6]Cheung, H.Y., Zhang, Q.F., 2008. Enhanced analysis of triterpenes, flavonoids and phenolic compounds in Prunella vulgaris L. by capillary zone electrophoresis with the addition of running buffer modifiers. J. Chromatogr. A, 1213(2):231-238.

[7]Cheung, H.Y., Cheung, S.H., Law, M.L., et al., 2006. Simultaneous determination of key bioactive components in Hedyotis diffusa by capillary electrophoresis. J. Chromatogr., 834(1-2):195-198.

[8]Feuillolay, C., Pecastaings, S., le Gac, C., et al., 2016. A Myrtus communis extract enriched in myrtucummulones and ursolic acid reduces resistance of Propionibacterium acnes biofilms to antibiotics used in acne vulgaris. Phytomedicine, 23(3):307-315.

[9]Gustavsson, B., Carlsson, G., Machover, D., et al., 2015. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin. Colorectal Cancer, 14(1):1-10.

[10]Kadioglu, O., Efferth, T., 2015. Pharmacogenomic characterization of cytotoxic compounds from Salvia officinalis in cancer cells. J. Nat. Prod., 78(4):762-775.

[11]Kang, L., Gao, Z., Huang, W., et al., 2015. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment. Acta Pharm. Sin. B, 5(3):169-175.

[12]Kashyap, D., Tuli, H.S., Sharma, A.K., 2016. Ursolic acid (UA): a metabolite with promising therapeutic potential. Life Sci., 146:201-213.

[13]Kilic, M., Kasperczyk, H., Fulda, S., et al., 2007. Role of hypoxia inducible factor-1α in modulation of apoptosis resistance. Oncogene, 26(14):2027-2038.

[14]Lee, K., Kang, J.E., Park, S.K., et al., 2010. LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1α via upregulation of VHL in a colon cancer cell line. Biochem. Pharmacol., 80(7):982-989.

[15]Li, Y., Xing, D., Chen, Q., et al., 2010. Enhancement of chemotherapeutic agent-induced apoptosis by inhibition of NF-κB using ursolic acid. Int. J. Cancer, 127(2):462-473.

[16]Lin, J., Chen, Y., Wei, L., et al., 2013. Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways. Int. J. Oncol., 43(5):1666-1674.

[17]Liu, Z.J., Semenza, G.L., Zhang, H.F., 2015. Hypoxia-inducible factor 1 and breast cancer metastasis. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 16(1):32-43.

[18]Meng, Y., Lin, Z.M., Ge, N., et al., 2015. Ursolic acid induces apoptosis of prostate cancer cells via the PI3K/Akt/ mTOR pathway. Am. J. Chin. Med., 43(7):1471-1486.

[19]Nabekura, T., 2010. Overcoming multidrug resistance in human cancer cells by natural compounds. Toxins, 2(6):1207-1224.

[20]Nabekura, T., Yamaki, T., Hiroi, T., et al., 2010. Inhibition of anticancer drug efflux transporter P-glycoprotein by rosemary phytochemicals. Pharmacol. Res., 61(3):259-263.

[21]Ni, D., Ding, H., Liu, S., et al., 2015. Superior intratumoral penetration of paclitaxel nanodots strengthens tumor restriction and metastasis prevention. Small, 11(21):2518-2526.

[22]Pathak, A.K., Bhutani, M., Nair, A.S., et al., 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.

[23]Prasad, S., Yadav, V.R., Sung, B., et al., 2012. Ursolic acid inhibits growth and metastasis of human colorectal cancer in an orthotopic nude mouse model by targeting multiple cell signaling pathways: chemosensitization with capecitabine. Clin. Cancer Res., 18(18):4942-4953.

[24]Prasad, S., Yadav, V.R., Sung, B., et al., 2016. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment. Oncotarget, 7(11):13182-13196.

[25]Selvakumaran, M., Amaravadi, R.K., Vasilevskaya, I.A., et al., 2013. Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy. Clin. Cancer Res., 19(11):2995-3007.

[26]Shan, J.Z., Xuan, Y.Y., Zheng, S., et al., 2009. Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway. J. Zhejiang Univ.-Sci. B, 10(9):668-674.

[27]Shan, J.Z., Xuan, Y.Y., Ruan, S.Q., et al., 2011. Proliferation-inhibiting and apoptosis-inducing effects of ursolic acid and oleanolic acid on multi-drug resistance cancer cells in vitro. Chin. J. Integr. Med., 17(8):607-611.

[28]Shan, J.Z., Xuan, Y.Y., Zhang, Q., et al., 2016. Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer. Protein Cell, 7(8):571-585.

[29]Siegel, R.L., Miller, K.D., Jemal, A., 2016. Cancer statistics, 2016. CA: Cancer J. Clin., 66(1):7-30.

[30]Wang, W.J., Sui, H., Qi, C., et al., 2016. Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1α in vitro. Oncol. Rep., 36(1):428-440.

[31]Weng, H., Tan, Z.J., Hu, Y.P., et al., 2014. Ursolic acid induces cell cycle arrest and apoptosis of gallbladder carcinoma cells. Cancer Cell Int., 14(1):96.

[32]Zhang, Q., Bai, X., Chen, W., et al., 2013. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling. Carcinogenesis, 34(5):962-973.

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