Abstract
Objective
To investigate the proliferation-inhibiting and apoptosis-inducing effects of ursolic acid (UA) and oleanolic acid (OA) on multi-drug resistance (MDR) cancer cells in vitro.
Methods
UA and OA in different concentrations (0–100 μmol/L) were added separately to cultures of different cancer cell lines, including the human colon cancer cell lines SW480 and SW620, human acute myelocytic leukemia cancer cell lines HL60 and HL60/ADR, human chronic myelogenous leukemia cell lines K562 and K562/ADR, and the human breast cancer cell lines MCF-7 and MCF-7/ADR. Effects of UA and OA on cell proliferation were detected by 3-(4,5-dimethyl-2-thiazole)-2-5-biphenly-tetrazole bromide (MTT) method and effects on cell apoptosis were tested by flow cytometry (FCM) and Western blot at 24, 48, and 72 h after treatment.
Results
Both UA and OA showed significant inhibition on parent and MDR cell lines in a time- and concentration-dependent manner; the drug-resistant multiple of them on K562 and K562/ADR as well as on HL60 and HL60/ADR was 1; the effects of UA were better than those of OA in inhibiting cell growth of solid colonic cancer and breast cancer. After SW480 cells were treated by UA at the concentrations of 0–40 μmol/L for 48 h, FCM showed that annexin V (AV) positive cells and hypodiploid peak ratio increased along with the increase in the drug’s concentrations; and Western blot found that expressions of Bcl-2, Bcl-xL and survivin decreased in a concentration-dependent manner.
Conclusions
Both UA and OA have antitumor effects on cancer cells with MDR, and the optimal effect is shown by UA on colonic cancer cells. Also, UA shows cell apoptosis-inducing effect on SW480, possibly by way of down-regulating the expressions of apoptosis antagonistic proteins, Bcl-2, Bcl-xL, and survivin.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002(2):48–58.
Choi CH. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 2005(5):30–42.
Chen XH, Gao RL, Qian XD, Wang X, Tan PL, Yin LM, et al. Inhibition effect of hedyotic diffusa willd injection on HL-60 cells and its mechanism. Chin J Exp Hematol (Chin) 2008;16:1035–1038.
Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003;3:768–780.
Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. 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 2003;63:4375–4383.
Das B, Yeger H, Tsuchida R, Torkin R, Gee MF, Thorner PS, et al. A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Res 2005;65:7267–7275.
Subbaramaiah K, Michaluart P, Sporn MB, Dannenberg AJ. Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Res 2000;60:2399–2404.
Shan JZ, Xuan YY, Zheng S, Dong Q, Zhang SZ. Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway. J Zhejiang Univ Sci B 2009;10:668–674.
Tang R, Faussat AM, Majdak P, Perrot JY, Chaoui D, Legrand O, et al. Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1. Leukemia 2004;18:1246–1251.
Zorzos HS, Lazaris AC, Korkolopoulou PA, Kavantzas NG, Tseleni-Balafouta S, Patsouris ES, et al. Multidrug resistance proteins and topoisomerase IIalpha expression in colon cancer: association with metastatic potential. Pathology 2003;35:315–318.
Xia Z, Zhu Z, Zhang L, Royal C, Liu Z, Chen Q, et al. Specific reversal of MDR1/P-gp-dependent multidrug resistance by RNA interference in colon cancer cells. Oncol Rep 2008;20:1433–1439.
Gradilone A, Pulcinelli FM, Lotti LV, Trifirò E, Martino S, Gandini O, et al. Celecoxib upregulates multidrug resistance proteins in colon cancer: lack of synergy with standard chemotherapy. Curr Cancer Drug Targets 2008;8:414–420.
Katayama M, Nakano H, Ishiuchi A, Wu W, Oshima R, Sakurai J, et al. Protein pattern difference in the colon cancer cell lines examined by two-dimensional differential in-gel electrophoresis and mass spectrometry. Surg Today 2006;36:1085–1093.
Hewitt RE, Brown KE, Corcoran M, Stetler-Stevenson WG. Increased expression of tissue inhibitor of metalloproteinases type 1 (TIMP-1) in a more tumourigenic colon cancer cell line. J Pathol 2000;192:455–459.
Ndozangue-Touriguine O, Sebbagh M, Merino D, Micheau O, Bertoglio J, Breard J. A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma. Oncogene 2008;27:6012–6022.
Thomadaki H, Scorilas A. Molecular profile of the BCL2 family of the apoptosis related genes in breast cancer cells after treatment with cytotoxic/cytostatic drugs. Connect Tissue Res 2008;49:261–264.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by the National Plan for Supporting High Technique Research and Development (863 Plan, No. 2006AA02Z341), and the Supporting Items of Zhejiang Ministry of Sciences and Technology (No. 2008C30037)
Rights and permissions
About this article
Cite this article
Shan, Jz., Xuan, Yy., Ruan, Sq. et al. 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, 607–611 (2011). https://doi.org/10.1007/s11655-011-0815-y
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11655-011-0815-y