Ursolic Acid Induces Cell Cycle Arrest and Apoptosis of Gallbladder Carcinoma Cells

Overview

Journal Cancer Cell Int

Publisher Biomed Central

Date 2014 Nov 11

PMID 25383044

Citations 25

Authors

Hao Weng

Zhu-Jun Tan

Yun-Ping Hu

Yi-Jun Shu

Run-Fa Bao

Lin Jiang

Xiang-Song Wu

Mao-Lan Li

Qian Ding

Xu-An Wang

Shan-Shan Xiang

Huai-Feng Li

Yang Cao

Feng Tao

Ying-Bin Liu

Affiliations

Soon will be listed here.

Abstract

Background: Ursolic acid (UA), a plant extract used in traditional Chinese medicine, exhibits potential anticancer effects in various human cancer cell lines in vitro. In the present study, we evaluated the anti-tumoral properties of UA against gallbladder carcinoma and investigated the potential mechanisms responsible for its effects on proliferation, cell cycle arrest and apoptosis in vitro.

Methods: The anti-tumor activity of UA against GBC-SD and SGC-996 cells was assessed using MTT and colony formation assays. An annexin V/PI double-staining assay was used to detect cell apoptosis. Cell cycle changes were detected using flow cytometry. Rhodamine 123 staining was used to assess the mitochondrial membrane potential (ΔΨm) and validate UA's ability to induce apoptosis in both cell lines. The effectiveness of UA in gallbladder cancer was further verified in vivo by establishing a xenograft GBC model in nude mice. Finally, the expression levels of cell cycle- and apoptosis-related proteins were analyzed by western blotting.

Results: Our results suggest that UA can significantly inhibit the growth of gallbladder cancer cells. MTT and colony formation assays indicated dose-dependent decreases in cell proliferation. S-phase arrest was observed in both cell lines after treatment with UA. Annexin V/PI staining suggested that UA induced both early and late phases of apoptosis. UA also decreased ΔΨm and altered the expression of molecules regulating the cell cycle and apoptosis. In vivo study showed intraperitoneally injection of UA can significantly inhibited the growth of xenograft tumor in nude mice and the inhibition efficiency is dose related. Activation of caspase-3,-9 and PARP indicated that mitochondrial pathways may be involved in UA-induced apoptosis.

Conclusions: Taken together, these results suggest that UA exhibits significant anti-tumor effects by suppressing cell proliferation, promoting apoptosis and inducing 7cell cycle arrest both in vitro and in vivo. It may be a potential agent for treating gallbladder cancer.

Citing Articles

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References

Dong P, Zhang Y, Gu J, Wu W, Li M, Yang J . Wogonin, an active ingredient of Chinese herb medicine Scutellaria baicalensis, inhibits the mobility and invasion of human gallbladder carcinoma GBC-SD cells by inducing the expression of maspin. J Ethnopharmacol. 2011; 137(3):1373-80. DOI: 10.1016/j.jep.2011.08.005. View

Wang J, Ren T, Xi T . Ursolic acid induces apoptosis by suppressing the expression of FoxM1 in MCF-7 human breast cancer cells. Med Oncol. 2010; 29(1):10-5. DOI: 10.1007/s12032-010-9777-8. View

Xu W, Lin H, Chen X, Zhang Y . Yin-yang balance therapy on regulating cancer stem cells. J Tradit Chin Med. 2011; 31(2):158-60. DOI: 10.1016/s0254-6272(11)60032-0. View

Tan Z, Zhang S, Li M, Wu X, Weng H, Ding Q . Regulation of cell proliferation and migration in gallbladder cancer by zinc finger X-chromosomal protein. Gene. 2013; 528(2):261-6. DOI: 10.1016/j.gene.2013.06.064. View

Shanmugam M, Ong T, Kumar A, Lun C, Ho P, Wong P . Ursolic acid inhibits the initiation, progression of prostate cancer and prolongs the survival of TRAMP mice by modulating pro-inflammatory pathways. PLoS One. 2012; 7(3):e32476. PMC: 3299664. DOI: 10.1371/journal.pone.0032476. View

Pathak A, Bhutani M, Nair A, Ahn K, Chakraborty A, Kadara H . Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res. 2007; 5(9):943-55. DOI: 10.1158/1541-7786.MCR-06-0348. View

Liu T, Tan Z, Jiang L, Gu J, Wu X, Cao Y . Curcumin induces apoptosis in gallbladder carcinoma cell line GBC-SD cells. Cancer Cell Int. 2013; 13(1):64. PMC: 3733655. DOI: 10.1186/1475-2867-13-64. View

Liu Z, Li D, Yu L, Niu F . Gallic acid as a cancer-selective agent induces apoptosis in pancreatic cancer cells. Chemotherapy. 2012; 58(3):185-94. DOI: 10.1159/000337103. View

Levites Y, Youdim M, Maor G, Mandel S . Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol. 2002; 63(1):21-9. DOI: 10.1016/s0006-2952(01)00813-9. View

10.

Manu K, Kuttan G . 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. 2008; 8(7):974-81. DOI: 10.1016/j.intimp.2008.02.013. View

11.

Tan Z, Li M, Wu W, Zhang L, Ding Q, Wu X . NLK is a key regulator of proliferation and migration in gallbladder carcinoma cells. Mol Cell Biochem. 2012; 369(1-2):27-33. DOI: 10.1007/s11010-012-1365-0. View

12.

Lavrik I, Golks A, Krammer P . Caspases: pharmacological manipulation of cell death. J Clin Invest. 2005; 115(10):2665-72. PMC: 1236692. DOI: 10.1172/JCI26252. View

13.

Tang C, Lu Y, Xie J, Wang F, Zou J, Yang J . Downregulation of survivin and activation of caspase-3 through the PI3K/Akt pathway in ursolic acid-induced HepG2 cell apoptosis. Anticancer Drugs. 2009; 20(4):249-58. DOI: 10.1097/CAD.0b013e328327d476. View

14.

Zhang Z, Wang X, Wu W, Wang J, Wang Y, Wu X . Effects of matrine on proliferation and apoptosis in gallbladder carcinoma cells (GBC-SD). Phytother Res. 2011; 26(6):932-7. DOI: 10.1002/ptr.3657. View

15.

Wang J, Liu L, Qiu H, Zhang X, Guo W, Chen W . Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells. PLoS One. 2013; 8(5):e63872. PMC: 3667855. DOI: 10.1371/journal.pone.0063872. View

16.

Lee H, Auh Q, Lee Y, Kang S, Chang S, Lee D . Growth inhibition and apoptosis-inducing effects of cudraflavone B in human oral cancer cells via MAPK, NF-κB, and SIRT1 signaling pathway. Planta Med. 2013; 79(14):1298-306. DOI: 10.1055/s-0033-1350619. View

17.

Earnshaw W, Martins L, Kaufmann S . Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem. 2000; 68:383-424. DOI: 10.1146/annurev.biochem.68.1.383. View

18.

Danial N . BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res. 2007; 13(24):7254-63. DOI: 10.1158/1078-0432.CCR-07-1598. View

19.

Checker R, Sandur S, Sharma D, Patwardhan R, Jayakumar S, Kohli V . Potent anti-inflammatory activity of ursolic acid, a triterpenoid antioxidant, is mediated through suppression of NF-κB, AP-1 and NF-AT. PLoS One. 2012; 7(2):e31318. PMC: 3282718. DOI: 10.1371/journal.pone.0031318. View

20.

Jiang M, Huang O, Zhang X, Xie Z, Shen A, Liu H . Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. Molecules. 2013; 18(1):701-20. PMC: 6269686. DOI: 10.3390/molecules18010701. View