Ursolic and Oleanolic Acids as Potential Anticancer Agents Acting in the Gastrointestinal Tract

Author(s): Mateusz Pięt, Roman Paduch*.

Journal Name: Mini-Reviews in Organic Chemistry

Volume 16 , Issue 1 , 2019

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Graphical Abstract:


Background: Cancer is one of the main causes of death worldwide. Contemporary therapies, including chemo- and radiotherapy, are burdened with severe side effects. Thus, there exists an urgent need to develop therapies that would be less devastating to the patient’s body. Such novel approaches can be based on the anti-tumorigenic activity of particular compounds or may involve sensitizing cells to chemotherapy and radiotherapy or reducing the side-effects of regular treatment.

Objective: Natural-derived compounds are becoming more and more popular in cancer research. Examples of such substances are Ursolic Acid (UA) and Oleanolic Acid (OA), plant-derived pentacyclic triterpenoids which possess numerous beneficial properties, including anti-tumorigenic activity.

Results: In recent years, ursolic and oleanolic acids have been demonstrated to exert a range of anticancer effects on various types of tumors. These compounds inhibit the viability and proliferation of cancer cells, prevent their migration and metastasis and induce their apoptosis. Both in vitro and in vivo studies indicate that UA and OA are promising anti-cancer agents that can prevent carcinogenesis at each step. Furthermore, cancers at all stages are susceptible to the activity of these compounds.

Neoplasms that are formed in the gastrointestinal tract, i.e. gastric, colorectal, pancreatic, and liver cancers, are among the most common and most lethal malignancies. Their localization in the digestive system, however, facilitates the action of orally-administered (potential) anti-cancer agents, making chemopreventive drugs more accessible.

Conclusion: In this paper, the anti-tumorigenic effect of ursolic and oleanolic acids on gastric, colon, pancreatic, and liver cancers, as well as the mechanisms underlying this process, are presented.

Keywords: Ursolic acid, oleanolic acid, gastric cancer, colon cancer, pancreatic cancer, liver cancer, anti-cancer properties.

Jang, S.M.; Yee, S.T.; Choi, J.; Choi, M.S.; Do, G.M.; Jeon, S.M.; Yeo, J.; Kim, M.J.; Seo, K.I.; Lee, M.K. Ursolic acid enhances the cellular immune system and pancreatic β-cell function in streptozotocin-induced diabetic mice fed a high-fat diet. Int. Immunopharmacol., 2009, 9(1), 113-119.
Pollier, J.; Goossens, A. Oleanolic acid. Phytochemistry, 2012, 77, 10-15.
Jin, Y.R.; Jin, J.L.; Li, C.H.; Piao, X.X.; Jin, N.G. Ursolic acid enhances mouse liver regeneration after partial hepatectomy. Pharm. Biol., 2012, 50(4), 523-528.
Shanmugam, M.K.; Dai, X.; Kumar, A.P.; Tan, B.K.; Sethi, G.; Bishayee, A. Ursolic acid in cancer prevention and treatment: Molecular targets, pharmacokinetics and clinical studies. Biochem. Pharmacol., 2013, 85, 1579-1587.
Shanmugam, M.K.; Dai, X.; Kumar, A.P.; Tan, B.K.; Sethi, G.; Bishayee, A. Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: Preclinical and clinical evidence. Cancer Lett., 2014, 346(2), 206-216.
Oprean, C.; Mioc, M.; Csányi, E.; Ambrus, R.; Bojin, F.; Tatu, C.; Cristea, M.; Ivan, A.; Danciu, C.; Dehelean, C.; Paunescu, V.; Soica, C. Improvement of ursolic and oleanolic acids’ antitumor activity by complexation with hydrophilic cyclodextrins. Biomed. Pharmacother., 2016, 83, 1095-1104.
Jung, T.Y.; Pham, T.N.; Umeyama, A.; Shoji, N.; Hashimoto, T.; Lee, J.J.; Takei, M. Ursolic acid isolated from Uncaria rhynchophylla activates human dendritic cells via TLR2 and/or TLR4 and induces the production of IFN-γ by CD4+ naïve T cells. Eur. J. Pharmacol., 2010, 643(2-3), 297-303.
do Nascimento, P.G.; Lemos, T.L.; Bizerra, A.M.; Arriaga, Â.M.; Ferreira, D.A.; Santiago, G.M.; Braz-Filho, R.; Costa, J.G. Antibacterial and antioxidant activities of ursolic acid and derivatives. Molecules, 2014, 19(1), 1317-1327.
Kurek, A.; Nadkowska, P.; Pliszka, S.; Wolska, K.I. Modulation of antibiotic resistance in bacterial pathogens by oleanolic acid and ursolic acid. Phytomedicine, 2012, 19(6), 515-519.
Kong, L.; Li, S.; Liao, Q.; Zhang, Y.; Sun, R.; Zhu, X.; Zhang, Q.; Wang, J.; Wu, X.; Fang, X.; Zhu, Y. Oleanolic acid and ursolic acid: Novel hepatitis C virus antivirals that inhibit NS5B activity. Antiviral Res., 2013, 98(1), 44-53.
Ramachandran, S.; Prasad, N.R. Effect of ursolic acid, a triterpenoid antioxidant, on Ultraviolet-B radiation-induced cytotoxicity, lipid peroxidation and DNA damage in human lymphocytes. Chem. Biol. Interact., 2008, 176(2-3), 99-107.
Jang, S.M.; Kim, M.J.; Choi, M.S.; Kwon, E.Y.; Lee, M.K. Inhibitory effects of ursolic acid on hepatic polyol pathway and glucose production in streptozotocin-induced diabetic mice. Metabolism, 2010, 59(4), 512-519.
Lee, J.; Yee, S.T.; Kim, J.J.; Choi, M.S.; Kwon, E.Y.; Seo, K.I.; Lee, M.K. Ursolic acid ameliorates thymic atrophy and hyperglycemia in streptozotocin-nicotinamide-induced diabetic mice. Chem. Biol. Interact., 2010, 188(3), 635-642.
Kunkel, S.D.; Elmore, C.J.; Bongers, K.S.; Ebert, S.M.; Fox, D.K.; Dyle, M.C.; Bullard, S.A.; Adams, C.M. Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease. PLoS One, 2012, 7(6), e39332.
Benincá, J.P.; Dalmarco, J.B.; Pizzolatti, M.G.; Fröde, T.S. Analysis of the anti-inflammatory properties of Rosmarinus officinalis L. in mice. Food Chem., 2011, 124, 468-475.
Checker, R.; Sandur, S.K.; Sharma, D.; Patwardhan, R.S.; Jayakumar, S.; Kohli, V.; Sethi, G.; Aggarwal, B.B.; Sainis, K.B. Potent anti-inflammatory activity of ursolic acid, a triterpenoid antioxidant, is mediated through suppression of NF-kB, AP-1 and NF-AT. PLoS One, 2012, 7(2), e31318.
Baek, S.Y.; Lee, J.; Lee, D.G.; Park, M.K.; Lee, J.; Kwok, S.K.; Cho, M.L.; Park, S.H. Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation. Acta Pharmacol. Sin., 2014, 35(9), 1177-1187.
Machado, D.G.; Neis, V.B.; Balen, G.O.; Colla, A.; Cunha, M.P.; Dalmarco, J.B.; Pizzolatti, M.G.; Prediger, R.D.; Rodrigues, A.L. Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: Evidence for the involvement of the dopaminergic system. Pharmacol. Biochem. Behav., 2012, 103(2), 204-211.
Lu, J.; Zheng, Y.L.; Wu, D.M.; Luo, L.; Sun, D.X.; Shan, Q. Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. Biochem. Pharmacol., 2007, 74(7), 1078-1090.
Lu, J.; Wu, D.M.; Zheng, Y.L.; Hu, B.; Zhang, Z.F.; Ye, Q.; Liu, C.M.; Shan, Q.; Wang, Y.J. Ursolic acid attenuates D-galactose-induced inflammatory response in mouse prefrontal cortex through inhibiting AGEs/RAGE/NF-kB pathway activation. Cereb. Cortex, 2010, 20(11), 2540-2548.
Han, N.; Bakovic, M. Biologically active triterpenoids and their cardioprotective and anti-inflammatory effects. J. Bioanal. Biomed., 2015, 01(s12)
Ishikawa, T.; Donatini Rdos, S.; Diaz, I.E.; Yoshida, M.; Bacchi, E.M.; Kato, E.T. Evaluation of gastroprotective activity of Plinia edulis (Vell.) Sobral (Myrtaceae) leaves in rats. J. Ethnopharmacol., 2008, 118(3), 527-529.
Saravanan, R.; Viswanathan, P.; Pugalendi, K.V. Protective effect of ursolic acid on ethanol-mediated experimental liver damage in rats. Life Sci., 2006, 78(7), 713-718.
Gutiérrez-Rebolledo, G.A.; Siordia-Reyes, A.G.; Meckes-Fischer, M.; Jiménez-Arellanes, A. Hepatoprotective properties of oleanolic and ursolic acids in antitubercular drug-induced liver damage. Asian Pac. J. Trop. Med., 2016, 9(7), 644-651.
Kuttan, G.; Pratheeshkumar, P.; Aryan Manu, K.; Kuttan, R. Inhibition of tumor progression by naturallyoccurring terpenoids. Pharm. Biol., 2011, 49, 995-1007.
Tian, T.; Liu, X.; Lee, E-S.; Sun, J.; Feng, Z.; Zhao, L.; Zhao, Ch. Synthesis of novel oleanolic acid and ursolic acid in C-28 position derivatives as potential anticancer agents. Arch. Pharm. Res., 2017, 40, 458-468.
Chen, H.; Gao, Y.; Wang, A.; Zhou, X.; Zheng, Y.; Zhou, J. Evolution in medicinal chemistry of ursolic acid derivatives as anticancer agents. Eur. J. Med. Chem., 2015, 92, 648-655.
Kashyap, D.; Tuli, H.S.; Sharma, A.K. Ursolic Acid (UA): A metabolite with promising therapeutic potential. Life Sci., 2016, 146, 201-213.
Safe, S.; Chadalapaka, G.; Jutooru, I.; Chintharlapalli, S.; Papineni, S. Pentacyclic triterpenes as promising agents in cancer: Highlights of pentacyclic triterpenes in the cancer setting; Nova Science Publishers, Inc.: New York, 2011, pp. pp. 277-306.
Muto, Y.; Ninomiya, M.; Fujiki, H. Present status of research on cancer chemoprevention in Japan. Jpn. J. Clin. Oncol., 1990, 20, 219-224.
Salvador, J.A.R.; Leal, A.S.; Alho, D.P.S.; Gonçalves, B.M.F.; Valdeira, A.S.; Mendes, V.I.S.; Jing, Y. Highlights of pentacyclic triterpenoids in the cancer settings. Stud. Nat. Prod. Chem, 2014, 41, 33-73.
Wang, X.; Zhang, F.; Yang, L.; Mei, Y.; Long, H.; Zhang, X.; Zhang, J.; Qimuge-Suyila, S.X. Ursolic acid inhibits proliferation and induces apoptosis of cancer cells in vitro and in vivo. J. Biomed. Biotechnol., 2011, 2011, 419343.
Zhang, H.; Li, X.; Ding, J.; Xu, H.; Dai, X.; Hou, Z.; Zhang, K.; Sun, K.; Sun, W. Delivery of Ursolic Acid (UA) in polymeric nanoparticles effectively promotes the apoptosis of gastric cancer cells through enhanced inhibition of cyclooxygenase 2 (COX-2). Int. J. Pharm., 2013, 441(1-2), 261-268.
Yang, Y.; Jiang, M.; Hu, J.; Lv, X.; Yu, L.; Qian, X.; Liu, B. Enhancement of radiation effects by ursolic acid in BGC-823 human adenocarcinoma gastric cancer cell line. PLoS One, 2015, 10(7), e0133169.
Lu, Y.; Zhu, M.; Chen, W.; Yin, L.; Zhu, J.; Chen, N.; Chen, W. Oleanolic acid induces apoptosis of MKN28 cells via AKT and JNK signaling pathways. Pharm. Biol., 2014, 52(6), 789-795.
Li, R.; Wang, X.; Zhang, X.H.; Chen, H.H.; Liu, Y.D. Ursolic acid promotes apoptosis of SGC-7901 gastric cancer cells through ROCK/PTEN mediated mitochondrial translocation of cofilin-1. Asian Pac. J. Cancer Prev., 2014, 15(22), 9593-9597.
Kim, E.S.; Moon, A. Ursolic acid inhibits the invasive phenotype of SNU-484 human gastric cancer cells. Oncol. Lett., 2015, 9(2), 897-902.
Xiang, F.; Pan, C.; Kong, Q.; Wu, R.; Jiang, J.; Zhan, Y.; Xu, J.; Gu, X.; Kang, X. Ursolic acid inhibits the proliferation of gastric cancer cells by targeting miR-133a. Oncol. Res., 2014, 22(5-6), 267-273.
He, Q.Y.; Wang, R.; Sun, X-C. Cytotoxicity of methanolic extract of Swertia petiolata against gastric cancer cell line SNU-5 is via induction of apoptosis. S. Afr. J. Bot., 2017, 109, 196-202.
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
Coups, E.J.; Hay, J.; Ford, J.S. Awareness of the role of physical activity in colon cancer prevention. Patient Educ. Couns., 2008, 72(2), 246-251.
Birt, D.F.; Phillips, G.J. Diet, genes, and microbes: Complexities of colon cancer prevention. Toxicol. Pathol., 2014, 42(1), 182-188.
Astin, M.; Griffin, T.; Neal, R.D.; Rose, P.; Hamilton, W. The diagnostic value of symptoms for colorectal cancer in primary care: A systematic review. Br. J. Gen. Pract., 2011, 61(586), e231-e243.
Adelstein, B.A.; Macaskill, P.; Chan, S.F.; Katelaris, P.H.; Irwig, L. Most bowel cancer symptoms do not indicate colorectal cancer and polyps: A systematic review. BMC Gastroenterol., 2011, 11, 65.
Nam, H.; Kim, M.M. Ursolic acid induces apoptosis of SW480 cells via p53 activation. Food Chem. Toxicol., 2013, 62, 579-583.
Wang, W.; Zhao, C.; Jou, D.; Lü, J.; Zhang, C.; Lin, L.; Lin, J. Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3. Anticancer Res., 2013, 33(10), 4279-4284.
Shan, J.; Xuan, Y.; Zheng, S.; Dong, Q.; Zhang, S. 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(9), 668-674.
Prasad, S.; Yadav, V.R.; Sung, B.; Reuter, S.; Kannappan, R.; Deorukhkar, A.; Diagaradjane, P.; Wei, C.; Baladandayuthapani, V.; Krishnan, S.; Guha, S.; Aggarwal, B.B. 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., 2012, 18(18), 4942-4953.
Wang, J.; Liu, L.; Qiu, H.; Zhang, X.; Guo, W.; Chen, W.; Tian, Y.; Fu, L.; Shi, D.; Cheng, J.; Huang, W.; Deng, W. Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells. PLoS One, 2013, 8(5), e63872.
Lin, J.; Chen, Y.; Wei, L.; Shen, A.; Sferra, T.J.; Hong, Z.; Peng, J. Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways. Int. J. Oncol., 2013, 43(4), 1235-1243.
Kim, J.H.; Kim, Y.H.; Song, G.Y.; Kim, D.E.; Jeong, Y.J.; Liu, K.H.; Chung, Y.H.; Oh, S. Ursolic acid and its natural derivative corosolic acid suppress the proliferation of APC-mutated colon cancer cells through promotion of β-catenin degradation. Food Chem. Toxicol., 2014, 67, 87-95.
Shan, J.; Xuan, Y.; Zhang, Q.; Zhu, C.; Liu, Z.; Zhang, S. Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer. Protein Cell, 2016, 7(8), 571-585.
Juan, M.E.; Planas, J.M.; Ruiz-Gutierrez, V.; Daniel, H.; Wenzel, U. Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Br. J. Nutr., 2008, 100(1), 36-43.
Guo, Y.; Han, B.; Luo, K.; Ren, Z.; Cai, L.; Sun, L. NOX2-ROS-HIF-1α signaling is critical for the inhibitory effect of oleanolic acid on rectal cancer cell proliferation. Biomed. Pharmacother., 2017, 85, 733-739.
Panasyuk, G.; Nemazanyy, I.; Zhyvoloup, A.; Bretner, M.; Litchfield, D.W.; Filonenko, V.; Gout, I.T. Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17. J. Biol. Chem., 2006, 281(42), 31188-31201.
Ci, Y.; Shi, K.; An, J.; Yang, Y.; Hui, K.; Wu, P.; Shi, L.; Xu, C. ROS inhibit autophagy by downregulating ULK1 mediated by the phosphorylation of p53 in selenite-treated NB4 cells. Cell Death Dis., 2014, 5, e1542.
Li, L.; Wei, L.; Shen, A.; Chu, J.; Lin, J.; Peng, J. Oleanolic acid modulates multiple intracellular targets to inhibit colorectal cancer growth. Int. J. Oncol., 2015, 47(6), 2247-2254.
Ye, X.; Weinberg, R.A. Epithelial-Mesenchymal plasticity: A central regulator of cancer progression. Trends Cell Biol., 2015, 25(11), 675-686.
Lin, J.; Chen, Y.; Wei, L.; Hong, Z.; Sferra, T.J.; Peng, J. Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways. Int. J. Oncol., 2013, 43(5), 1666-1674.
Stathis, A.; Moore, M.J. Advanced pancreatic carcinoma: Current treatment and future challenges. Nat. Rev. Clin. Oncol., 2010, 7(3), 163-172.
Li, J.; Liang, X.; Yang, X. Ursolic acid inhibits growth and induces apoptosis in gemcitabine-resistant human pancreatic cancer via the JNK and PI3K/Akt/NF-κB pathways. Oncol. Rep., 2012, 28(2), 501-510.
Prasad, S.; Yadav, V.R.; Sung, B.; Gupta, S.C.; Tyagi, A.K.; Aggarwal, B.B. 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, 2016, 7(11), 13182-13196.
Wei, J.; Liu, H.; Liu, M.; Wu, N.; Zhao, J.; Xiao, L.; Han, L.; Chu, E.; Lin, X. Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells. Oncol. Rep., 2012, 28(4), 1339-1345.
Wei, J.; Liu, M.; Liu, H.; Wang, H.; Wang, F.; Zhang, Y.; Han, L.; Lin, X. Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells. J. Appl. Toxicol., 2013, 33(8), 756-765.
Yang, L.; Liu, X.; Lu, Z.; Yuet-Wa Chan, J.; Zhou, L.; Fung, K.P.; Wu, P.; Wu, S. Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor. Cancer Lett., 2010, 298(1), 128-138.
Ramos, A.A.; Lima, C.F.; Pereira, M.L.; Fernandes-Ferreira, M.; Pereira-Wilson, C. Antigenotoxic effects of quercetin, rutin and ursolic acid on HepG2 cells: Evaluation by the comet assay. Toxicol. Lett., 2008, 177(1), 66-73.
Dong, H.; Yang, X.; Xie, J.; Xiang, L.; Li, Y.; Ou, M.; Chi, T.; Liu, Z.; Yu, S.; Gao, Y.; Chen, J.; Shao, J.; Jia, L. UP12, a novel ursolic acid derivative with potential for targeting multiple signaling pathways in hepatocellular carcinoma. Biochem. Pharmacol., 2015, 93(2), 151-162.
Yan, S.L.; Huang, C.Y.; Wu, S.T.; Yin, M.C. Oleanolic acid and ursolic acid induce apoptosis in four human liver cancer cell lines. Toxicol. In Vitro, 2010, 24(3), 842-848.
Liese, J.; Abhari, B.A.; Fulda, S. Smac mimetic and oleanolic acid synergize to induce cell death in human hepatocellular carcinoma cells. Cancer Lett., 2015, 365(1), 47-58.
Lange, M.; Abhari, B.A.; Hinrichs, T.M.; Fulda, S.; Liese, J. Identification of a novel oxidative stress induced cell death by Sorafenib and oleanolic acid in human hepatocellular carcinoma cells. Biochem. Pharmacol., 2016, 118, 9-17.

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Year: 2019
Page: [78 - 91]
Pages: 14
DOI: 10.2174/1570193X15666180612090816
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