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Current Bioactive Compounds

Editor-in-Chief

ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Review Article

Toxicity, Safety, and Pharmacotherapeutic Properties of Ursolic Acid: Current Status, Challenges, and Future Perspectives against Lung Cancer

Author(s): Chandrakumar Subramanian, Solaipriya Solairaja, Nageswara Rao Dunna and Sivaramakrishnan Venkatabalasubramanian*

Volume 19, Issue 5, 2023

Published on: 29 December, 2022

Article ID: e241022210333 Pages: 16

DOI: 10.2174/1573407219666221024142326

Price: $65

Abstract

Lung cancer is often associated with the second leading cause of mortality in males globally. Despite clinical advancements, their incidence in humans has not decreased. Hence identifying and developing alternative or complementary therapeutic agents with evidence targeting lung cancer is of considerable interest. Ursolic Acid (UA): a dietary flavonoid present in herbs, vegetables, and fruits can effectively alleviate the hallmarks of lung cancer. As a molecular therapeutic agent, UA disrupts prolonged inflammation, augments antioxidant enzyme defense, attenuates tumor growth signal and tissue invasion/metastasis, limits unrestrained proliferation, fosters apoptosis and regulates immune response in lung cancer. This review will most notably focus on the current source of UA availability, phytochemistry, bioavailability, safety, toxicity, and salient pharmacotherapeutic properties in addition to the preclinical and clinical information currently available to recommend UA as a potential therapeutic agent for lung cancer targeting and prevention.

Graphical Abstract

[1]
Bade, B.C.; Dela Cruz, C.S. Lung cancer 2020. Clin. Chest Med., 2020, 41(1), 1-24.
[http://dx.doi.org/10.1016/j.ccm.2019.10.001] [PMID: 32008623]
[2]
de Groot, P.M.; Wu, C.C.; Carter, B.W.; Munden, R.F. The epidemiology of lung cancer. Transl. Lung Cancer Res., 2018, 7(3), 220-233.
[http://dx.doi.org/10.21037/tlcr.2018.05.06] [PMID: 30050761]
[3]
Hacker, S.; Handels, H. A framework for representation and visualization of 3D shape variability of organs in an interactive anatomical atlas. Methods Inf. Med., 2009, 48(3), 272-281.
[http://dx.doi.org/10.3414/ME0551] [PMID: 19387505]
[4]
Hiley, C.T.; Le Quesne, J.; Santis, G.; Sharpe, R.; de Castro, D.G.; Middleton, G.; Swanton, C. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease. Lancet, 2016, 388(10048), 1002-1011.
[http://dx.doi.org/10.1016/S0140-6736(16)31340-X] [PMID: 27598680]
[5]
Ferlay, J.; Shin, H.R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer, 2010, 127(12), 2893-2917.
[http://dx.doi.org/10.1002/ijc.25516] [PMID: 21351269]
[6]
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.
[http://dx.doi.org/10.1002/ijc.29210] [PMID: 25220842]
[7]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[8]
Kim, H.B.; Shim, J.Y.; Park, B.; Lee, Y.J. Long-term exposure to air pollutants and cancer mortality: A meta-analysis of cohort studies. Int. J. Environ. Res. Public Health, 2018, 15(11), 2608.
[http://dx.doi.org/10.3390/ijerph15112608] [PMID: 30469439]
[9]
Luce, D.; Stücker, I. Investigation of occupational and environmental causes of respiratory cancers (ICARE): A multicenter, population-based case-control study in France. BMC Public Health, 2011, 11(1), 928.
[http://dx.doi.org/10.1186/1471-2458-11-928] [PMID: 22171573]
[10]
Raaschou-Nielsen, O.; Bak, H.; Sørensen, M.; Jensen, S.S.; Ketzel, M.; Hvidberg, M.; Schnohr, P.; Tjønneland, A.; Overvad, K.; Loft, S. Air pollution from traffic and risk for lung cancer in three Danish cohorts. Cancer Epidemiol. Biomarkers Prev., 2010, 19(5), 1284-1291.
[http://dx.doi.org/10.1158/1055-9965.EPI-10-0036] [PMID: 20447920]
[11]
Zhang, Y.; Mo, J.; Weschler, C.J. Reducing health risks from indoor exposures in rapidly developing urban China. Environ. Health Perspect., 2013, 121(7), 751-755.
[http://dx.doi.org/10.1289/ehp.1205983] [PMID: 23665813]
[12]
Barta, J.A.; Powell, C.A.; Wisnivesky, J.P. Global epidemiology of lung cancer. Ann. Glob. Health, 2019, 85(1), 8.
[http://dx.doi.org/10.5334/aogh.2419] [PMID: 30741509]
[13]
Smith, C.J.; Perfetti, T.A.; Garg, R.; Hansch, C. IARC carcinogens reported in cigarette mainstream smoke and their calculated log P values. Food Chem. Toxicol., 2003, 41(6), 807-817.
[http://dx.doi.org/10.1016/S0278-6915(03)00021-8] [PMID: 12738186]
[14]
Smith, C.J.; Perfetti, T.A.; Rumple, M.A.; Rodgman, A.; Doolittle, D.J. “IARC Group 2B carcinogens” reported in cigarette mainstream smoke. Food Chem. Toxicol., 2001, 39(2), 183-205.
[http://dx.doi.org/10.1016/S0278-6915(00)00164-2] [PMID: 11267712]
[15]
Ohno, Y.; Koyama, H.; Dinkel, J. Lung cancer. In: MRI of the Lung. Medical Radiology; Kauczor, H.U.; Wielpütz, M.O., Eds.; Springer: Cham, 2016; pp. 293-341.
[http://dx.doi.org/10.1007/174_2016_93]
[16]
Shtivelman, E.; Hensing, T.; Simon, G.R.; Dennis, P.A.; Otterson, G.A.; Bueno, R.; Salgia, R. Molecular pathways and therapeutic targets in lung cancer. Oncotarget, 2014, 5(6), 1392-1433.
[http://dx.doi.org/10.18632/oncotarget.1891] [PMID: 24722523]
[17]
Walter, F.M.; Rubin, G.; Bankhead, C.; Morris, H.C.; Hall, N.; Mills, K.; Dobson, C.; Rintoul, R.C.; Hamilton, W.; Emery, J. Symptoms and other factors associated with time to diagnosis and stage of lung cancer: A prospective cohort study. Br. J. Cancer, 2015, 112(S1)(Suppl. 1), S6-S13.
[http://dx.doi.org/10.1038/bjc.2015.30] [PMID: 25734397]
[18]
Oser, M.G.; Niederst, M.J.; Sequist, L.V.; Engelman, J.A. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol., 2015, 16(4), e165-e172.
[http://dx.doi.org/10.1016/S1470-2045(14)71180-5] [PMID: 25846096]
[19]
Schabath, M.B.; Cote, M.L. Cancer progress and priorities: Lung cancer. Cancer Epidemiol. Biomarkers Prev., 2019, 28(10), 1563-1579.
[http://dx.doi.org/10.1158/1055-9965.EPI-19-0221] [PMID: 31575553]
[20]
Guo, Y.; Yang, L.; Liu, L.; Wei, J.; Teng, F.; Zhang, J.; Zhu, Y.; Xing, P.; Li, J. Comparative study of clinicopathological characteristics and prognosis between combined and pure small cell lung cancer (SCLC) after surgical resection. Thorac. Cancer, 2020, 11(10), 2782-2792.
[http://dx.doi.org/10.1111/1759-7714.13591] [PMID: 32779385]
[21]
Tjong, M.C.; Mak, D.Y.; Shahi, J.; Li, G.J.; Chen, H.; Louie, A.V. Current management and progress in radiotherapy for small cell lung cancer. Front. Oncol., 2020, 10, 1146.
[http://dx.doi.org/10.3389/fonc.2020.01146] [PMID: 32760673]
[22]
Ferlay, J.; Colombet, M.; Soerjomataram, I.; Mathers, C.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer, 2019, 144(8), 1941-1953.
[http://dx.doi.org/10.1002/ijc.31937] [PMID: 30350310]
[23]
Mohan, A.; Garg, A.; Gupta, A.; Sahu, S.; Choudhari, C.; Vashistha, V.; Ansari, A.; Pandey, R.; Bhalla, A.; Madan, K.; Hadda, V.; Iyer, H.; Jain, D.; Kumar, R.; Mittal, S.; Tiwari, P.; Pandey, R.; Guleria, R. Clinical profile of lung cancer in North India: A 10-year analysis of 1862 patients from a tertiary care center. Lung India, 2020, 37(3), 190-197.
[http://dx.doi.org/10.4103/lungindia.lungindia_333_19] [PMID: 32367839]
[24]
Buyel, J.F. Plants as sources of natural and recombinant anti-cancer agents. Biotechnol. Adv., 2018, 36(2), 506-520.
[http://dx.doi.org/10.1016/j.biotechadv.2018.02.002] [PMID: 29408560]
[25]
Huang, Q.; Chen, H.; Ren, Y.; Wang, Z.; Zeng, P.; Li, X.; Wang, J.; Zheng, X. Anti-hepatocellular carcinoma activity and mechanism of chemopreventive compounds: Ursolic acid derivatives. Pharm. Biol., 2016, 54(12), 3189-3196.
[http://dx.doi.org/10.1080/13880209.2016.1214742] [PMID: 27564455]
[26]
López-Hortas, L.; Pérez-Larrán, P.; González-Muñoz, M.J.; Falqué, E.; Domínguez, H. Recent developments on the extraction and application of ursolic acid. A review. Food Res. Int., 2018, 103, 130-149.
[http://dx.doi.org/10.1016/j.foodres.2017.10.028] [PMID: 29389599]
[27]
Shanmugam, M.K.; Dai, X.; Kumar, A.P.; Tan, B.K.H.; Sethi, G.; Bishayee, A. Ursolic acid in cancer prevention and treatment: Molecular targets, pharmacokinetics and clinical studies. Biochem. Pharmacol., 2013, 85(11), 1579-1587.
[http://dx.doi.org/10.1016/j.bcp.2013.03.006] [PMID: 23499879]
[28]
Wang, X.H.; Zhou, S.Y.; Qian, Z.Z.; Zhang, H.L.; Qiu, L.H.; Song, Z.; Zhao, J.; Wang, P.; Hao, X.S.; Wang, H.Q. Evaluation of toxicity and single-dose pharmacokinetics of intravenous ursolic acid liposomes in healthy adult volunteers and patients with advanced solid tumors. Expert Opin. Drug Metab. Toxicol., 2013, 9(2), 117-125.
[http://dx.doi.org/10.1517/17425255.2013.738667] [PMID: 23134084]
[29]
Ngo, S.N.T.; Williams, D.B.; Head, R.J. Rosemary and cancer prevention: Preclinical perspectives. Crit. Rev. Food Sci. Nutr., 2011, 51(10), 946-954.
[http://dx.doi.org/10.1080/10408398.2010.490883] [PMID: 21955093]
[30]
Shishodia, S.; Majumdar, S.; Banerjee, S.; Aggarwal, B.B. 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(15), 4375-4383.
[PMID: 12907607]
[31]
Yin, R.; Li, T.; Tian, J.X.; Xi, P.; Liu, R.H. Ursolic acid, a potential anticancer compound for breast cancer therapy. Crit. Rev. Food Sci. Nutr., 2018, 58(4), 568-574.
[http://dx.doi.org/10.1080/10408398.2016.1203755] [PMID: 27469428]
[32]
Mantzorou, M.; Zarros, A.; Vasios, G.; Theocharis, S.; Pavlidou, E.; Giaginis, C. Cranberry: A promising natural source of potential nutraceuticals with anticancer activity. Anticancer. Agents Med. Chem., 2019, 19(14), 1672-1686.
[http://dx.doi.org/10.2174/1871520619666190704163301] [PMID: 31272361]
[33]
Tan, H.; Zhao, C.; Zhu, Q.; Katakura, Y.; Tanaka, H.; Ohnuki, K.; Shimizu, K. Ursolic acid isolated from the leaves of loquat (Eriobotrya japonica) inhibited osteoclast differentiation through targeting exportin 5. J. Agric. Food Chem., 2019, 67(12), 3333-3340.
[http://dx.doi.org/10.1021/acs.jafc.8b06954] [PMID: 30827108]
[34]
Borrás-Linares, I. Stojanović Z.; Quirantes-Piné, R.; Arráez-Román, D.; Švarc-Gajić J.; Fernández-Gutiérrez, A.; Segura-Carretero, A. Rosmarinus officinalis leaves as a natural source of bioactive compounds. Int. J. Mol. Sci., 2014, 15(11), 20585-20606.
[http://dx.doi.org/10.3390/ijms151120585] [PMID: 25391044]
[35]
Ahmad, A.; Abuzinadah, M.F.; Alkreathy, H.M.; Banaganapalli, B.; Mujeeb, M. Ursolic acid rich ocimum sanctum L leaf extract loaded nanostructured lipid carriers ameliorate adjuvant induced arthritis in rats by inhibition of COX-1, COX-2, TNF-α and IL-1: Pharmacological and docking studies. PLoS One, 2018, 13(3)e0193451
[http://dx.doi.org/10.1371/journal.pone.0193451] [PMID: 29558494]
[36]
Baliga, M.S.; Shivashankara, A.R.; Venkatesh, S.; Bhat, H.P.; Palatty, L.P.; Bhandari, G. Phytochemicals in the prevention of ethanol-induced hepatotoxicity: A revisit. In: Dietary Interventions in Liver Disease: Foods, Nutrients, and Dietary Supplements; Watson, R.R.; Preedy, V.R., Eds.; Elsevier Amsterdam, 2019; pp. 79-89.
[http://dx.doi.org/10.1016/B978-0-12-814466-4.00007-0]
[37]
He, X.; Liu, R.H. Triterpenoids isolated from apple peels have potent antiproliferative activity and may be partially responsible for apple’s anticancer activity. J. Agric. Food Chem., 2007, 55(11), 4366-4370.
[http://dx.doi.org/10.1021/jf063563o] [PMID: 17488026]
[38]
Kalogeropoulos, N.; Yanni, A.E.; Koutrotsios, G.; Aloupi, M. Bioactive microconstituents and antioxidant properties of wild edible mushrooms from the island of Lesvos, Greece. Food Chem. Toxicol., 2013, 55, 378-385.
[http://dx.doi.org/10.1016/j.fct.2013.01.010] [PMID: 23354393]
[39]
Szakiel, A. Pączkowski, C.; Koivuniemi, H.; Huttunen, S. Comparison of the triterpenoid content of berries and leaves of lingonberry Vaccinium vitis-idaea from Finland and Poland. J. Agric. Food Chem., 2012, 60(19), 4994-5002.
[http://dx.doi.org/10.1021/jf300375b] [PMID: 22490120]
[40]
Kondo, M.; MacKinnon, S.L.; Craft, C.C.; Matchett, M.D.; Hurta, R.A.R.; Neto, C.C. Ursolic acid and its esters: Occurrence in cranberries and other Vaccinium fruit and effects on matrix metalloproteinase activity in DU145 prostate tumor cells. J. Sci. Food Agric., 2011, 91(5), 789-796.
[http://dx.doi.org/10.1002/jsfa.4330] [PMID: 21351105]
[41]
Silva, N.H.C.S.; Morais, E.S.; Freire, C.S.R.; Freire, M.G.; Silvestre, A.J.D. Extraction of high value triterpenic acids from Eucalyptus globulus biomass using hydrophobic deep eutectic solvents. Molecules, 2020, 25(1), 210.
[http://dx.doi.org/10.3390/molecules25010210] [PMID: 31947898]
[42]
Zuo, L.L.; Wang, Z.Y.; Fan, Z.L.; Tian, S.Q.; Liu, J.R. Evaluation of antioxidant and antiproliferative properties of three Actinidia (Actinidia kolomikta, Actinidia arguta, Actinidia chinensis) extracts in vitro. Int. J. Mol. Sci., 2012, 13(5), 5506-5518.
[http://dx.doi.org/10.3390/ijms13055506] [PMID: 22754311]
[43]
Seo, D.Y.; Lee, S.R.; Heo, J.W.; No, M.H.; Rhee, B.D.; Ko, K.S.; Kwak, H.B.; Han, J. Ursolic acid in health and disease. Korean J. Physiol. Pharmacol., 2018, 22(3), 235-248.
[http://dx.doi.org/10.4196/kjpp.2018.22.3.235] [PMID: 29719446]
[44]
Seki, H.; Sawai, S.; Ohyama, K.; Mizutani, M.; Ohnishi, T.; Sudo, H.; Fukushima, E.O.; Akashi, T.; Aoki, T.; Saito, K.; Muranaka, T. Triterpene functional genomics in licorice for identification of CYP72A154 involved in the biosynthesis of glycyrrhizin. Plant Cell, 2011, 23(11), 4112-4123.
[http://dx.doi.org/10.1105/tpc.110.082685] [PMID: 22128119]
[45]
Pironi, A.M.; de Araújo, P.R.; Fernandes, M.A.; Salgado, H.R.N.; Chorilli, M. Characteristics, biological properties and analytical methods of ursolic acid: A review. Crit. Rev. Anal. Chem., 2018, 48(1), 86-93.
[http://dx.doi.org/10.1080/10408347.2017.1390425] [PMID: 29039968]
[46]
Kashyap, D.; Tuli, H.S.; Sharma, A.K. Ursolic acid (UA): A metabolite with promising therapeutic potential. Life Sci., 2016, 146, 201-213.
[http://dx.doi.org/10.1016/j.lfs.2016.01.017] [PMID: 26775565]
[47]
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.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.031] [PMID: 25617694]
[48]
Mendes, V.I.S.; Bartholomeusz, G.A.; Ayres, M.; Gandhi, V.; Salvador, J.A.R. Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells. Eur. J. Med. Chem., 2016, 123, 317-331.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.045] [PMID: 27484517]
[49]
Mlala, S.; Oyedeji, A.O.; Gondwe, M.; Oyedeji, O.O. Ursolic acid and its derivatives as bioactive agents. Molecules, 2019, 24(15), 2751.
[http://dx.doi.org/10.3390/molecules24152751] [PMID: 31362424]
[50]
Shih, Y.H.; Chein, Y.C.; Wang, J.Y.; Fu, Y.S. Ursolic acid protects hippocampal neurons against kainate-induced excitotoxicity in rats. Neurosci. Lett., 2004, 362(2), 136-140.
[http://dx.doi.org/10.1016/j.neulet.2004.03.011] [PMID: 15193771]
[51]
Zhang, T.; Su, J.; Wang, K.; Zhu, T.; Li, X. Ursolic acid reduces oxidative stress to alleviate early brain injury following experimental subarachnoid hemorrhage. Neurosci. Lett., 2014, 579, 12-17.
[http://dx.doi.org/10.1016/j.neulet.2014.07.005] [PMID: 25026072]
[52]
Ma, J.Q.; Ding, J.; Zhang, L.; Liu, C.M. Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway. Clin. Res. Hepatol. Gastroenterol., 2015, 39(2), 188-197.
[http://dx.doi.org/10.1016/j.clinre.2014.09.007] [PMID: 25459994]
[53]
Tailleux, A.; Wouters, K.; Staels, B. Roles of PPARs in NAFLD: Potential therapeutic targets. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 2012, 1821(5), 809-818.
[http://dx.doi.org/10.1016/j.bbalip.2011.10.016] [PMID: 22056763]
[54]
Reddy, J.K.; Sambasiva Rao, M. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am. J. Physiol. Gastrointest. Liver Physiol., 2006, 290(5), G852-G858.
[http://dx.doi.org/10.1152/ajpgi.00521.2005] [PMID: 16603729]
[55]
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
[http://dx.doi.org/10.1371/journal.pone.0039332] [PMID: 22745735]
[56]
Li, S.; Meng, F.; Liao, X.; Wang, Y.; Sun, Z.; Guo, F.; Li, X.; Meng, M.; Li, Y.; Sun, C. Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats. PLoS One, 2014, 9(1)e86724
[http://dx.doi.org/10.1371/journal.pone.0086724] [PMID: 24489777]
[57]
Jung, S.H.; Ha, Y.J.; Shim, E.K.; Choi, S.Y.; Jin, J.L.; Yun-Choi, H.S.; Lee, J.R. Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator. Biochem. J., 2007, 403(2), 243-250.
[http://dx.doi.org/10.1042/BJ20061123] [PMID: 17201692]
[58]
Broniatowski, M.; Flasiński, M.; Hąc-Wydro, K. Antagonistic effects of α-tocopherol and ursolic acid on model bacterial membranes. Biochim. Biophys. Acta Biomembr., 2015, 1848(10)(10 Pt A), 2154-2162.
[http://dx.doi.org/10.1016/j.bbamem.2015.05.009] [PMID: 26003534]
[59]
do Nascimento, P.; Lemos, T.; Bizerra, A.; Arriaga, Â.; Ferreira, D.; Santiago, G.; Braz-Filho, R.; Costa, J. Antibacterial and antioxidant activities of ursolic acid and derivatives. Molecules, 2014, 19(1), 1317-1327.
[http://dx.doi.org/10.3390/molecules19011317] [PMID: 24451251]
[60]
Srinivasan, R.; Natarajan, D.; Shivakumar, M.S. Spectral characterization and antibacterial activity of an isolated compound from Memecylon edule leaves. J. Photochem. Photobiol. B, 2017, 168, 20-24.
[http://dx.doi.org/10.1016/j.jphotobiol.2017.01.019] [PMID: 28152388]
[61]
Subramaniam, S.; Rajendran, N.; Muralidharan, S.; Subramaniam, G.; Raju, R.; Sivasubramanian, A. Dual role of select plant based nutraceuticals as antimicrobial agents to mitigate food borne pathogens and as food preservatives. RSC Advances, 2015, 5(94), 77168-77174.
[http://dx.doi.org/10.1039/C5RA15039F]
[62]
Geerlofs, L.; He, Z.; Xiao, S.; Xiao, Z-C. Efficacy of berberine as a preservative against mold and yeast in poultry feed. Approaches Poultry, Dairy. Vet. Sci., 2019, 6(5), 601-605.
[http://dx.doi.org/10.31031/APDV.2019.06.000650]
[63]
Cornejo, G.J.; Chamorro, C.G.A.; Garduno, S.L.; Hernandez, P.R.; Jimenez, A.M.A. Acute and subacute toxicity (28 days) of a mixture of ursolic acid and oleanolic acid obtained from Bouvardia ternifolia in mice. Bol. Latinoam. Caribe Plantas Med. Aromat., 2012, 11, 91-102.
[64]
Singh, G.B.; Singh, S.; Bani, S.; Gupta, B.D.; Banerjee, S.K. Anti-inflammatory activity of oleanolic acid in rats and mice. J. Pharm. Pharmacol., 2011, 44(5), 456-458.
[http://dx.doi.org/10.1111/j.2042-7158.1992.tb03646.x] [PMID: 1359067]
[65]
Geerlofs, L.; He, Z.; Xiao, S.; Xiao, Z.C. Repeated dose (90 days) oral toxicity study of ursolic acid in Han-Wistar rats. Toxicol. Rep., 2020, 7, 610-623.
[http://dx.doi.org/10.1016/j.toxrep.2020.04.005] [PMID: 32435599]
[66]
Oliveira Costa, J.F.; Barbosa-Filho, J.M.; de Azevedo Maia, G.L.; Guimarães, E.T.; Meira, C.S.; Ribeiro-dos-Santos, R.; Pontes de Carvalho, L.C.; Soares, M.B.P. Potent anti-inflammatory activity of betulinic acid treatment in a model of lethal endotoxemia. Int. Immunopharmacol., 2014, 23(2), 469-474.
[http://dx.doi.org/10.1016/j.intimp.2014.09.021] [PMID: 25281393]
[67]
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.
[PMID: 24122993]
[68]
Pathak, A.K.; Bhutani, M.; Nair, A.S.; Ahn, K.S.; Chakraborty, A.; Kadara, H.; Guha, S.; Sethi, G.; Aggarwal, B.B. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol. Cancer Res., 2007, 5(9), 943-955.
[http://dx.doi.org/10.1158/1541-7786.MCR-06-0348] [PMID: 17855663]
[69]
Gupta, S.C.; Francis, S.K.; Nair, M.S.; Mo, Y.Y.; Aggarwal, B.B. Azadirone, a limonoid tetranortriterpene, induces death receptors and sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through a p53 protein-independent mechanism: Evidence for the role of the ROS-ERK-CHOP-death receptor pathway. J. Biol. Chem., 2013, 288(45), 32343-32356.
[http://dx.doi.org/10.1074/jbc.M113.455188] [PMID: 24078627]
[70]
Prasad, S.; Gupta, S.C.; Tyagi, A.K. Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett., 2017, 387, 95-105.
[http://dx.doi.org/10.1016/j.canlet.2016.03.042] [PMID: 27037062]
[71]
Castrejón-Jiménez, N.S.; Leyva-Paredes, K.; Baltierra-Uribe, S.L.; Castillo-Cruz, J.; Campillo-Navarro, M.; Hernández-Pérez, A.D.; Luna-Angulo, A.B.; Chacón-Salinas, R.; Coral-Vázquez, R.M.; Estrada-García, I.; Sánchez-Torres, L.E.; Torres-Torres, C.; García-Pérez, B.E. Ursolic and oleanolic acids induce mitophagy in a549 human lung cancer cells. Molecules, 2019, 24(19), 3444.
[http://dx.doi.org/10.3390/molecules24193444] [PMID: 31547522]
[72]
Chen, C.J.; Shih, Y.L.; Yeh, M.Y.; Liao, N.C.; Chung, H.Y.; Liu, K.L.; Lee, M.H.; Chou, P.Y.; Hou, H.Y.; Chou, J.S.; Chung, J.G. Ursolic acid induces apoptotic cell death through AIF and endo G release through a mitochondria-dependent pathway in NCI-H292 human lung cancer cells in vitro. In vivo (Brooklyn), 2019, 33(2), 383-391.
[http://dx.doi.org/10.21873/invivo.11485]
[73]
Liu, W.; Tan, X.; Shu, L.; Sun, H.; Song, J.; Jin, P.; Yu, S.; Sun, M.; Jia, X. Ursolic acid inhibits cigarette smoke extract-induced human bronchial epithelial cell injury and prevents development of lung cancer. Molecules, 2012, 17(8), 9104-9115.
[http://dx.doi.org/10.3390/molecules17089104] [PMID: 22858837]
[74]
Klein, K.; He, K.; Younes, A.I.; Barsoumian, H.B.; Chen, D.; Ozgen, T.; Mosaffa, S.; Patel, R.R.; Gu, M.; Novaes, J.; Narayanan, A.; Cortez, M.A.; Welsh, J.W. Role of mitochondria in cancer immune evasion and potential therapeutic approaches. Front. Immunol., 2020, 11573326
[http://dx.doi.org/10.3389/fimmu.2020.573326] [PMID: 33178201]
[75]
Roos, W.P.; Kaina, B. DNA damage-induced cell death: From specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett., 2013, 332(2), 237-248.
[http://dx.doi.org/10.1016/j.canlet.2012.01.007] [PMID: 22261329]
[76]
Yang, K.; Chen, Y.; Zhou, J.; Ma, L.; Shan, Y.; Cheng, X.; Wang, Y.; Zhang, Z.; Ji, X.; Chen, L.; Dai, H.; Zhu, B.; Li, C.; Tao, Z.; Hu, X.; Yin, W. Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non-small-cell lung carcinoma harbouring EGFR T790M mutations. Br. J. Pharmacol., 2019, 176(24), 4609-4624.
[http://dx.doi.org/10.1111/bph.14793] [PMID: 31322286]
[77]
Lai, M.Y.; Leung, H.W.C.; Yang, W.H.; Chen, W.H.; Lee, H.Z. Up-regulation of matrix metalloproteinase family gene involvement in ursolic acid-induced human lung non-small carcinoma cell apoptosis. Anticancer Res., 2007, 27(1A), 145-153.
[PMID: 17352226]
[78]
Chou, Y.C.; Chang, M.Y.; Wang, M.J.; Harnod, T.; Hung, C.H.; Lee, H.T.; Shen, C.C.; Chung, J.G. PEITC induces apoptosis of human brain glioblastoma GBM8401 cells through the extrinsic- and intrinsic signaling pathways. Neurochem. Int., 2015, 81, 32-40.
[http://dx.doi.org/10.1016/j.neuint.2015.01.001] [PMID: 25582659]
[79]
Mandal, M.; Adam, L.; Kumar, R. Redistribution of activated caspase-3 to the nucleus during butyric acid-induced apoptosis. Biochem. Biophys. Res. Commun., 1999, 260(3), 775-780.
[http://dx.doi.org/10.1006/bbrc.1999.0966] [PMID: 10403841]
[80]
Jantas, D.; Piotrowski, M.; Lason, W. An involvement of PI3-K/Akt activation and inhibition of AIF translocation in neuroprotective effects of undecylenic acid (UDA) against pro-apoptotic factors-induced cell death in human neuroblastoma SH-SY5Y cells. J. Cell. Biochem., 2015, 116(12), 2882-2895.
[http://dx.doi.org/10.1002/jcb.25236] [PMID: 26012840]
[81]
Verma, D.K.; Gupta, S.; Biswas, J.; Joshi, N.; Sivarama Raju, K.; Wahajuddin, M.; Singh, S. Metabolic enhancer piracetam attenuates the translocation of mitochondrion-specific proteins of caspase-independent pathway, poly [ADP-Ribose] polymerase 1 up-regulation and oxidative DNA fragmentation. Neurotox. Res., 2018, 34(2), 198-219.
[http://dx.doi.org/10.1007/s12640-018-9878-2] [PMID: 29532444]
[82]
Hsu, Y.L.; Kuo, P.L.; Lin, C.C. Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. Life Sci., 2004, 75(19), 2303-2316.
[http://dx.doi.org/10.1016/j.lfs.2004.04.027] [PMID: 15350828]
[83]
Malarkannan, S. Molecular mechanisms of FasL-mediated ‘reverse-signaling’. Mol. Immunol., 2020, 127, 31-37.
[http://dx.doi.org/10.1016/j.molimm.2020.08.010] [PMID: 32905906]
[84]
Delbridge, A.R.D.; Grabow, S.; Strasser, A.; Vaux, D.L. Thirty years of BCL-2: Translating cell death discoveries into novel cancer therapies. Nat. Rev. Cancer, 2016, 16(2), 99-109.
[http://dx.doi.org/10.1038/nrc.2015.17] [PMID: 26822577]
[85]
Meng, Y.; Lin, Z.M.; Ge, N.; Zhang, D.L.; Huang, J.; Kong, F. Ursolic acid induces apoptosis of prostate cancer cells via the PI3K/Akt/mTOR pathway. Am. J. Chin. Med., 2015, 43(7), 1471-1486.
[http://dx.doi.org/10.1142/S0192415X15500834] [PMID: 26503559]
[86]
Kim, S.H.; Ryu, H.G.; Lee, J.; Shin, J.; Harikishore, A.; Jung, H.Y.; Kim, Y.S.; Lyu, H.N.; Oh, E.; Baek, N.I.; Choi, K.Y.; Yoon, H.S.; Kim, K.T. Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells. Sci. Rep., 2015, 5(1), 14570.
[http://dx.doi.org/10.1038/srep14570] [PMID: 26412148]
[87]
López-Sánchez, I.; Valbuena, A.; Vázquez-Cedeira, M.; Khadake, J.; Sanz-García, M.; Carrillo-Jiménez, A.; Lazo, P.A. VRK1 interacts with p53 forming a basal complex that is activated by UV-induced DNA damage. FEBS Lett., 2014, 588(5), 692-700.
[http://dx.doi.org/10.1016/j.febslet.2014.01.040] [PMID: 24492002]
[88]
Vega, F.M.; Sevilla, A.; Lazo, P.A. p53 Stabilization and accumulation induced by human vaccinia-related kinase 1. Mol. Cell. Biol., 2004, 24(23), 10366-10380.
[http://dx.doi.org/10.1128/MCB.24.23.10366-10380.2004] [PMID: 15542844]
[89]
Jiang, K.; Chi, T.; Li, T.; Zheng, G.; Fan, L.; Liu, Y.; Chen, X.; Chen, S.; Jia, L.; Shao, J.W. Correction: A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: Suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways. Nanoscale, 2018, 10(13), 6212-6213.
[http://dx.doi.org/10.1039/C8NR90055H] [PMID: 29595211]
[90]
Gou, W.; Luo, N.; Wei, H.; Wu, H.; Yu, X.; Duan, Y.; Bi, C.; Ning, H.; Hou, W.; Li, Y. Ursolic acid derivative UA232 evokes apoptosis of lung cancer cells induced by endoplasmic reticulum stress. Pharm. Biol., 2020, 58(1), 707-715.
[http://dx.doi.org/10.1080/13880209.2020.1794013] [PMID: 32726164]
[91]
Walter, P.; Ron, D. The unfolded protein response: From stress pathway to homeostatic regulation. Science, 2011, 334(6059), 1081-1086.
[http://dx.doi.org/10.1126/science.1209038] [PMID: 22116877]
[92]
Doultsinos, D.; Avril, T.; Lhomond, S.; Dejeans, N.; Guédat, P.; Chevet, E. Control of the unfolded protein response in health and disease. SLAS Discov., 2017, 22(7), 787-800.
[http://dx.doi.org/10.1177/2472555217701685] [PMID: 28453376]
[93]
Rozpedek, W.; Pytel, D.; Mucha, B.; Leszczynska, H.; Diehl, J.A.; Majsterek, I. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med., 2016, 16(6), 533-544.
[http://dx.doi.org/10.2174/1566524016666160523143937] [PMID: 27211800]
[94]
Painter, J.D.; Galle-Treger, L.; Akbari, O. Role of autophagy in lung inflammation. Front. Immunol., 2020, 11, 1337.
[http://dx.doi.org/10.3389/fimmu.2020.01337] [PMID: 32733448]
[95]
Li, X.; He, S.; Ma, B. Autophagy and autophagy-related proteins in cancer. Mol. Cancer, 2020, 19(1), 12.
[http://dx.doi.org/10.1186/s12943-020-1138-4] [PMID: 31969156]
[96]
Deng, S.; Shanmugam, M.K.; Kumar, A.P.; Yap, C.T.; Sethi, G.; Bishayee, A. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer, 2019, 125(8), 1228-1246.
[http://dx.doi.org/10.1002/cncr.31978] [PMID: 30748003]
[97]
Wang, M.; Yu, H.; Wu, R.; Chen, Z.Y.; Hu, Q.; Zhang, Y.F.; Gao, S.H.; Zhou, G.B. Autophagy inhibition enhances the inhibitory-effects of ursolic acid on lung cancer cells. Int. J. Mol. Med., 2020, 46(5), 1816-1826.
[http://dx.doi.org/10.3892/ijmm.2020.4714] [PMID: 32901853]
[98]
Hasima, N.; Ozpolat, B. Regulation of autophagy by polyphenolic compounds as a potential therapeutic strategy for cancer. Cell Death Dis., 2014, 5(11)e1509
[http://dx.doi.org/10.1038/cddis.2014.467] [PMID: 25375374]
[99]
Saxton, R.A.; Sabatini, D.M. MTOR signaling in growth, metabolism, and disease. Cell, 2017, 168(6), 960-976.
[http://dx.doi.org/10.1016/j.cell.2017.02.004] [PMID: 28283069]
[100]
Cagnol, S.; Chambard, J.C. ERK and cell death: Mechanisms of ERK-induced cell death-apoptosis, autophagy and senescence. FEBS J., 2010, 277(1), 2-21.
[http://dx.doi.org/10.1111/j.1742-4658.2009.07366.x] [PMID: 19843174]
[101]
Tuli, H.S.; Sharma, A.K.; Sandhu, S.S.; Kashyap, D. Cordycepin: A bioactive metabolite with therapeutic potential. Life Sci., 2013, 93(23), 863-869.
[http://dx.doi.org/10.1016/j.lfs.2013.09.030] [PMID: 24121015]
[102]
Liu, K.; Guo, L.; Miao, L.; Bao, W.; Yang, J.; Li, X.; Xi, T.; Zhao, W. Ursolic acid inhibits epithelial–mesenchymal transition by suppressing the expression of astrocyte-elevated gene-1 in human nonsmall cell lung cancer A549 cells. Anticancer Drugs, 2013, 24(5), 494-503.
[http://dx.doi.org/10.1097/CAD.0b013e328360093b] [PMID: 23511428]
[103]
Song, L.; Li, W.; Zhang, H.; Liao, W.; Dai, T.; Yu, C.; Ding, X.; Zhang, L.; Li, J. Over-expression of AEG-1 significantly associates with tumour aggressiveness and poor prognosis in human non-small cell lung cancer. J. Pathol., 2009, 219(3), 317-326.
[http://dx.doi.org/10.1002/path.2595] [PMID: 19644957]
[104]
Huang, C.Y.; Lin, C.Y.; Tsai, C.W.; Yin, M.C. Inhibition of cell proliferation, invasion and migration by ursolic acid in human lung cancer cell lines. Toxicol. In Vitro, 2011, 25(7), 1274-1280.
[http://dx.doi.org/10.1016/j.tiv.2011.04.014] [PMID: 21539908]
[105]
Wang, C.M.; Tsai, S-J.; Jhan, Y-L.; Yeh, K-L.; Chou, C.H. Anti-proliferative activity of triterpenoids and sterols isolated from Alstonia scholaris against non-small-cell lung carcinoma cells. Molecules, 2017, 22(12), 2119.
[http://dx.doi.org/10.3390/molecules22122119] [PMID: 29194373]
[106]
Roskoski, R. Jr Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacol. Res., 2019, 139, 471-488.
[http://dx.doi.org/10.1016/j.phrs.2018.11.035] [PMID: 30508677]
[107]
Son, J.; Lee, S.Y. Therapeutic potential of ursonic acid: Comparison with ursolic acid. Biomolecules, 2020, 10(11), 1505.
[http://dx.doi.org/10.3390/biom10111505] [PMID: 33147723]
[108]
Crusz, S.M.; Balkwill, F.R. Inflammation and cancer: Advances and new agents. Nat. Rev. Clin. Oncol., 2015, 12(10), 584-596.
[http://dx.doi.org/10.1038/nrclinonc.2015.105] [PMID: 26122183]
[109]
Thun, M.J.; Henley, S.J.; Gansler, T. Inflammation and cancer: An epidemiological perspective. In: Novartis Foundation Symposium; Chadwick, Derek J.; Goode, Jamie A., Eds.; John Wiley & Sons: UK, 2004; 256, pp. 6-28.
[http://dx.doi.org/10.1002/0470856734.ch2]
[110]
Conlon, K.C.; Miljkovic, M.D.; Waldmann, T.A. Cytokines in the treatment of cancer. J. Interferon Cytokine Res., 2019, 39(1), 6-21.
[http://dx.doi.org/10.1089/jir.2018.0019] [PMID: 29889594]
[111]
Tuli, H.S.; Kashyap, D.; Sharma, A.K.; Sandhu, S.S. Molecular aspects of melatonin (MLT)-mediated therapeutic effects. Life Sci., 2015, 135, 147-157.
[http://dx.doi.org/10.1016/j.lfs.2015.06.004] [PMID: 26135621]
[112]
Takada, K.; Nakane, T.; Masuda, K.; Ishii, H. Ursolic acid and oleanolic acid, members of pentacyclic triterpenoid acids, suppress TNF-α-induced E-selectin expression by cultured umbilical vein endothelial cells. Phytomedicine, 2010, 17(14), 1114-1119.
[http://dx.doi.org/10.1016/j.phymed.2010.04.006] [PMID: 20579861]
[113]
Frezzetti, D.; Gallo, M.; Maiello, M.R.; D’Alessio, A.; Esposito, C.; Chicchinelli, N.; Normanno, N.; De Luca, A. VEGF as a potential target in lung cancer. Expert Opin. Ther. Targets, 2017, 21(10), 959-966.
[http://dx.doi.org/10.1080/14728222.2017.1371137] [PMID: 28831824]
[114]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[115]
Zhang, Q.; Li, Q.; Chen, Y.; Huang, X.; Yang, I.H.; Cao, L.; Wu, W.K.; Tan, H.M. Homocysteine-impaired angiogenesis is associated with VEGF/VEGFR inhibition. Front Biosci - Elit., 2012, 4(7), 2525-2535.
[http://dx.doi.org/10.2741/e563]
[116]
Lin, C.C.; Huang, C.Y.; Mong, M.C.; Chan, C.Y.; Yin, M.C. Antiangiogenic potential of three triterpenic acids in human liver cancer cells. J. Agric. Food Chem., 2011, 59(2), 755-762.
[http://dx.doi.org/10.1021/jf103904b] [PMID: 21175131]
[117]
Liu, G.; Friggeri, A.; Yang, Y.; Milosevic, J.; Ding, Q.; Thannickal, V.J.; Kaminski, N.; Abraham, E. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J. Exp. Med., 2010, 207(8), 1589-1597.
[http://dx.doi.org/10.1084/jem.20100035] [PMID: 20643828]
[118]
Luo, J.; Hu, S.; Wei, T.; Sun, J.; Liu, N.; Wang, J. TGF-beta 1 levels are associated with lymphocyte percentages in patients with lung cancer treated with radiation therapy. OncoTargets Ther., 2018, 11, 8349-8355.
[http://dx.doi.org/10.2147/OTT.S175956] [PMID: 30568457]
[119]
Sharabi, A.; Tsokos, M.G.; Ding, Y.; Malek, T.R.; Klatzmann, D.; Tsokos, G.C. Regulatory T cells in the treatment of disease. Nat. Rev. Drug Discov., 2018, 17(11), 823-844.
[http://dx.doi.org/10.1038/nrd.2018.148] [PMID: 30310234]
[120]
Yu, H.; Lee, H.; Herrmann, A.; Buettner, R.; Jove, R. Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat. Rev. Cancer, 2014, 14(11), 736-746.
[http://dx.doi.org/10.1038/nrc3818] [PMID: 25342631]
[121]
Zhang, N.; Liu, S.; Shi, S.; Chen, Y.; Xu, F.; Wei, X.; Xu, Y. Solubilization and delivery of Ursolic-acid for modulating tumor microenvironment and regulatory T cell activities in cancer immunotherapy. J. Control. Release, 2020, 320, 168-178.
[http://dx.doi.org/10.1016/j.jconrel.2020.01.015] [PMID: 31926193]
[122]
Bykov, V.J.N.; Eriksson, S.E.; Bianchi, J.; Wiman, K.G. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer, 2018, 18(2), 89-102.
[http://dx.doi.org/10.1038/nrc.2017.109] [PMID: 29242642]
[123]
Togawa, H.; Nakanishi, K.; Mukaiyama, H.; Hama, T.; Shima, Y.; Sako, M.; Miyajima, M.; Nozu, K.; Nishii, K.; Nagao, S.; Takahashi, H.; Iijima, K.; Yoshikawa, N. Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease. Am. J. Physiol. Renal Physiol., 2011, 300(2), F511-F520.
[http://dx.doi.org/10.1152/ajprenal.00038.2010] [PMID: 21084407]
[124]
Song, B.; Zhang, Q.; Yu, M.; Qi, X.; Wang, G.; Xiao, L.; Yi, Q.; Jin, W. Ursolic acid sensitizes radioresistant NSCLC cells expressing HIF-1α through reducing endogenous GSH and inhibiting HIF-1α. Oncol. Lett., 2017, 13(2), 754-762.
[http://dx.doi.org/10.3892/ol.2016.5468] [PMID: 28356955]
[125]
Samarakoon, S.R.; Ediriweera, M.K.; Wijayabandara, L.; Fernando, N.; Tharmarajah, L.; Tennekoon, K.H.; Piyathilaka, P.; Adhikari, A. Isolation of cytotoxic triterpenes from the mangrove plant, <i>Scyphiphora hydrophyllacea</i> C.F.Gaertn (Rubiaceae). Trop. J. Pharm. Res., 2018, 17(3), 475-481.
[http://dx.doi.org/10.4314/tjpr.v17i3.13]
[126]
Cheng, Q.L.; Li, H.L.; Huang, Z.Q.; Chen, Y.J.; Liu, T.S. 2β, 3β,23-trihydroxy-urs-12-ene-28-olic acid (TUA) isolated from Actinidia chinensis Radix inhibits NCI-H460 cell proliferation by decreasing NF-κB expression. Chem. Biol. Interact., 2015, 240, 1-11.
[http://dx.doi.org/10.1016/j.cbi.2015.06.038] [PMID: 26134000]
[127]
Xiang, L.; Chi, T.; Tang, Q.; Yang, X.; Ou, M.; Chen, X.; Yu, X.; Chen, J.; Ho, R.J.Y.; Shao, J.; Jia, L. A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis. Oncotarget, 2015, 6(11), 9295-9312.
[http://dx.doi.org/10.18632/oncotarget.3261] [PMID: 25823660]
[128]
Wang, J.; Jiang, Z.; Xiang, L.; Li, Y.; Ou, M.; Yang, X.; Shao, J.; Lu, Y.; Lin, L.; Chen, J.; Dai, Y.; Jia, L. Synergism of ursolic acid derivative US597 with 2-deoxy-D-glucose to preferentially induce tumor cell death by dual-targeting of apoptosis and glycolysis. Sci. Rep., 2015, 4(1), 5006.
[http://dx.doi.org/10.1038/srep05006] [PMID: 25833312]
[129]
Wang, X.; Zhang, F.; Yang, L.; Mei, Y.; Long, H.; Zhang, X.; Zhang, J. Qimuge-Suyila; Su, X. Ursolic acid inhibits proliferation and induces apoptosis of cancer cells in vitro and in vivo. J. Biomed. Biotechnol., 2011, 2011, 1-8.
[http://dx.doi.org/10.1155/2011/419343] [PMID: 21716649]
[130]
Chen, Q.; Luo, J.; Wu, C.; Lu, H.; Cai, S.; Bao, C.; Liu, D.; Kong, J. The miRNA1495p/MyD88 axis is responsible for ursolic acidmediated attenuation of the stemness and chemoresistance of nonsmall cell lung cancer cells. Environ. Toxicol., 2020, 35(5), 561-569.
[http://dx.doi.org/10.1002/tox.22891] [PMID: 31855318]
[131]
Cárdenas, C.; Quesada, A.R.; Medina, M.Á. Effects of ursolic acid on different steps of the angiogenic process. Biochem. Biophys. Res. Commun., 2004, 320(2), 402-408.
[http://dx.doi.org/10.1016/j.bbrc.2004.05.183] [PMID: 15219842]
[132]
Cheng, W.; Dahmani, F.Z.; Zhang, J.; Xiong, H.; Wu, Y.; Yin, L.; Zhou, J.; Yao, J. Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin. Nanotechnology, 2017, 28(7)075102
[http://dx.doi.org/10.1088/1361-6528/aa53c6] [PMID: 28091396]
[133]
Qian, Z.; Wang, X.; Song, Z.; Zhang, H.; Zhou, S.; Zhao, J.; Wang, H. A phase I trial to evaluate the multiple-dose safety and antitumor activity of ursolic acid liposomes in subjects with advanced solid tumors. BioMed Res. Int., 2015, 2015, 1-7.
[http://dx.doi.org/10.1155/2015/809714] [PMID: 25866811]
[134]
Srinivasan, R.; Aruna, A.; Lee, J.S.; Kim, M.; Shivakumar, M.S.; Natarajan, D. Antioxidant and antiproliferative potential of bioactive molecules ursolic acid and thujone isolated from Memecylon edule and Elaeagnus indica and their inhibitory effect on topoisomerase II by molecular docking approach. BioMed Res. Int., 2020, 2020, 1-12.
[http://dx.doi.org/10.1155/2020/8716927] [PMID: 32149143]
[135]
Feng, X.M.; Su, X.L. Anticancer effect of ursolic acid via mitochondria dependent pathways. (Review) Oncol. Lett., 2019, 17(6), 4761-4767.
[http://dx.doi.org/10.3892/ol.2019.10171] [PMID: 31186681]
[136]
Iqbal, J.; Abbasi, B.A.; Ahmad, R.; Mahmood, T.; Kanwal, S.; Ali, B.; Khalil, A.T.; Shah, S.A.; Alam, M.M.; Badshah, H. Ursolic acid a promising candidate in the therapeutics of breast cancer: Current status and future implications. Biomed. Pharmacother., 2018, 108, 752-756.
[http://dx.doi.org/10.1016/j.biopha.2018.09.096] [PMID: 30248543]

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