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Review Article

Ursolic acid: a pentacyclic triterpenoid that exhibits anticancer therapeutic potential by modulating multiple oncogenic targets

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Received 29 Aug 2022, Accepted 20 Dec 2022, Published online: 04 Jan 2023

References

  • Ahn, K. S., Sethi, G., Jain, A. K., Jaiswal, A. K., & Aggarwal, B. B. (2006). Genetic deletion of NAD (P) H: Quinone oxidoreductase 1 abrogates activation of nuclear factor-κB, IκBα kinase, c-Jun N-terminal kinase, Akt, p38, and p44/42 mitogen-activated protein kinases and potentiates apoptosis. The Journal of Biological Chemistry, 281(29), 19798–19808. https://doi.org/10.1074/jbc.M601162200
  • Andersson, D., Liu, J. J., Nilsson, A., & Duan, R. D. (2003). Ursolic acid inhibits proliferation and stimulates apoptosis in HT29 cells following activation of alkaline sphingomyelinase. Anticancer Research, 23(4), 3317–3322.
  • Antônio, E., Antunes, O. D. R. A., de Araújo, I. S., Khalil, N. M., & Mainardes, R. M. (2017). Poly (lactic acid) nanoparticles loaded with ursolic acid: Characterization and in vitro evaluation of radical scavenging activity and cytotoxicity. Materials Science and Engineering: C, 71, 156–166. https://doi.org/10.1016/j.msec.2016.09.080
  • Arshad Qamar, K., Dar, A., S Siddiqui, B., Kabir, N., Aslam, H., Ahmed, S., Erum, S., Habib, S., & Begum, S. (2010). Anticancer activity of Ocimum basilicum and the effect of ursolic acid on the cytoskeleton of MCF-7 human breast cancer cells. Letters in Drug Design & Discovery, 7(10), 726–736. https://doi.org/10.2174/1570180811007010726
  • Baishya, R., Nayak, D. K., Kumar, D., Sinha, S., Gupta, A., Ganguly, S., & Debnath, M. C. (2016). Ursolic acid loaded PLsGA nanoparticles: In vitro and in vivo evaluation to explore tumor targeting ability on B16F10 melanoma cell lines. Pharmaceutical Research, 33(11), 2691–2703. https://doi.org/10.1007/s11095-016-1994-1
  • Banudevi, S., Swaminathan, S., & Maheswari, K. U. (2015). Pleiotropic role of dietary phytochemicals in cancer: Emerging perspectives for combinational therapy. Nutrition and Cancer, 67(7), 1021–1048. https://doi.org/10.1080/01635581.2015.1073762
  • Boisgard, A. -S., Lamrayah, M., Dzikowski, M., Salmon, D., Kirilov, P., Primard, C., Pirot, F., Fromy, B., & Verrier, B. (2017). Innovative drug vehicle for local treatment of inflammatory skin diseases: Ex vivo and in vivo screening of five topical formulations containing poly (lactic acid)(pla) nanoparticles. European Journal of Pharmaceutics and Biopharmaceutics, 116, 51–60. https://doi.org/10.1016/j.ejpb.2016.09.021
  • Byrne, J. D., Betancourt, T., & Brannon-Peppas, L. (2008). Active targeting schemes for nanoparticle systems in cancer therapeutics. Advanced Drug Delivery Reviews, 60(15), 1615–1626. https://doi.org/10.1016/j.addr.2008.08.005
  • Cárdenas, C., Quesada, A. R., & Medina, M. A. (2004). Effects of ursolic acid on different steps of the angiogenic process. Biochemical and Biophysical Research Communications, 320(2), 402–408. https://doi.org/10.1016/j.bbrc.2004.05.183
  • Carkeet, C., Grann, K., Randolph, R. K., Venzon, D. S., & Izzy, S., (Eds.). (2012). Phytochemicals: Health promotion and therapeutic potential. CRC Press.
  • Chai, E. Z. P., Siveen, K. S., Shanmugam, M. K., Arfuso, F., & Sethi, G. (2015). Analysis of the intricate relationship between chronic inflammation and cancer. The Biochemical Journal, 468(1), 1–15. https://doi.org/10.1042/BJ20141337
  • Chen, Q., Luo, J., Wu, C., Lu, H., Cai, S., Bao, C., Liu, D., & Kong, J. (2020). The miRna-149-5p/MyD88 axis is responsible for ursolic acid-mediated attenuation of the stemness and chemoresistance of non-small cell lung cancer cells. Environmental Toxicology, 35(5), 561–569. https://doi.org/10.1002/tox.22891
  • Chen, C. -J., Shih, Y. -L., Yeh, M. -Y., Liao, N. -C., Chung, H. Y., Liu, K. -L., CHUNG, H. -Y., LEE, M. -H., CHOU, P. -Y., HOU, H. -Y., CHOU, J. -S., & Chung, J. G. (2019). 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, 33(2), 383–391. https://doi.org/10.21873/invivo.11485
  • Chen, C. F., Yang, J. S., Chen, W. K., Lu, C. C., Chiang, J. H., Chiu, H. Y., Tsai, S., Juan, Y., Huang, H., & Way, T. D. (2018). Ursolic acid elicits intrinsic apoptotic machinery by downregulating the phosphorylation of AKT/BAD signaling in human cisplatin‑resistant oral cancer CAR cells. Oncology Reports, 40(3), 1752–1760. https://doi.org/10.3892/or.2018.6530
  • Choudhury, B., Kandimalla, R., Elancheran, R., Bharali, R., & Kotoky, J. (2018). Garcinia Morella fruit, a promising source of antioxidant and anti-inflammatory agents induces breast cancer cell death via triggering apoptotic pathway. Biomedicine & Pharmacotherapy, 103, 562–573. https://doi.org/10.1016/j.biopha.2018.04.068
  • Dai, X., Zhang, J., Arfuso, F., Chinnathambi, A., Zayed, M. E., Alharbi, S. A., Kumar, A. P., Ahn, K. S., & Sethi, G. (2015). Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Experimental Biology and Medicine, 240(6), 760–773. https://doi.org/10.1177/1535370215579167
  • Dar, B. A., Lone, A. M., Shah, W. A., & Qurishi, M. A. (2016). Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents. European Journal of Medicinal Chemistry, 111, 26–32. https://doi.org/10.1016/j.ejmech.2016.01.026
  • De Angel, R. E., Smith, S. M., Glickman, R. D., Perkins, S. N., & Hursting, S. D. (2010). Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancer. Nutrition and Cancer, 62(8), 1074–1086. https://doi.org/10.1080/01635581.2010.492092
  • Deng, S., Shanmugam, M. K., Kumar, A. P., Yap, C. T., Sethi, G., & Bishayee, A. (2019). Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer, 125(8), 1228–1246. https://doi.org/10.1002/cncr.31978
  • 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. (2014). Antibacterial and antioxidant activities of ursolic acid and derivatives. Molecules (Basel, Switzerland), 19(1), 1317–1327. https://doi.org/10.3390/molecules19011317
  • 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. (2015). UP12, a novel ursolic acid derivative with potential for targeting multiple signaling pathways in hepatocellular carcinoma. Biochemical Pharmacology, 93(2), 151–162. https://doi.org/10.1016/j.bcp.2014.11.014
  • Es-Saady, D., Simon, A., Ollier, M., Maurizis, J. C., Chulia, A. J., & Delage, C. (1996). Inhibitory effect of ursolic acid on B16 proliferation through cell cycle arrest. Cancer Letters, 106(2), 193–197. https://doi.org/10.1016/0304-3835(96)04312-1
  • Fan, J. P., Liao, D. D., & Zhang, X. H. (2016). Ultrasonic assisted extraction of ursolic acid from apple pomace: A novel and facile technique. Separation Science and Technology, 51(8), 1344–1350. https://doi.org/10.1080/01496395.2016.1165253
  • Feng, X. M., & Su, X. L. (2019). Anticancer effect of ursolic acid via mitochondria‑dependent pathways (Review). Oncology Letters, 17(6), 4761–4767. https://doi.org/10.3892/ol.2019.10171
  • Gai, L., Cai, N., Wang, L., Xu, X., & Kong, X. (2013). Ursolic acid induces apoptosis via Akt/NF-κB signaling suppression in T24 human bladder cancer cells. Molecular Medicine Reports, 7(5), 1673–1677. https://doi.org/10.3892/mmr.2013.1364
  • Gai, W. T., Yu, D. P., Wang, X. S., & Wang, P. T. (2016). Anticancer effect of ursolic acid activates apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin1 in prostate cancer. Oncology Letters, 12(4), 2880–2885. https://doi.org/10.3892/ol.2016.5015
  • Gao, N., Cheng, S., Budhraja, A., Gao, Z., Chen, J., Liu, E. -H., Huang, C., Chen, D., Yang, Z., Liu, Q., Li, P., Shi, X., & Zhang, Z. (2012). Ursolic acid induces apoptosis in human leukaemia cells and exhibits anti-leukaemic activity in nude mice through the PKB pathway. British Journal of Pharmacology, 165(6), 1813–1826. https://doi.org/10.1111/j.1476-5381.2011.01684.x
  • Ghate, N. B., Chaudhuri, D., Das, A., Panja, S., & Mandal, N. (2015). An antioxidant extract of the insectivorous plant Drosera burmannii Vahl. alleviates iron-induced oxidative stress and hepatic injury in mice. PloS One, 10(5), e0128221. https://doi.org/10.1371/journal.pone.0128221
  • Guo, W., Xu, B., Wang, X., Zheng, B., Du, J., & Liu, S. (2020). The analysis of the anti-tumor mechanism of ursolic acid using connectively map approach in breast cancer cells line MCF-7. Cancer Management and Research, 12, 3469. https://doi.org/10.2147/CMAR.S241957
  • Harmand, P. O., Duval, R., Delage, C., & Simon, A. (2005). Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu melanoma cells. International Journal of Cancer, 114(1), 1–11. https://doi.org/10.1002/ijc.20588
  • Hill, R. A., & Connolly, J. D. (2013). Triterpenoids. Natural Product Reports, 30(7), 1028–1065. https://doi.org/10.1039/C3NP70032A
  • Huang, H. C., Huang, C. Y., Lin-shiau, S. Y., & Lin, J. K. (2009). Ursolic acid inhibits IL-1β or TNF-α-induced C6 glioma invasion through suppressing the association ZIP/p62 with PKC-ζ and downregulating the MMP-9 expression. Molecular Carcinogenesis: Published in Cooperation with the University of Texas MD Anderson Cancer Center, 48(6), 517–531. https://doi.org/10.1002/mc.20490
  • Hussain, H., Green, I. R., Ali, I., Khan, I. A., Ali, Z., Al-Sadi, A. M., & Ahmed, I. (2017). Ursolic acid derivatives for pharmaceutical use: A patent review (2012-2016). Expert Opinion on Therapeutic Patents, 27(9), 1061–1072. https://doi.org/10.1080/13543776.2017.1344219
  • Jäger, S., Trojan, H., Kopp, T., Laszczyk, M. N., & Scheffler, A. (2009). Pentacyclic triterpene distribution in various plants–rich sources for a new group of multi-potent plant extracts. Molecules, 14(6), 2016–2031. https://doi.org/10.3390/molecules14062016
  • Jain, S., Dwivedi, J., Jain, P. K., Satpathy, S., & Patra, A. (2016). Medicinal plants for treatment of cancer: A brief review. Pharmacognosy Journal, 8(2), 87–102. https://doi.org/10.5530/pj.2016.2.1
  • Jamal, M., Amir, M., Ali, Z., & Mujeeb, M. (2018). A comparative study for the extraction methods and solvent selection for isolation, quantitative estimation and validation of ursolic acid in the leaves of Lantana camara by HPTLC method. Future Journal of Pharmaceutical Sciences, 4(2), 229–233. https://doi.org/10.1016/j.fjps.2018.07.002
  • Jiang, K., Chi, T., Li, T., Zheng, G., Fan, L., Liu, Y., Chen, X., Chen, S., Jia, L., & Shao, J. (2017). 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, 9(27), 9428–9439. https://doi.org/10.1039/C7NR01677H
  • Jin, H., Pi, J., Yang, F., Jiang, J., Wang, X., Bai, H., Shao, M., Huang, L., Zhu, H., Yang, P., Li, L., Li, T., Cai, J., & Chen, Z. W. (2016). Folate-chitosan nanoparticles loaded with ursolic acid confer anti-breast cancer activities in vitro and in vivo. Scientific Reports, 6(1), 1–11. https://doi.org/10.1038/srep30782
  • Kaewthawee, N., & Brimson, S. (2013). The effects of ursolic acid on cytokine production via the MAPK pathways in leukemic T-cells. EXCLI Journal, 12, 102.
  • Kang, D. Y., Sp, N., Lee, J. M., & Jang, K. J. (2021). Antitumor effects of ursolic acid through mediating the inhibition of STAT3/PD-L1 signaling in non-small cell lung cancer cells. Biomedicines, 9(3), 297. https://doi.org/10.3390/biomedicines9030297
  • Kashyap, D., Tuli, H. S., Garg, V. K., Bhatnagar, S., & Sharma, A. K. (2018). Ursolic acid and quercetin: Promising anticancer phytochemicals with antimetastatic and antiangiogenic potential. Tumor and Microenvironment, 1(1), 9. https://doi.org/10.4103/tme.tme_3_17
  • Kashyap, D., Tuli, H. S., & Sharma, A. K. (2016). Ursolic acid (UA): A metabolite with promising therapeutic potential. Life sciences, 146, 201–213. https://doi.org/10.1016/j.lfs.2016.01.017
  • Kassi, E., Papoutsi, Z., Pratsinis, H., Aligiannis, N., Manoussakis, M., & Moutsatsou, P. (2007). Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells. Journal of Cancer Research and Clinical Oncology, 133(7), 493–500. https://doi.org/10.1007/s00432-007-0193-1
  • Kassi, E., Sourlingas, T. G., Spiliotaki, M., Papoutsi, Z., Pratsinis, H., Aligiannis, N., & Moutsatsou, P. (2009). Ursolic acid triggers apoptosis and Bcl-2 downregulation in MCF-7 breast cancer cells. Cancer Investigation, 27(7), 723–733. https://doi.org/10.1080/07357900802672712
  • Kim, G. H., Kan, S. Y., Kang, H., Lee, S., Ko, H. M., Kim, J. H., & Lim, J. H. (2019). Ursolic acid suppresses cholesterol biosynthesis and exerts anti-cancer effects in hepatocellular carcinoma cells. International Journal of Molecular Sciences, 20(19), 4767. https://doi.org/10.3390/ijms20194767
  • Kim, C., Lee, J. H., Kim, S. H., Sethi, G., & Ahn, K. S. (2015). Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model. Oncotarget, 6(6), 4020. https://doi.org/10.18632/oncotarget.3004
  • Kim, K. H., Seo, H. S., Choi, H. S., Choi, I., Shin, Y. C., & Ko, S. G. (2011). Induction of apoptotic cell death by ursolic acid through mitochondrial death pathway and extrinsic death receptor pathway in MDA-MB-231 cells. Archives of Pharmacal Research, 34(8), 1363–1372. https://doi.org/10.1007/s12272-011-0817-5
  • Kim, K., Shin, E. A., Jung, J. H., Park, J. E., Kim, D. S., Shim, B. S., & Kim, S. H. (2018). Ursolic acid induces apoptosis in colorectal cancer cells partially via upregulation of MicroRNA-4500 and inhibition of JAK2/STAT3 phosphorylation. International Journal of Molecular Sciences, 20(1), 114. https://doi.org/10.3390/ijms20010114
  • Koh, Y. C., Ho, C. T., & Pan, M. H. (2020). Recent advances in cancer chemoprevention with phytochemicals. Journal of Food and Drug Analysis, 28(1), 14–37. https://doi.org/10.1016/j.jfda.2019.11.001
  • Kowalczyk, M. C., Walaszek, Z., Kowalczyk, P., Kinjo, T., Hanausek, M., & Slaga, T. J. (2009). Differential effects of several phytochemicals and their derivatives on murine keratinocytes in vitro and in vivo: Implications for skin cancer prevention. Carcinogenesis, 30(6), 1008–1015. https://doi.org/10.1093/carcin/bgp069
  • Kreuter, J. (2007). Nanoparticles—a historical perspective. International Journal of Pharmaceutics, 331(1), 1–10. https://doi.org/10.1016/j.ijpharm.2006.10.021
  • Lee, K. C., Chen, Y. L., Lin, P. Y., & Chuang, W. L. (2018). Ursolic acid-induced apoptosis via regulation of the PI3K/Akt and MAPK signaling pathways in Huh-7 cells. Molecules, 23(8), 2016.
  • Lee, S. Y., Kim, Y. J., Chung, S. O., & Park, S. U. (2016). Recent studies on ursolic acid and its biological and pharmacological activity. EXCLI Journal, 15, 221.
  • Leng, S., Hao, Y., Du, D., Xie, S., Hong, L., Gu, H., Zhu, X., Zhang, J., Fan, D., & Kung, H. F. (2013). Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy. International Journal of Cancer, 133(12), 2781–2790. https://doi.org/10.1002/ijc.28301
  • Li, J., Guo, W. J., & Yang, Q. Y. (2002). Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World Journal of Gastroenterology, 8(3), 493. https://doi.org/10.3748/wjg.v8.i3.493
  • Li, L., Hou, Y., Yu, J., Lu, Y., Chang, L., Jiang, M., & Wu, X. (2017). Synergism of ursolic acid and cisplatin promotes apoptosis and enhances growth inhibition of cervical cancer cells via suppressing NF-κB p65. Oncotarget, 8(57), 97416–97427. https://doi.org/10.18632/oncotarget.22133
  • Limami, Y., Pinon, A., Leger, D. Y., Mousseau, Y., Cook-Moreau, J., Beneytout, J. -L., Delage, C., Liagre, B., & Simon, A. (2011). HT-29 colorectal cancer cells undergoing apoptosis overexpress COX-2 to delay ursolic acid-induced cell death. Biochimie, 93(4), 749–757. https://doi.org/10.1016/j.biochi.2011.01.003
  • Lin, J., Chen, Y., Wei, L., Hong, Z., Sferra, T. J., & Peng, J. (2013). Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways. International Journal of Oncology, 43(5), 1666–1674. https://doi.org/10.3892/ijo.2013.2101
  • Lin, C. -W., Chin, H. -K., Lee, S. -L., Chiu, C. -F., Chung, J. -G., Lin, Z. -Y., Wu, C. -Y., Liu, Y. -C., Hsiao, Y. -T., Feng, C. -H., Bai, L. -Y., & Weng, J. R. (2019). Ursolic acid induces apoptosis and autophagy in oral cancer cells. Environmental Toxicology, 34(9), 983–991. https://doi.org/10.1002/tox.22769
  • Lin, W., & Ye, H. (2020). Anticancer activity of ursolic acid on human ovarian cancer cells via ROS and MMP mediated apoptosis, cell cycle arrest and downregulation of PI3K/AKT pathway. Journal of the Balkan Union of Oncology, 25(2), 750–756.
  • Liu, J. (1995). Pharmacology of oleanolic acid and ursolic acid. Journal of Ethnopharmacology, 49(2), 57–68. https://doi.org/10.1016/0378-8741(95)90032-2
  • Liu, P., Du, R., & Yu, X. (2019). Ursolic acid exhibits potent anticancer effects in human metastatic melanoma cancer cells (SK-MEL-24) via apoptosis induction, inhibition of cell migration and invasion, cell cycle arrest, and inhibition of mitogen-activated protein kinase (MAPK)/ERK signaling pathway. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 25, 1283.
  • Liu, C., Ho, P. C. L., Wong, F. C., Sethi, G., Wang, L. Z., & Goh, B. C. (2015). Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects. Cancer letters, 362(1), 8–14. https://doi.org/10.1016/j.canlet.2015.03.019
  • Liu, T., Ma, H., Shi, W., Duan, J., Wang, Y., Zhang, C., Li, C., Lin, J., Li, S., Lv, J., & Lin, L. (2017). Inhibition of STAT3 signaling pathway by ursolic acid suppresses growth of hepatocellular carcinoma. International Journal of Oncology, 51(2), 555–562. https://doi.org/10.3892/ijo.2017.4035
  • Liu, B., Piao, X., Guo, L., Liu, S., Chai, F., & Gao, L. (2016). Ursolic acid protects against ulcerative colitis via anti-inflammatory and antioxidant effects in mice. Molecular Medicine Reports, 13(6), 4779–4785. https://doi.org/10.3892/mmr.2016.5094
  • Liu, J., Wan, J., & He, C. W. (2010). Rationale for the use of natural anti-inflammatory agents in cancer chemotherapy. North American Journal of Medicine & Science, 3(3), 160. https://doi.org/10.7156/v3i3p160
  • Liu, L., Wu, J., Zhang, J., Li, Z., Wang, C., Chen, M., Wang, Y., Sun, Y., Wang, L., & Luo, C. (2012). A compatibility assay of ursolic acid and foodborne microbial exopolysaccharides by antioxidant power and anti-proliferative properties in hepatocarcinoma cells. Journal of Food, Agriculture and Environment, 10, 111–114.
  • Li, G., Zhang, X., You, J., Song, C., Sun, Z., Xia, L., & Suo, Y. (2011). Highly sensitive and selective pre-column derivatization high-performance liquid chromatography approach for rapid determination of triterpenes oleanolic and ursolic acids and application to Swertia species: Optimization of triterpenic acids extraction and pre-column derivatization using response surface methodology. Analytica Chimica Acta, 688(2), 208–218. https://doi.org/10.1016/j.aca.2011.01.010
  • Li, Q., Zhao, W., Zeng, X., & Hao, Z. (2018). Ursolic acid attenuates atherosclerosis in ApoE−/− mice: Role of LOX-1 mediated by ROS/NF-κB pathway. Molecules, 23(5), 1101. https://doi.org/10.3390/molecules23051101
  • López-Hortas, L., Pérez-Larrán, P., González-Muñoz, M. J., Falqué, E., & Domínguez, H. (2018). Recent developments on the extraction and application of ursolic acid. A review. Food Research International, 103, 130–149. https://doi.org/10.1016/j.foodres.2017.10.028
  • Luo, J., Hu, Y. L., & Wang, H. (2017). Ursolic acid inhibits breast cancer growth by inhibiting proliferation, inducing autophagy and apoptosis, and suppressing inflammatory responses via the PI3K/AKT and NFκB signaling pathways in vitro. Experimental and Therapeutic Medicine, 14(4), 3623–3631. https://doi.org/10.3892/etm.2017.4965
  • Lu, J., Wu, D. -M., Zheng, Y. -L., Hu, B., Zhang, Z. -F., Ye, Q., Liu, C. -M., Shan, Q., & Wang, Y. J. (2010). Ursolic acid attenuates D-Galactose-Induced inflammatory response in mouse prefrontal cortex through inhibiting AGEs/RAGE/NF- B pathway activation. Cerebral Cortex, 20(11), 2540–2548. https://doi.org/10.1093/cercor/bhq002
  • Maeda, H. (2010). Nitroglycerin enhances vascular blood flow and drug delivery in hypoxic tumor tissues: Analogy between angina pectoris and solid tumors and enhancement of the EPR effect. Journal of Controlled Release, 142(3), 296–298. https://doi.org/10.1016/j.jconrel.2010.01.002
  • Manayi, A., Nikan, M., Nobakht-Haghighi, N., & Abdollahi, M. (2018). Advances in the anticancer value of the ursolic acid through nanodelivery. Current Medicinal Chemistry, 25(37), 4866–4875. https://doi.org/10.2174/0929867324666170713102918
  • Mandal, S., Gamit, N., Varier, L., Dharmarajan, A., & Warrier, S. (2021). Inhibition of breast cancer stem-like cells by a triterpenoid, ursolic acid, via activation of Wnt antagonist, sFRP4 and suppression of miRNA-499a-5p. Life Sciences, 265, 118854. https://doi.org/10.1016/j.lfs.2020.118854
  • Martin-Aragon, S., De Las Heras, B., Sanchez-Reus, M. I., & Benedi, J. (2001). Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride-induced liver damage in rats and primary cultures of rat hepatocytes. Experimental and Toxicologic Pathology, 53(2–3), 199–206. https://doi.org/10.1078/0940-2993-00185
  • Mendes, V. I., Bartholomeusz, G. A., Ayres, M., Gandhi, V., & Salvador, J. A. (2016). Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells. European Journal of Medicinal Chemistry, 123, 317–331. https://doi.org/10.1016/j.ejmech.2016.07.045
  • Meng, Y., Lin, Z. M., Ge, N., Zhang, D. L., Huang, J., & Kong, F. (2015). Ursolic acid induces apoptosis of prostate cancer cells via the PI3K/Akt/mTOR pathway. The American Journal of Chinese Medicine, 43(07), 1471–1486. https://doi.org/10.1142/S0192415X15500834
  • Messner, B., Zeller, I., Ploner, C., Frotschnig, S., Ringer, T., Steinacher-Nigisch, A., Ritsch, A., Laufer, G., Huck, C., & Bernhard, D. (2011). Ursolic acid causes DNA-damage, p53-mediated, mitochondria- and caspase-dependent human endothelial cell apoptosis, and accelerates atherosclerotic plaque formation in vivo. Atherosclerosis, 219(2), 402–408. https://doi.org/10.1016/j.atherosclerosis.2011.05.025
  • Mishra, T., Arya, R. K., Meena, S., Joshi, P., Pal, M., Meena, B., Rana, T. S., Datta, D., & Upreti, D. (2016). Isolation, characterization and anticancer potential of cytotoxic triterpenes from Betula utilis bark. PloS One, 11(7), e0159430. https://doi.org/10.1371/journal.pone.0159430
  • Nam, H., & Kim, M. M. (2013). Ursolic acid induces apoptosis of SW480 cells via p53 activation. Food and Chemical Toxicology, 62, 579–583. https://doi.org/10.1016/j.fct.2013.09.024
  • Navin, R., & Kim, S. M. (2016). Therapeutic interventions using ursolic acid for cancer treatment. Medicinal Chemistry, 6(05), 339–344. https://doi.org/10.4172/2161-0444.1000367
  • Numonov, S., Sharopov, F., Qureshi, M. N., Gaforzoda, L., Gulmurodov, I., Khalilov, Q., Setzer, W. N., Habasi, M., & Aisa, H. A. (2020). The ursolic acid-rich extract of Dracocephalum heterophyllum Benth. with potent antidiabetic and cytotoxic activities. Applied Sciences, 10(18), 6505. https://doi.org/10.3390/app10186505
  • Oprean, C., Zambori, C., Borcan, F., Soica, C., Zupko, I., Minorics, R., Bojin, F., Ambrus, R., Muntean, D., Danciu, C., Pinzaru, I. A., Dehelean, C., Paunescu, V., & Tanasie, G. (2016). Anti-proliferative and antibacterial in vitro evaluation of the polyurethane nanostructures incorporating pentacyclic triterpenes. Pharmaceutical Biology, 54(11), 2714–2722. https://doi.org/10.1080/13880209.2016.1180538
  • Padhye, S., Ahmad, A., Oswal, N., & Sarkar, F. H. (2009). Emerging role of Garcinol, the antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs. Journal of Hematology & Oncology, 2(1), 1–13. https://doi.org/10.1186/1756-8722-2-38
  • Pathak, A. K., Bhutani, M., Nair, A. S., Ahn, K. S., Chakraborty, A., Kadara, H., Guha, S., Sethi, G., & Aggarwal, B. B. (2007). Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Molecular Cancer Research, 5(9), 943–955. https://doi.org/10.1158/1541-7786.MCR-06-0348
  • Pemminati, S., Gopalakrishna, H. N., Rai, A., Shetty, S., Vinod, A., Pai, P. G., & Shenoy, A. K. (2011). Anxiolytic effect of chronic administration of ursolic acid in rats. Journal of Applied Pharmaceutical Sciences, 1(3), 68–71.
  • Pironi, A. M., de Araújo, P. R., Fernandes, M. A., Salgado, H. R. N., & Chorilli, M. (2018). Characteristics, biological properties and analytical methods of ursolic acid: A review. Critical Reviews in Analytical Chemistry, 48(1), 86–93. https://doi.org/10.1080/10408347.2017.1390425
  • Prasad, S., Yadav, V. R., Sung, B., Gupta, S. C., Tyagi, A. K., & Aggarwal, B. B. (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. https://doi.org/10.18632/oncotarget.7537
  • 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. (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. Journal of the American Association for Cancer Research, 18(18), 4942–4953. https://doi.org/10.1158/1078-0432.CCR-11-2805
  • Prasannan, R., Kalesh, K. A., Shanmugam, M. K., Nachiyappan, A., Ramachandran, L., Nguyen, A. H., Kumar, A. P., Lakshmanan, M., Ahn, K. S., & Sethi, G. (2012). Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer. Biochemical Pharmacology, 84(10), 1268–1276. https://doi.org/10.1016/j.bcp.2012.07.015
  • Rai, S. N., Zahra, W., Singh, S. S., Birla, H., Keswani, C., Dilnashin, H., Singh, S. S., Rathore, A. S., Singh, R., Singh, R. K., & Singh, S. P. (2019). Anti-inflammatory activity of ursolic acid in MPTP-induced parkinsonian mouse model. Neurotoxicity Research, 36(3), 452–462. https://doi.org/10.1007/s12640-019-00038-6
  • Ramachandran, L., Manu, K. A., Shanmugam, M. K., Li, F., Siveen, K. S., Vali, S., Kapoor, S., Abbasi, T., Surana, R., Smoot, D. T., Ashktorab, H., Tan, P., Ahn, K. S., Yap, C. W., Kumar, A. P., & Sethi, G. (2012). Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer. The Journal of Biological Chemistry, 287(45), 38028–38040. https://doi.org/10.1074/jbc.M112.388702
  • Roy, A., Ahuja, S., & Bharadvaja, N. (2017). A review on medicinal plants against cancer. Journal of Plant Sciences and Agricultural Research, 2(1), 008.
  • Samivel, R., Nagarajan, R. P., Subramanian, U., Khan, A. A., Masmali, A., Almubrad, T., & Akhtar, S. (2020). Inhibitory effect of ursolic acid on ultraviolet B radiation-induced oxidative stress and proinflammatory response-mediated senescence in human skin dermal fibroblasts. Oxidative Medicine and Cellular Longevity, 2020, 1–17. https://doi.org/10.1155/2020/1246510
  • Samsonowicz, M., Kalinowska, M., & Gryko, K. (2021). Enhanced antioxidant activity of ursolic acid by complexation with copper (II): Experimental and theoretical study. Materials, 14(2), 264. https://doi.org/10.3390/ma14020264
  • Saraswati, S., Agrawal, S. S., & Alhaider, A. A. (2013). Ursolic acid inhibits tumor angiogenesis and induces apoptosis through mitochondrial-dependent pathway in Ehrlich ascites carcinoma tumor. Chemico-Biological Interactions, 206(2), 153–165. https://doi.org/10.1016/j.cbi.2013.09.004
  • Sawhney, M., Rohatgi, N., Kaur, J., Shishodia, S., Sethi, G., Gupta, S. D., Deo, S. V. S., Shukla, N. K., Aggarwal, B. B., & Ralhan, R. (2007). Expression of NF-κB parallels COX-2 expression in oral precancer and cancer: Association with smokeless tobacco. International Journal of Cancer, 120(12), 2545–2556. https://doi.org/10.1002/ijc.22657
  • Scherrer, E. C., Valadares, Y. M., Alves, C. C. S., Ferreira, G. F., Leão, M. P., Soares, J. A., Silva, F. S., Carli, A. P., Cardoso, O., Machado, F. S., & Castro, S. B. R. (2019). Ursolic acid derivatives induced apoptosis and reduces the NF-κB in human lung adenocarcinoma cells. Journal of Cancer Therapy, 10(10), 863–876. https://doi.org/10.4236/jct.2019.1010073
  • Seo, D. Y., Lee, S. R., Heo, J. -W., No, M. -H., Rhee, B. D., Ko, K. S., Kwak, H. -B., & Han, J. (2018). Ursolic acid in health and disease. The Korean Journal of Physiology & Pharmacology, 22(3), 235. https://doi.org/10.4196/kjpp.2018.22.3.235
  • Sethi, G., Ahn, K. S., Sung, B., & Aggarwal, B. B. (2008). Pinitol targets nuclear factor-κB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis. Molecular Cancer Therapeutics, 7(6), 1604–1614. https://doi.org/10.1158/1535-7163.MCT-07-2424
  • Sethi, G., Sung, B., Kunnumakkara, A. B., & Aggarwal, B. B. (2009). Targeting TNF for treatment of cancer and autoimmunity. Therapeutic Targets of the TNF Superfamily 647 , 37–51.
  • Shaikh, R., Pund, M., Dawane, A., & Iliyas, S. (2014). Evaluation of anticancer, antioxidant, and possible anti-inflammatory properties of selected medicinal plants used in Indian traditional medication. Journal of Traditional and Complementary Medicine, 4(4), 253–257. https://doi.org/10.4103/2225-4110.128904
  • Shanmugam, M. K., Dai, X., Kumar, A. P., Tan, B. K., Sethi, G., & Bishayee, A. (2013). Ursolic acid in cancer prevention and treatment: Molecular targets, pharmacokinetics and clinical studies. Biochemical Pharmacology, 85(11), 1579–1587. https://doi.org/10.1016/j.bcp.2013.03.006
  • Shanmugam, M. K., Manu, K. A., Ong, T. H., Ramachandran, L., Surana, R., Bist, P., Lim, L. H., Kumar, A. P., Hui, K. M., & Sethi, G. (2011). Inhibition of CXCR4/CXCL12 signaling axis by ursolic acid leads to suppression of metastasis in transgenic adenocarcinoma of mouse prostate model. International Journal of Cancer, 129(7), 1552–1563. https://doi.org/10.1002/ijc.26120
  • Shao, J. W., Dai, Y. C., Xue, J. P., Wang, J. C., Lin, F. P., & Guo, Y. H. (2011). In vitro and in vivo anticancer activity evaluation of ursolic acid derivatives. European Journal of Medicinal Chemistry, 46(7), 2652–2661. https://doi.org/10.1016/j.ejmech.2011.03.050
  • Shibue, T., Takeda, K., Oda, E., Tanaka, H., Murasawa, H., Takaoka, A., Tanaka, H., Morishita, Y., Akira, S., Taniguchi, T., & Tanaka, N. (2003). Integral role of Noxa in p53-mediated apoptotic response. Genes & Development, 17(18), 2233–2238. https://doi.org/10.1101/gad.1103603
  • Shin, E. M., Hay, H. S., Lee, M. H., Goh, J. N., Tan, T. Z., Sen, Y. P., Lim, S. W., Yousef, E. M., Ong, H. T., Thike, A. A., Kong, X., Wu, Z., Mendoz, E., Sun, W., Salto-Tellez, M., Lim, C. T., Lobie, P. E., Lim, Y. P., Yap, C. T. … Tergaonkar, V. (2014). DEAD-box helicase DP103 defines metastatic potential of human breast cancers. The Journal of Clinical Investigation, 124(9), 3807–3824. https://doi.org/10.1172/JCI73451
  • Shishodia, S., Majumdar, S., Banerjee, S., & Aggarwal, B. B. (2003). Ursolic acid inhibits nuclear factor-κB activation induced by carcinogenic agents through suppression of IκBα kinase and p65 phosphorylation: Correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Research, 63(15), 4375–4383.
  • Shyu, M. H., Kao, T. C., & Yen, G. C. (2010). Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP. Journal of Agricultural and Food Chemistry, 58(10), 6110–6118. https://doi.org/10.1021/jf100574j
  • Sohn, K. H., Lee, H. Y., Chung, H. Y., Young, H. S., Yi, S. Y., & Kim, K. W. (1995). Anti-angiogenic activity of triterpene acids. Cancer Letters, 94(2), 213–218. https://doi.org/10.1016/0304-3835(95)03856-r
  • Sohn, E. J., Won, G., Lee, J., Yoon, S. W., Lee, I., Kim, H. J., & Kim, S. H. (2016). Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell. International Journal of Biological Sciences, 12(11), 1279. https://doi.org/10.7150/ijbs.13453
  • Subbaramaiah, K., Michaluart, P., Sporn, M. B., & Dannenberg, A. J. (2000). Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Research, 60(9), 2399–2404.
  • Szakiel, A., Pączkowski, C., Pensec, F., & Bertsch, C. (2012). Fruit cuticular waxes as a source of biologically active triterpenoids. Phytochemistry Reviews, 11(2), 263–284. https://doi.org/10.1007/s11101-012-9241-9
  • Talekar, M., Kendall, J., Denny, W., & Garg, S. (2011). Targeting of nanoparticles in cancer: Drug delivery and diagnostics. Anti-Cancer Drugs, 22(10), 949–962. https://doi.org/10.1097/CAD.0b013e32834a4554
  • Tang, X., Gao, J., Chen, J., Fang, F., Wang, Y., Dou, H., Xu, Q., & Qian, Z. (2005). Inhibition by [corrected] ursolic acid of [corrected] calcium-induced mitochondrial permeability transition and release of two proapoptotic proteins. Biochemical and Biophysical Research Communications, 337(1), 320–324. https://doi.org/10.1016/j.bbrc.2005.09.062
  • Tang, Q., Liu, Y., Li, T., Yang, X., Zheng, G., Chen, H., Jia, L., & Shao, J. (2016). A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: Multiple targets for cancer metastasis prevention and treatment. Oncotarget, 7(45), 73114. https://doi.org/10.18632/oncotarget.12232
  • Tewari, D., Nabavi, S. F., Nabavi, S. M., Sureda, A., Farooqi, A. A., Atanasov, A. G., Vacca, R. A., Sethi, G., & Bishayee, A. (2018). Targeting activator protein 1 signaling pathway by bioactive natural agents: Possible therapeutic strategy for cancer prevention and intervention. Pharmacological Research, 128, 366–375. https://doi.org/10.1016/j.phrs.2017.09.014
  • Tsai, S. J., & Yin, M. C. (2008). Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. Journal of Food Science, 73(7), H174–178. https://doi.org/10.1111/j.1750-3841.2008.00864.x
  • Tuhy, H. -Y., Huang, A. -M., Wei, B. -L., Gan, K. -H., Hour, T. -C., Yang, S. -C., Pu, Y. -S., & Lin, C. -N. (2009). Ursolic acid derivatives induce cell cycle arrest and apoptosis in NTUB1 cells associated with reactive oxygen species. Bioorganic & Medicinal Chemistry, 17(20), 7265–7274. https://doi.org/10.1016/j.bmc.2009.08.046
  • Wang, J., Liu, L., Qiu, H., Zhang, X., Guo, W., Chen, W., Fu, L., Shi, D., Cheng, J., Huang, W., Deng, W., & Tian, Y. (2013). Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells. PloS One, 8(5), e63872. https://doi.org/10.1371/journal.pone.0063872
  • Wang, J. S., Ren, T. N., & Xi, T. (2012). Ursolic acid induces apoptosis by suppressing the expression of FoxM1 in MCF-7 human breast cancer cells. Medical Oncology, 29(1), 10–15. https://doi.org/10.1007/s12032-010-9777-8
  • Wang, H., Sim, M. K., Loke, W. K., Chinnathambi, A., Alharbi, S. A., Tang, F. R., & Sethi, G. (2017). Potential protective effects of ursolic acid against gamma irradiation-induced damage are mediated through the modulation of diverse inflammatory mediators. Frontiers in Pharmacology, 8, 352. https://doi.org/10.3389/fphar.2017.00352
  • Wang, X., Wang, Y., Chen, Z. G., & Shin, D. M. (2009). Advances of cancer therapy by nanotechnology. Cancer Research and Treatment, 41(1), 1–11. https://doi.org/10.4143/crt.2009.41.1.1
  • Wang, X., Zhang, F., Yang, L., Mei, Y., Long, H., Zhang, X., Zhang, J., & Su, X. (2011). Ursolic acid inhibits proliferation and induces apoptosis of cancer cells in vitro and in vivo. Journal of Biomedicine & Biotechnology, 2011, 1–8. https://doi.org/10.1155/2011/419343
  • Wei, Z. Y., Chi, K. Q., Wang, K. S., Wu, J., Liu, L. P., & Piao, H. R. (2018). Design, synthesis, evaluation, and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents. Bioorganic & Medicinal Chemistry Letters, 28(10), 1797–1803. https://doi.org/10.1016/j.bmcl.2018.04.021
  • Weng, H., Tan, Z. -J., Hu, Y. -P., Shu, Y. -J., Bao, R. -F., Jiang, L., Wu, X. -S., Li, M. -L., Ding, Q., Wang, X. -A., Xiang, S. -S., Li, H. -F., Cao, Y., Tao, F., & Liu, Y. B. (2014). Ursolic acid induces cell cycle arrest and apoptosis of gallbladder carcinoma cells. Cancer cell international, 14(1), 1–10. https://doi.org/10.1186/s12935-014-0096-6
  • Woo, C. C., Hsu, A., Kumar, A. P., Sethi, G., & Tan, K. H. B. (2013). Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: The role of p38 MAPK and ROS. PloS One, 8(10), e75356. https://doi.org/10.1371/journal.pone.0075356
  • Woźniak, Ł., Skąpska, S., & Marszałek, K. (2015). Ursolic acid—a pentacyclic triterpenoid with a wide spectrum of pharmacological activities. Molecules, 20(11), 20614–20641. https://doi.org/10.3390/molecules201119721
  • Wu, C. C., Huang, Y. F., Hsieh, C. P., Chueh, P. J., & Chen, Y. L. (2016). Combined use of zoledronic acid augments ursolic acid-induced apoptosis in human osteosarcoma cells through enhanced oxidative stress and autophagy. Molecules, 21(12), 1640. https://doi.org/10.3390/molecules21121640
  • Wu, B., Wang, X., Chi, Z. F., Hu, R., Zhang, R., Yang, W., & Liu, Z. G. (2012). Ursolic acid-induced apoptosis in K562 cells involving upregulation of PTEN gene expression and inactivation of the PI3K/Akt pathway. Archives of Pharmacal Research, 35(3), 543–548. https://doi.org/10.1007/s12272-012-0318-1
  • Wu, P. -P., Zhang, B. J., Cui, X. -P., Yang, Y., Jiang, Z. -Y., Zhou, Z. -H., Zhang, B. -J., Zhong, Y. -Y., Mai, Y. -Y., Ouyang, Z., Chen, H. -S., Zheng, J., Zhao, S. -Q., & Zhang, K. (2017). Synthesis and biological evaluation of novel ursolic acid analogues as potential α-glucosidase inhibitors. Scientific Reports, 7(1), 1–12. https://doi.org/10.1038/srep45578
  • Xiang, F., Fan, Y., Ni, Z., Liu, Q., Zhu, Z., Chen, Z., Hao, W., Yue, H., Wu, R., & Kang, X. (2019). Ursolic acid reverses the chemoresistance of breast cancer cells to paclitaxel by targeting MiRNA-149-5p/myd88. Frontiers in Oncology, 9, 501. https://doi.org/10.3389/fonc.2019.00501
  • Xiang, F., Pan, C., Kong, Q., Wu, R., Jiang, J., Zhan, Y., Xu, J., Gu, X., & Kang, X. (2015). Ursolic acid inhibits the proliferation of gastric cancer cells by targeting miR-133a. Oncology Research, 22(5), 267. https://doi.org/10.3727/096504015X14410238486685
  • Xiulian, R., Chunshan, Z., Qifeng, W., Jianbo, X., Qifu, L., & Xiaosheng, T. (2004). Study on the separation and purification of ursolic acid from Ilex kudingcha. Zhongguo yao xue za zhi (Zhongguo yao xue huiin: 1989), 39(8), 571–574.
  • Xu, H., Zhou, Z., Dong, J., & Lei, M. (2018). Suppression of cervical cancer cell survival by ursolic acid extracted from Catalpa bungei leaves. Pharmacognosy Magazine, 14(56), 425. https://doi.org/10.4103/pm.pm_408_17
  • Xu, X., Zhu, G. -Q., Zhang, K., Zhou, Y. -C., Li, X. -L., Xu, W., Zhang, H., Shao, Y., Zhang, Z. -Y., & Sun, W. H. (2017). Cyclooxygenase-2 mediated synergistic effect of ursolic acid in combination with paclitaxel against human gastric carcinoma. Oncotarget, 8(54), 92770. https://doi.org/10.18632/oncotarget.21576
  • 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. (2019). Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non-small-cell lung carcinoma harbouring EGFR T790M mutations. British Journal of Pharmacology, 176(24), 4609–4624. https://doi.org/10.1111/bph.14793
  • Yan, X., & Xu, B. (2020). Ursolic acid induces apoptosis of lung cancer cells by regulating miR-21/KLF6 axis. International Journal of Clinical and Experimental Medicine, 13(9), 6306–6315.
  • Yeh, C. T., Wu, C. H., & Yen, G. C. (2010). Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Molecular Nutrition & Food Research, 54(9), 1285–1295. https://doi.org/10.1002/mnfr.200900414
  • Yim, E. K., Lee, M. J., Lee, K. H., Um, S. J., & Park, J. S. (2006). Antiproliferative and antiviral mechanisms of ursolic acid and dexamethasone in cervical carcinoma cell lines. International Journal of Gynecologic Cancer, 16(6), 2023–2031. https://doi.org/10.1111/j.1525-1438.2006.00726.x
  • Yin, R., Li, T., Tian, J. X., Xi, P., & Liu, R. H. (2018). Ursolic acid, a potential anticancer compound for breast cancer therapy. Critical Reviews in Food Science and Nutrition, 58(4), 568–574. https://doi.org/10.1080/10408398.2016.1203755
  • Yoon, Y., Lim, J. W., Kim, J., Kim, Y., & Chun, K. H. (2016). Discovery of ursolic acid prodrug (NX-201): Pharmacokinetics and in vivo antitumor effects in PANC-1 pancreatic cancer. Bioorganic & Medicinal Chemistry Letters, 26(22), 5524–5527. https://doi.org/10.1016/j.bmcl.2016.10.008
  • Yu, D., Kan, Z., Shan, F., Zang, J., & Zhou, J. (2020). Triple strategies to improve oral bioavailability by fabricating coamorphous forms of ursolic acid with piperine: Enhancing water-solubility, permeability, and inhibiting cytochrome p450 isozymes. Molecular Pharmaceutics, 17(12), 4443–4462. https://doi.org/10.1021/acs.molpharmaceut.0c00443
  • Zacchigna, M., Cateni, F., Drioli, S., Procida, G., & Altieri, T. (2014). Peg–ursolic acid conjugate: Synthesis and in vitro release studies. Scientia Pharmaceutica, 82(2), 411–422. https://doi.org/10.3797/scipharm.1309-17
  • Zhang, J., Ahn, K. S., Kim, C., Shanmugam, M. K., Siveen, K. S., Arfuso, F., Samym, R. P., Deivasigamanim, A., Lim, L. H. K., Wang, L., Goh, B. C., Kumar, A. P., Hui, K. M., & Sethi, G. (2016). Nimbolide-induced oxidative stress abrogates STAT3 signaling cascade and inhibits tumor growth in transgenic adenocarcinoma of mouse prostate model. Antioxidants & Redox Signaling, 24(11), 575–589. https://doi.org/10.1089/ars.2015.6418
  • Zhang, L., Cai, Q. Y., Liu, J., Peng, J., Chen, Y. Q., Sferra, T. J., & Lin, J. M. (2019). Ursolic acid suppresses the invasive potential of colorectal cancer cells by regulating the TGFβ1/ZEB1/miR200c signalings pathway. Oncology Letters, 18(3), 3274–3282. https://doi.org/10.3892/ol.2019.10604
  • Zhang, Y., Huang, L., Shi, H., Chen, H., Tao, J., Shen, R., & Wang, T. (2018). Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance. Cancer Science, 109(1), 94–102. https://doi.org/10.1111/cas.13425
  • Zhang, X., Li, T., Gong, E. S., & Liu, R. H. (2020). Antiproliferative activity of ursolic acid in MDA-MB-231 human breast cancer cells through Nrf2 pathway regulation. Journal of Agricultural and Food Chemistry, 68(28), 7404–7415. https://doi.org/10.1021/acs.jafc.0c03202

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