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Mini-Reviews in Medicinal Chemistry

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ISSN (Online): 1875-5607

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Review Article

Role of Pentacyclic Triterpenoid Acids in the Treatment of Bladder Cancer

Author(s): Anindita Ghosh and Chinmay Kumar Panda*

Volume 22, Issue 9, 2022

Published on: 13 January, 2022

Page: [1331 - 1340] Pages: 10

DOI: 10.2174/1389557521666211022145052

Price: $65

Abstract

Bladder cancer carries a poor prognosis and has proven resistance to chemotherapy. Pentacyclic Triterpenoid Acids (PTAs) are natural bioactive compounds that have a well-known impact on cancer research because of their cytotoxic and chemopreventive activities. This review focuses on bladder cancer which can no longer be successfully treated by DNA damaging drugs. Unlike most of the existing drugs against bladder cancer, PTAs are non-toxic to normal cells. Collecting findings from both in vitro and in vivo studies, it has been concluded that PTAs may serve as promising agents in future bladder cancer therapy. In this review, the roles of various PTAs in bladder cancer have been explored, and their mechanisms of action in the treatment of bladder cancer have been described. Specific PTAs have been shortlisted from each of the chief skeletons of pentacyclic triterpenoids, which could be effective against bladder cancer because of their mode of action. This review thereby throws light on the multi targets and mechanisms of PTAs, which are responsible for their selective anticancer effects and provides guidelines for further research and development of new natural antitumor compounds.

Keywords: Pentacyclic triterpenoid acids, bladder cancer, chemotherapy, immunotherapy, natural bioactive compounds, specific proteins, apoptosis.

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[1]
Metts, M.C.; Metts, J.C.; Milito, S.J.; Thomas, C.R. Jr Bladder cancer: A review of diagnosis and management. J. Natl. Med. Assoc., 2000, 92(6), 285-294.
[PMID: 10918764]
[2]
Wu, Q.; Wong, J.P.C.; Kwok, H.F. Putting the brakes on tumorigenesis with natural products of plant origin: Insights into the molecular mechanisms of actions and immune targets for bladder cancer treatment. Cells, 2020, 9(5), 1213-1232.
[http://dx.doi.org/10.3390/cells9051213] [PMID: 32414171]
[3]
Prakash, G.; Pal, M.; Odaiyappan, K.; Shinde, R.; Mishra, J.; Jalde, D.; Rajkumar, B.; Prabhash, K.; Joshi, A.; Noronha, V.; Murthy, V.; Krishnatry, R.; Desai, S.; Menon, S.; Sable, N.; Popat, P.; Rangarajan, V.; Agrawal, A.; Bakshi, G. Bladder cancer demographics and outcome data from 2013 at a tertiary cancer hospital in India. Indian J. Cancer, 2019, 56(1), 54-58.
[http://dx.doi.org/10.4103/ijc.IJC_351_18] [PMID: 30950446]
[4]
Antoni, S.; Ferlay, J.; Soerjomataram, I.; Znaor, A.; Jemal, A.; Bray, F. Bladder cancer incidence and mortality: A global overview and recent trends. Eur. Urol., 2017, 71(1), 96-108.
[http://dx.doi.org/10.1016/j.eururo.2016.06.010] [PMID: 27370177]
[5]
Lynch, C.F.; Cohen, M.B. Urinary system. Cancer, 1995, 75(1)(Suppl.), 316-329.
[http://dx.doi.org/10.1002/1097-0142(19950101)75:1+<316:AID-CNCR2820751314>3.0.CO;2-T] [PMID: 8001003]
[6]
Zi, X.; Simoneau, A.R. Flavokawain A, a novel chalcone from kava extract, induces apoptosis in bladder cancer cells by involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice. Cancer Res., 2005, 65(8), 3479-3486.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3803] [PMID: 15833884]
[7]
Cheung, G.; Sahai, A.; Billia, M.; Dasgupta, P.; Khan, M.S. Recent advances in the diagnosis and treatment of bladder cancer. BMC Med., 2013, 11(1), 13-20.
[http://dx.doi.org/10.1186/1741-7015-11-13] [PMID: 23327481]
[8]
Chang, J.S.; Lara, P.N., Jr; Pan, C.X. Progress in personalizing chemotherapy for bladder cancer. Adv. Urol., 2012, 2012, 364919.
[http://dx.doi.org/10.1155/2012/364919] [PMID: 22400017]
[9]
Steffensen, K.D.; Waldstrøm, M.; Jakobsen, A. The relationship of platinum resistance and ERCC1 protein expression in epithelial ovarian cancer. Int. J. Gynecol. Cancer, 2009, 19(5), 820-825.
[http://dx.doi.org/10.1111/IGC.0b013e3181a12e09] [PMID: 19574766]
[10]
Dash, A.; Galsky, M.D.; Vickers, A.J.; Serio, A.M.; Koppie, T.M.; Dalbagni, G.; Bochner, B.H. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer, 2006, 107(3), 506-513.
[http://dx.doi.org/10.1002/cncr.22031] [PMID: 16773629]
[11]
Nakano, Y.; Tanno, S.; Koizumi, K.; Nishikawa, T.; Nakamura, K.; Minoguchi, M.; Izawa, T.; Mizukami, Y.; Okumura, T.; Kohgo, Y. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br. J. Cancer, 2007, 96(3), 457-463.
[http://dx.doi.org/10.1038/sj.bjc.6603559] [PMID: 17224927]
[12]
Raghavan, D. Pre-emptive (neo-adjuvant) intravenous chemotherapy for invasive bladder cancer. Br. J. Urol., 1988, 61(1), 1-8.
[http://dx.doi.org/10.1111/j.1464-410X.1988.tb09152.x] [PMID: 3277688]
[13]
Motterle, G; Karnes, RJ Timing of treatment for muscle-invasive bladder cancer in the neo-adjuvant chemotherapy era. 2020, 5
[http://dx.doi.org/10.21037/amj.2020.03.07]
[14]
Raghavan, D. Chemotherapy for invasive bladder cancer: Five simple rules learned over 30 years. Bladder Cancer, 2015, 1(1), 3-13.
[http://dx.doi.org/10.3233/BLC-150010] [PMID: 30561439]
[15]
Al-Gallab, M.I.; Naddaf, L.A.; Kanan, M.R. The management of non-invasive bladder tumours with Doxorubicin intravesical instillation after transurethral resection. Sultan Qaboos Univ. Med. J., 2009, 9(1), 53-58.
[PMID: 21509275]
[16]
Finnbladder, N.B. de TratamientoOncologico CU, EORTC Genito-Urinary Group, Australian Bladder Cancer Study Group, National Cancer Institute of Canada Clinical Trials Group. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. Lancet, 1999, 354(9178), 533-540.
[http://dx.doi.org/10.1016/S0140-6736(99)02292-8] [PMID: 10470696]
[17]
Sarkis, A.S.; Bajorin, D.F.; Reuter, V.E.; Herr, H.W.; Netto, G.; Zhang, Z.F.; Schultz, P.K.; Cordon-Cardo, C.; Scher, H.I. Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J. Clin. Oncol., 1995, 13(6), 1384-1390.
[http://dx.doi.org/10.1200/JCO.1995.13.6.1384] [PMID: 7751883]
[18]
Peng, M.; Deng, J.; Zhou, S.; Xiao, D.; Long, J.; Zhang, N.; He, C.; Mo, M.; Yang, X. Dual inhibition of pirarubicin-induced AKT and ERK activations by phenformin sensitively suppresses bladder cancer growth. Front. Pharmacol., 2019, 10, 1159-1173.
[http://dx.doi.org/10.3389/fphar.2019.01159] [PMID: 31649535]
[19]
Gordon, S.R.; Maute, R.L.; Dulken, B.W.; Hutter, G.; George, B.M.; McCracken, M.N.; Gupta, R.; Tsai, J.M.; Sinha, R.; Corey, D.; Ring, A.M.; Connolly, A.J.; Weissman, I.L. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature, 2017, 545(7655), 495-499.
[http://dx.doi.org/10.1038/nature22396] [PMID: 28514441]
[20]
Han, J.; Gu, X.; Li, Y.; Wu, Q. Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect. Biomed. Pharmacother., 2020, 129, 110393-110398.
[http://dx.doi.org/10.1016/j.biopha.2020.110393] [PMID: 32559616]
[21]
Wang, Y.; Chen, L.; Yu, M.; Fang, Y.; Qian, K.; Wang, G.; Ju, L.; Xiao, Y.; Wang, X. Immune-related signature predicts the prognosis and immunotherapy benefit in bladder cancer. Cancer Med., 2020, 9(20), 7729-7741.
[http://dx.doi.org/10.1002/cam4.3400] [PMID: 32841548]
[22]
Gupta, S.; Kamat, A.M. NICE’s rejection of pembrolizumab for platinum-refractory urothelial carcinoma: Is there a greater good? Nat. Rev. Urol., 2020, 17(9), 491-492.
[http://dx.doi.org/10.1038/s41585-020-0357-1] [PMID: 32632305]
[23]
Wu, Z.; Lai, L.; Li, M.; Zhang, L.; Zhang, W. Acute liver failure caused by pembrolizumab in a patient with pulmonary metastatic liver cancer: A case report. Medicine (Baltimore), 2017, 96(51), e9431-e9434.
[http://dx.doi.org/10.1097/MD.0000000000009431] [PMID: 29390572]
[24]
Reddy, A.V.; Pariser, J.J.; Pearce, S.M.; Weichselbaum, R.R.; Smith, N.D.; Steinberg, G.D.; Liauw, S.L. Patterns of failure after radical cystectomy for pT3-4 bladder cancer: Implications for adjuvant radiation therapy. Int. J. Radiat. Oncol. Biol. Phys., 2016, 94(5), 1031-1039.
[25]
Runowicz, C.D.; Leach, C.R.; Henry, N.L.; Henry, K.S.; Mackey, H.T.; Cowens-Alvarado, R.L.; Cannady, R.S.; Pratt-Chapman, M.L.; Edge, S.B.; Jacobs, L.A.; Hurria, A.; Marks, L.B.; LaMonte, S.J.; Warner, E.; Lyman, G.H.; Ganz, P.A. American cancer society/American society of clinical oncology breast cancer survivorship care guideline. CA Cancer J. Clin., 2016, 66(1), 43-73.
[http://dx.doi.org/10.3322/caac.21319] [PMID: 26641959]
[26]
Chudzik, M.; Korzonek-Szlacheta, I.; Król, W. Triterpenes as potentially cytotoxic compounds. Molecules, 2015, 20(1), 1610-1625.
[http://dx.doi.org/10.3390/molecules20011610] [PMID: 25608043]
[27]
Yang, X.; Flaig, T.W. Novel targeted agents for the treatment of bladder cancer: translating laboratory advances into clinical application. Int. Braz J Urol, 2010, 36(3), 273-282.
[http://dx.doi.org/10.1590/S1677-55382010000300003] [PMID: 20602819]
[28]
Han, L.; Yao, S.; Cao, S.; Mo, G.; Li, J.; Cao, Y.; Huang, F. Triterpenoid saponins from anemone flaccida suppress tumor cell proliferation by regulating MAPK, PD1/PDL1, and STAT3 signaling pathways and altering cancer metabolism. OncoTargets Ther., 2019, 12, 10917-10930.
[http://dx.doi.org/10.2147/OTT.S212666] [PMID: 31849495]
[29]
Siddique, H.R.; Saleem, M. Beneficial health effects of lupeol triterpene: A review of preclinical studies. Life Sci., 2011, 88(7-8), 285-293.
[http://dx.doi.org/10.1016/j.lfs.2010.11.020] [PMID: 21118697]
[30]
Fulda, S. Betulinic acid: A natural product with anticancer activity. Mol. Nutr. Food Res., 2009, 53(1), 140-146.
[http://dx.doi.org/10.1002/mnfr.200700491] [PMID: 19065582]
[31]
de Almeida, P.D.; Boleti, A.P.; Rüdiger, A.L.; Lourenço, G.A.; da Veiga, Junior, V.F.; Lima, E.S. Anti-inflammatory activity of triterpenes isolated from Protium paniculatum oil-resins. Evid. Based Complement. Alternat. Med., 2015, 2015, 293768.
[http://dx.doi.org/10.1155/2015/293768] [PMID: 27034686]
[32]
Laszczyk, M.N. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med., 2009, 75(15), 1549-1560.
[http://dx.doi.org/10.1055/s-0029-1186102] [PMID: 19742422]
[33]
Chadalapaka, G.; Jutooru, I.; Burghardt, R.; Safe, S. Drugs that target specificity proteins downregulate epidermal growth factor receptor in bladder cancer cells. Mol. Cancer Res., 2010, 8(5), 739-750.
[http://dx.doi.org/10.1158/1541-7786.MCR-09-0493] [PMID: 20407012]
[34]
Yadav, V.R.; Prasad, S.; Sung, B.; Kannappan, R.; Aggarwal, B.B. Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer. Toxins (Basel), 2010, 2(10), 2428-2466.
[http://dx.doi.org/10.3390/toxins2102428] [PMID: 22069560]
[35]
Ji, L.; Zhong, B.; Jiang, X.; Mao, F.; Liu, G.; Song, B.; Wang, C.Y.; Jiao, Y.; Wang, J.P.; Xu, Z.B.; Li, X.; Zhan, B. Actein induces autophagy and apoptosis in human bladder cancer by potentiating ROS/JNK and inhibiting AKT pathways. Oncotarget, 2017, 8(68), 112498-112515.
[http://dx.doi.org/10.18632/oncotarget.22274] [PMID: 29348843]
[36]
Wu, G.S.; Lu, J.J.; Guo, J.J.; Li, Y.B.; Tan, W.; Dang, Y.Y.; Zhong, Z.F.; Xu, Z.T.; Chen, X.P.; Wang, Y.T. Ganoderic acid DM, a natural triterpenoid, induces DNA damage, G1 cell cycle arrest and apoptosis in human breast cancer cells. Fitoterapia, 2012, 83(2), 408-414.
[http://dx.doi.org/10.1016/j.fitote.2011.12.004] [PMID: 22178684]
[37]
Kim, G.J.; Jo, H.J.; Lee, K.J.; Choi, J.W.; An, J.H. Oleanolic acid induces p53-dependent apoptosis via the ERK/JNK/AKT pathway in cancer cell lines in prostatic cancer xenografts in mice. Oncotarget, 2018, 9(41), 26370-26386.
[http://dx.doi.org/10.18632/oncotarget.25316] [PMID: 29899865]
[38]
Salvador, J.A. Pentacyclic triterpenes as promising agents in cancer; Nova Science Publishers, 2010.
[39]
Liby, K.T.; Yore, M.M.; Sporn, M.B. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat. Rev. Cancer, 2007, 7(5), 357-369.
[http://dx.doi.org/10.1038/nrc2129] [PMID: 17446857]
[40]
Yan, X.J.; Gong, L.H.; Zheng, F.Y.; Cheng, K.J.; Chen, Z.S.; Shi, Z. Triterpenoids as reversal agents for anticancer drug resistance treatment. Drug Discov. Today, 2014, 19(4), 482-488.
[http://dx.doi.org/10.1016/j.drudis.2013.07.018] [PMID: 23954181]
[41]
Woźniak, Ł.; Skąpska, S.; Marszałek, K. Ursolic acid-a pentacyclic triterpenoid with a wide spectrum of pharmacological activities. Molecules, 2015, 20(11), 20614-20641.
[http://dx.doi.org/10.3390/molecules201119721] [PMID: 26610440]
[42]
Zhu, Z.; Qian, Z.; Yan, Z.; Zhao, C.; Wang, H.; Ying, G. A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors. Int. J. Nanomedicine, 2013, 8, 129-136.
[PMID: 23319864]
[43]
Ali-Seyed, M.; Jantan, I.; Vijayaraghavan, K.; Bukhari, S.N. Betulinic acid: Recent advances in chemical modifications, effective delivery, and molecular mechanisms of a promising anticancer therapy. Chem. Biol. Drug Des., 2016, 87(4), 517-536.
[http://dx.doi.org/10.1111/cbdd.12682] [PMID: 26535952]
[44]
Jäger, S.; Laszczyk, M.N.; Scheffler, A. A preliminary pharmacokinetic study of betulin, the main pentacyclic triterpene from extract of outer bark of birch (Betulae alba cortex). Molecules, 2008, 13(12), 3224-3235.
[http://dx.doi.org/10.3390/molecules13123224] [PMID: 19104487]
[45]
Kamble, S.M.; Goyal, S.N.; Patil, C.R. Multifunctional pentacyclic triterpenoids as adjuvants in cancer chemotherapy: A review. RSC Advances, 2014, 4(63), 33370-33382.
[http://dx.doi.org/10.1039/C4RA02784A]
[46]
Shevchuk, O.O.; Posokhova, E.A.; Sakhno, L.A.; Nikolaev, V.G. Theoretical ground for adsorptive therapy of anthracyclines cardiotoxicity. Exp. Oncol., 2012, 34(4), 314-322.
[PMID: 23302988]
[47]
Ghante, M.H.; Jamkhande, P.G. Role of pentacyclic triterpenoids in chemoprevention and anticancer treatment: An overview on targets and underling mechanisms. J. Pharmacopuncture, 2019, 22(2), 55-67.
[PMID: 31338244]
[48]
Zhang, X.; Hu, J.; Chen, Y. Betulinic acid and the pharmacological effects of tumor suppression (Review). Mol. Med. Rep., 2016, 14(5), 4489-4495.
[http://dx.doi.org/10.3892/mmr.2016.5792] [PMID: 27748864]
[49]
Gheorgheosu, D.; Duicu, O.; Dehelean, C.; Soica, C.; Muntean, D. Betulinic acid as a potent and complex antitumor phytochemical: A minireview. Anticancer. Agents Med. Chem., 2014, 14(7), 936-945.
[http://dx.doi.org/10.2174/1871520614666140223192148]
[50]
Ji, C.J.; Zeng, G.Z.; Han, J.; He, W.J.; Zhang, Y.M.; Tan, N.H. Zizimauritic acids A-C, three novel nortriterpenes from Ziziphus mauritiana. Bioorg. Med. Chem. Lett., 2012, 22(20), 6377-6380.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.074] [PMID: 22989532]
[51]
Sutariya, B.; Taneja, N.; Saraf, M. Betulinic acid, isolated from the leaves of Syzygium cumini (L.) Skeels, ameliorates the proteinuria in experimental membranous nephropathy through regulating Nrf2/NF-κB pathways. Chem. Biol. Interact., 2017, 274, 124-137.
[http://dx.doi.org/10.1016/j.cbi.2017.07.011] [PMID: 28711658]
[52]
Shin, J.; Lee, H.J.; Jung, D.B.; Jung, J.H.; Lee, H.J.; Lee, E.O.; Lee, S.G.; Shim, B.S.; Choi, S.H.; Ko, S.G.; Ahn, K.S.; Jeong, S.J.; Kim, S.H. Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic PC-3 prostate cancer cells. PLoS One, 2011, 6(6), e21492.
[http://dx.doi.org/10.1371/journal.pone.0021492] [PMID: 21731766]
[53]
Chowdhury, A.R.; Mandal, S.; Mittra, B.; Sharma, S.; Mukhopadhyay, S.; Majumder, H.K. Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: Identification of the inhibitory step, the major functional group responsible and development of more potent derivatives. Med. Sci. Monit., 2002, 8(7), BR254-BR265.
[PMID: 12118187]
[54]
Ragasa, CY; Borlagdan, MS; Aurigue, FB; Brkljača, R; Urban, S Chemical constituents of Hoya cagayanensis CM Burton. J. Appl. Pharmaceut. Sci., 2017, 7(5), 061-065.
[55]
Ghosh, A.; Sarkar, A.; Mitra, P.; Banerji, A.; Banerji, J.; Mandal, S.; Das, M. Crystal structure and DFT calculations of 3, 4-seco-lup-20 (29)-en-3-oic acid isolated from Wrightiatinctoria: Stacking of supramolecular dimers in the crystal lattice. J. Mol. Struct., 2010, 980(1-3), 7-12.
[http://dx.doi.org/10.1016/j.molstruc.2010.06.011]
[56]
Sadhu, S.K.; Khatun, A.; Ohtsuki, T.; Ishibashi, M. Constituents from Hoya parasitica and their cell growth inhibitory activity. Planta Med., 2008, 74(7), 760-763.
[http://dx.doi.org/10.1055/s-2008-1074523] [PMID: 18446671]
[57]
Ghosh, A.; Roy, R.; Chatterjee, E.; Bankura, B.; Guru, S.; Panda, C.K. Induction of apoptosis in human bladder cancer cells by triterpenoids isolated from Holarrhena antidysenterica through differential reactive oxygen species generation. Nat. Prod. Res., 2020, •••, 1-8.
[http://dx.doi.org/10.1080/14786419.2020.1819272] [PMID: 32954865]
[58]
Murakami, C.; Myoga, K.; Kasai, R.; Ohtani, K.; Kurokawa, T.; Ishibashi, S.; Dayrit, F.; Padolina, W.G.; Yamasaki, K. Screening of plant constituents for effect on glucose transport activity in Ehrlich ascites tumour cells. Chem. Pharm. Bull. (Tokyo), 1993, 41(12), 2129-2131.
[http://dx.doi.org/10.1248/cpb.41.2129] [PMID: 8118906]
[59]
Tchivounda, H.P.; Koudogbo, B.; Besace, Y.; Casadevall, E. Triterpene saponins from Cylicodiscus gabunensis. Phytochemistry, 1991, 30(8), 2711-2716.
[http://dx.doi.org/10.1016/0031-9422(91)85129-N] [PMID: 1367781]
[60]
Lozano-Mena, G.; Juan, M.E.; García-Granados, A.; Planas, J.M. Determination of maslinic acid, a pentacyclic triterpene from olives, in rat plasma by high-performance liquid chromatography. J. Agric. Food Chem., 2012, 60(41), 10220-10225.
[http://dx.doi.org/10.1021/jf3023996] [PMID: 23003682]
[61]
Cho, J.; Tremmel, L.; Rho, O.; Camelio, A.M.; Siegel, D.; Slaga, T.J.; DiGiovanni, J. Evaluation of pentacyclic triterpenes found in Perilla frutescens for inhibition of skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Oncotarget, 2015, 6(36), 39292-39306.
[http://dx.doi.org/10.18632/oncotarget.5751] [PMID: 26513295]
[62]
Kim, Y.K.; Yoon, S.K.; Ryu, S.Y. Cytotoxic triterpenes from stem bark of Physocarpus intermedius. Planta Med., 2000, 66(5), 485-486.
[http://dx.doi.org/10.1055/s-2000-8585] [PMID: 10909277]
[63]
Alam, S.; Khan, F. 3D-QSAR studies on maslinic acid analogs for anticancer activity against breast cancer cell line MCF-7. Sci. Rep., 2017, 7(1), 6019.
[http://dx.doi.org/10.1038/s41598-017-06131-0] [PMID: 28729623]
[64]
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.
[http://dx.doi.org/10.1016/j.canlet.2014.01.016] [PMID: 24486850]
[65]
Liu, J.; Zheng, L.; Zhong, J.; Wu, N.; Liu, G.; Lin, X. Oleanolic acid induces protective autophagy in cancer cells through the JNK and mTOR pathways. Oncol. Rep., 2014, 32(2), 567-572.
[http://dx.doi.org/10.3892/or.2014.3239] [PMID: 24912497]
[66]
Jäger, S.; Trojan, H.; Kopp, T.; Laszczyk, M.N.; Scheffler, A. Pentacyclic triterpene distribution in various plants - rich sources for a new group of multi-potent plant extracts. Molecules, 2009, 14(6), 2016-2031.
[http://dx.doi.org/10.3390/molecules14062016] [PMID: 19513002]
[67]
Yamaguchi, H.; Noshita, T.; Kidachi, Y.; Umetsu, H.; Hayashi, M.; Komiyama, K.; Funayama, S.; Ryoyama, K. Isolation of ursolic acid from apple peels and its specific efficacy as a potent antitumor agent. J. Health Sci., 2008, 54(6), 654-660.
[http://dx.doi.org/10.1248/jhs.54.654]
[68]
Liao, Q.; Yang, W.; Jia, Y.; Chen, X.; Gao, Q.; Bi, K. LC-MS determination and pharmacokinetic studies of ursolic acid in rat plasma after administration of the traditional Chinese medicinal preparation Lu-Ying extract. Yakugaku Zasshi, 2005, 125(6), 509-515.
[http://dx.doi.org/10.1248/yakushi.125.509] [PMID: 15930819]
[69]
Mullauer, F.B.; Kessler, J.H.; Medema, J.P. Betulinic acid induces cytochrome c release and apoptosis in a Bax/Bak-independent, permeability transition pore dependent fashion. Apoptosis, 2009, 14(2), 191-202.
[http://dx.doi.org/10.1007/s10495-008-0290-x] [PMID: 19115109]
[70]
Tan, Y.; Yu, R.; Pezzuto, J.M. Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. Clin. Cancer Res., 2003, 9(7), 2866-2875.
[PMID: 12855667]
[71]
Jutooru, I.; Chadalapaka, G.; Sreevalsan, S.; Lei, P.; Barhoumi, R.; Burghardt, R.; Safe, S. Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth. Exp. Cell Res., 2010, 316(13), 2174-2188.
[http://dx.doi.org/10.1016/j.yexcr.2010.04.027] [PMID: 20435036]
[72]
M., Patel H.; Rane, R.; Thapliyal, N.; Palkar, M.; Shaikh, M.; Karpoormat, R. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors from the natural origin: A recent perspective. Anticancer. Agents Med. Chem., 2015, 15(8), 988-1011.
[73]
H., Safe S.; L Prather, P.; K Brents, L.; Chadalapaka, G.; Jutooru, I. Unifying mechanisms of action of the anticancer activities of triterpenoids and synthetic analogs. Anticancer. Agents Med. Chem., 2012, 12(10), 1211-1220.
[74]
Nicholson, R.I.; Gee, J.M.; Harper, M.E. EGFR and cancer prognosis. Eur. J. Cancer, 2001, 37(Suppl. 4), S9-S15.
[http://dx.doi.org/10.1016/S0959-8049(01)00231-3] [PMID: 11597399]
[75]
Thakor, P.; Song, W.; Subramanian, R.B.; Thakkar, V.R.; Vesey, D.A.; Gobe, G.C. Maslinic acid inhibits proliferation of renal cell carcinoma cell lines and suppresses angiogenesis of endothelial cells. J. Kidney Cancer VHL, 2017, 4(1), 16-24.
[http://dx.doi.org/10.15586/jkcvhl.2017.64] [PMID: 28405545]
[76]
Siewert, B.; Pianowski, E.; Csuk, R. Esters and amides of maslinic acid trigger apoptosis in human tumor cells and alter their mode of action with respect to the substitution pattern at C-28. Eur. J. Med. Chem., 2013, 70, 259-272.
[http://dx.doi.org/10.1016/j.ejmech.2013.10.016] [PMID: 24161703]
[77]
Liu, Y.; Lu, H.; Dong, Q.; Hao, X.; Qiao, L. Maslinic acid induces anticancer effects in human neuroblastoma cells mediated via apoptosis induction and caspase activation, inhibition of cell migration and invasion and targeting MAPK/ERK signaling pathway. AMB Express, 2020, 10(1), 104.
[http://dx.doi.org/10.1186/s13568-020-01035-1] [PMID: 32488691]
[78]
Reyes-Zurita, F.J.; Pachón-Peña, G.; Lizárraga, D.; Rufino-Palomares, E.E.; Cascante, M.; Lupiáñez, J.A. The natural triterpene maslinic acid induces apoptosis in HT29 colon cancer cells by a JNK-p53-dependent mechanism. BMC Cancer, 2011, 11(1), 154.
[http://dx.doi.org/10.1186/1471-2407-11-154] [PMID: 21524306]
[79]
Li, C.; Yang, Z.; Zhai, C.; Qiu, W.; Li, D.; Yi, Z.; Wang, L.; Tang, J.; Qian, M.; Luo, J.; Liu, M. Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor α by inhibiting NF-κB signaling pathway. Mol. Cancer, 2010, 9(1), 1-13.
[http://dx.doi.org/10.1186/1476-4598-9-73] [PMID: 31901224]
[80]
Martín, R.; Carvalho-Tavares, J.; Ibeas, E.; Hernández, M.; Ruiz-Gutierrez, V.; Nieto, M.L. Acidic triterpenes compromise growth and survival of astrocytoma cell lines by regulating reactive oxygen species accumulation. Cancer Res., 2007, 67(8), 3741-3751.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4759] [PMID: 17440087]
[81]
Hsum, Y.W.; Yew, W.T.; Hong, P.L.; Soo, K.K.; Hoon, L.S.; Chieng, Y.C.; Mooi, L.Y. Cancer chemopreventive activity of maslinic acid: Suppression of COX-2 expression and inhibition of NF-κB and AP-1 activation in Raji cells. Planta Med., 2011, 77(2), 152-157.
[http://dx.doi.org/10.1055/s-0030-1250203] [PMID: 20669087]
[82]
Žiberna, L.; Šamec, D.; Mocan, A.; Nabavi, S.F.; Bishayee, A.; Farooqi, A.A.; Sureda, A.; Nabavi, S.M. Oleanolic acid alters multiple cell signaling pathways: Implication in cancer prevention and therapy. Int. J. Mol. Sci., 2017, 18(3), 643-658.
[http://dx.doi.org/10.3390/ijms18030643] [PMID: 28300756]
[83]
Singh, R.P.; Dhanalakshmi, S.; Agarwal, R. Phytochemicals as cell cycle modulators--a less toxic approach in halting human cancers. Cell Cycle, 2002, 1(3), 156-161.
[http://dx.doi.org/10.4161/cc.1.3.117] [PMID: 12429925]
[84]
Li, H.F.; Wang, X.A.; Xiang, S.S.; Hu, Y.P.; Jiang, L.; Shu, Y.J.; Li, M.L.; Wu, X.S.; Zhang, F.; Ye, Y.Y.; Weng, H.; Bao, R.F.; Cao, Y.; Lu, W.; Dong, Q.; Liu, Y.B. Oleanolic acid induces mitochondrial-dependent apoptosis and G0/G1 phase arrest in gallbladder cancer cells. Drug Des. Devel. Ther., 2015, 9, 3017-3030.
[http://dx.doi.org/10.2147/DDDT.S84448] [PMID: 26109845]
[85]
Yun, J.M.; Kweon, M.H.; Kwon, H.; Hwang, J.K.; Mukhtar, H. Induction of apoptosis and cell cycle arrest by a chalcone panduratin A isolated from Kaempferia pandurata in androgen-independent human prostate cancer cells PC3 and DU145. Carcinogenesis, 2006, 27(7), 1454-1464.
[http://dx.doi.org/10.1093/carcin/bgi348] [PMID: 16497706]
[86]
Polyak, K.; Kato, J.Y.; Solomon, M.J.; Sherr, C.J.; Massague, J.; Roberts, J.M.; Koff, A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev., 1994, 8(1), 9-22.
[http://dx.doi.org/10.1101/gad.8.1.9] [PMID: 8288131]
[87]
Bates, S.; Vousden, K.H. Mechanisms of p53-mediated apoptosis. Cell. Mol. Life Sci., 1999, 55(1), 28-37.
[http://dx.doi.org/10.1007/s000180050267] [PMID: 10065149]
[88]
Kashyap, D.; Tuli, H.S.; Garg, V.K.; Bhatnagar, S.; Sharma, A.K. Ursolic acid and quercetin: Promising anticancer phytochemicals with antimetastatic and antiangiogenic potential. Tumor Microenviron., 2018, 1(1), 9-15.
[http://dx.doi.org/10.4103/tme.tme_3_17]
[89]
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(11), 1579-1587.
[http://dx.doi.org/10.1016/j.bcp.2013.03.006] [PMID: 23499879]
[90]
Zang, L.L.; Wu, B.N.; Lin, Y.; Wang, J.; Fu, L.; Tang, Z.Y. Research progress of ursolic acid’s anti-tumor actions. Chin. J. Integr. Med., 2014, 20(1), 72-79.
[http://dx.doi.org/10.1007/s11655-013-1541-4] [PMID: 24374755]
[91]
Gai, L.; Cai, N.; Wang, L.; Xu, X.; Kong, X. Ursolic acid induces apoptosis via Akt/NF-κB signaling suppression in T24 human bladder cancer cells. Mol. Med. Rep., 2013, 7(5), 1673-1677.
[http://dx.doi.org/10.3892/mmr.2013.1364] [PMID: 23483134]
[92]
Sun, C.H.; Chang, Y.H.; Pan, C.C. Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder. Histopathology, 2011, 58(7), 1054-1063.
[http://dx.doi.org/10.1111/j.1365-2559.2011.03856.x] [PMID: 21707707]
[93]
Kassi, E.; Papoutsi, Z.; Pratsinis, H.; Aligiannis, N.; Manoussakis, M.; Moutsatsou, P. Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells. J. Cancer Res. Clin. Oncol., 2007, 133(7), 493-500.
[http://dx.doi.org/10.1007/s00432-007-0193-1] [PMID: 17516089]
[94]
Zhang, Y; Kong, C; Zeng, Y; Wang, L; Li, Z; Wang, H; Xu, C; Sun, Y. Ursolic acid induces PC‐3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro. Molecular Carcinogenesis: Published in cooperation with the University of Texas MD Anderson Cancer Center, 2010, 49(4), 374-385.
[95]
Shanmugam, M.K.; Rajendran, P.; Li, F.; Nema, T.; Vali, S.; Abbasi, T.; Kapoor, S.; Sharma, A.; Kumar, A.P.; Ho, P.C.; Hui, K.M.; Sethi, G. Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice. J. Mol. Med. (Berl.), 2011, 89(7), 713-727.
[http://dx.doi.org/10.1007/s00109-011-0746-2] [PMID: 21465181]
[96]
Limami, Y.; Pinon, A.; Leger, D.Y.; Pinault, E.; Delage, C.; Beneytout, J.L.; Simon, A.; Liagre, B. The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells. Biochimie, 2012, 94(8), 1754-1763.
[http://dx.doi.org/10.1016/j.biochi.2012.04.006] [PMID: 22521508]
[97]
Zheng, Q.Y.; Jin, F.S.; Yao, C.; Zhang, T.; Zhang, G.H.; Ai, X. Ursolic acid-induced AMP-activated Protein Kinase (AMPK) activation contributes to growth inhibition and apoptosis in human bladder cancer T24 cells. Biochem. Biophys. Res. Commun., 2012, 419(4), 741-747.
[http://dx.doi.org/10.1016/j.bbrc.2012.02.093] [PMID: 22387548]
[98]
Tu, H.Y.; Huang, A.M.; Wei, B.L.; Gan, K.H.; Hour, T.C.; Yang, S.C.; Pu, Y.S.; Lin, C.N. Ursolic acid derivatives induce cell cycle arrest and apoptosis in NTUB1 cells associated with reactive oxygen species. Bioorg. Med. Chem., 2009, 17(20), 7265-7274.
[http://dx.doi.org/10.1016/j.bmc.2009.08.046] [PMID: 19758808]
[99]
Zheng, Q.Y.; Li, P.P.; Jin, F.S.; Yao, C.; Zhang, G.H.; Zang, T.; Ai, X. Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in human bladder cancer T24 cells. Cell. Signal., 2013, 25(1), 206-213.
[http://dx.doi.org/10.1016/j.cellsig.2012.09.012] [PMID: 23000344]
[100]
Mandic, A.; Hansson, J.; Linder, S.; Shoshan, M.C. Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J. Biol. Chem., 2003, 278(11), 9100-9106.
[http://dx.doi.org/10.1074/jbc.M210284200] [PMID: 12509415]
[101]
Anether, G.; Tinhofer, I.; Senfter, M.; Greil, R. Tetrocarcin-A--induced ER stress mediates apoptosis in B-CLL cells via a Bcl-2--independent pathway. Blood, 2003, 101(11), 4561-4568.
[http://dx.doi.org/10.1182/blood-2002-08-2501] [PMID: 12560233]
[102]
Chen, M.B.; Wu, X.Y.; Tao, G.Q.; Liu, C.Y.; Chen, J.; Wang, L.Q.; Lu, P.H. Perifosine sensitizes curcumin-induced anti-colorectal cancer effects by targeting multiple signaling pathways both in vivo and in vitro. Int. J. Cancer, 2012, 131(11), 2487-2498.
[http://dx.doi.org/10.1002/ijc.27548] [PMID: 22438101]
[103]
Zuco, V.; Supino, R.; Righetti, S.C.; Cleris, L.; Marchesi, E.; Gambacorti-Passerini, C.; Formelli, F. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett., 2002, 175(1), 17-25.
[http://dx.doi.org/10.1016/S0304-3835(01)00718-2] [PMID: 11734332]
[104]
Chintharlapalli, S.; Papineni, S.; Lei, P.; Pathi, S.; Safe, S. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer, 2011, 11(1), 371-383.
[http://dx.doi.org/10.1186/1471-2407-11-371] [PMID: 21864401]
[105]
Hordyjewska, A.; Ostapiuk, A.; Horecka, A.; Kurzepa, J. Betulin and betulinic acid: triterpenoids derivatives with a powerful biological potential. Phytochem. Rev., 2019, 18(3), 929-951.
[http://dx.doi.org/10.1007/s11101-019-09623-1]
[106]
Gao, Y.; Jia, Z.; Kong, X.; Li, Q.; Chang, D.Z.; Wei, D.; Le, X.; Suyun, H.; Huang, S.; Wang, L.; Xie, K. Combining betulinic acid and mithramycin a effectively suppresses pancreatic cancer by inhibiting proliferation, invasion, and angiogenesis. Cancer Res., 2011, 71(15), 5182-5193.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2016] [PMID: 21673052]
[107]
Lee, Y.J.; Shukla, S.D. Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes. Eur. J. Pharmacol., 2005, 508(1-3), 31-45.
[http://dx.doi.org/10.1016/j.ejphar.2004.12.006] [PMID: 15680252]
[108]
Zhang, S.; Ding, D.; Zhang, X.; Shan, L.; Liu, Z. Maslinic acid induced apoptosis in bladder cancer cells through activating p38 MAPK signaling pathway. Mol. Cell. Biochem., 2014, 392(1-2), 281-287.
[http://dx.doi.org/10.1007/s11010-014-2038-y] [PMID: 24687305]
[109]
Mu, D.W.; Guo, H.Q.; Zhou, G.B.; Li, J.Y.; Su, B. Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling. Int. J. Clin. Exp. Pathol., 2015, 8(11), 13864-13870.
[PMID: 26823699]
[110]
Chadalapaka, G.; Jutooru, I.; McAlees, A.; Stefanac, T.; Safe, S. Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives. Bioorg. Med. Chem. Lett., 2008, 18(8), 2633-2639.
[http://dx.doi.org/10.1016/j.bmcl.2008.03.031] [PMID: 18359628]
[111]
Zhu, Y.Y.; Huang, H.Y.; Wu, Y.L. [Retracted] Anticancer and apoptotic activities of oleanolic acid are mediated through cell cycle arrest and disruption of mitochondrial membrane potential in HepG2 human hepatocellular carcinoma cells. Mol. Med. Rep., 2021, 23(6), 1.
[http://dx.doi.org/10.3892/mmr.2021.12079] [PMID: 33846804]
[112]
Ghate, N.B.; Chaudhuri, D.; Sarkar, R.; Sajem, A.L.; Panja, S.; Rout, J.; Mandal, N. An antioxidant extract of tropical lichen, Parmotrema reticulatum, induces cell cycle arrest and apoptosis in breast carcinoma cell line MCF-7. PLoS One, 2013, 8(12), e82293.
[http://dx.doi.org/10.1371/journal.pone.0082293] [PMID: 24358166]
[113]
Qian, Y.; Guan, T.; Tang, X.; Huang, L.; Huang, M.; Li, Y.; Sun, H. Maslinic acid, a natural triterpenoid compound from Olea europaea, protects cortical neurons against oxygen-glucose deprivation-induced injury. Eur. J. Pharmacol., 2011, 670(1), 148-153.
[http://dx.doi.org/10.1016/j.ejphar.2011.07.037] [PMID: 21839077]
[114]
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]
[115]
Fulda, S.; Kroemer, G. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov. Today, 2009, 14(17-18), 885-890.
[http://dx.doi.org/10.1016/j.drudis.2009.05.015] [PMID: 19520182]
[116]
Eiznhamer, D.A.; Xu, Z.Q. Betulinic acid: A promising anticancer candidate. IDrugs, 2004, 7(4), 359-373.
[PMID: 15057642]
[117]
Li, X.; Song, Y.; Zhang, P.; Zhu, H.; Chen, L.; Xiao, Y.; Xing, Y. Oleanolic acid inhibits cell survival and proliferation of prostate cancer cells in vitro and in vivo through the PI3K/Akt pathway. Tumour Biol., 2016, 37(6), 7599-7613.
[http://dx.doi.org/10.1007/s13277-015-4655-9] [PMID: 26687646]
[118]
Feng, X.M.; Su, X.L. Anticancer effect of ursolic acid via mitochondria-dependent pathways. Oncol. Lett., 2019, 17(6), 4761-4767.
[http://dx.doi.org/10.3892/ol.2019.10171] [PMID: 31186681]
[119]
Yu, Y.; Wang, J.; Xia, N.; Li, B.; Jiang, X. Maslinic acid potentiates the antitumor activities of gemcitabine in vitro and in vivo by inhibiting NF-κB-mediated survival signaling pathways in human gallbladder cancer cells. Oncol. Rep., 2015, 33(4), 1683-1690.
[http://dx.doi.org/10.3892/or.2015.3755] [PMID: 25633045]
[120]
Patil, K.R.; Mohapatra, P.; Patel, H.M.; Goyal, S.N.; Ojha, S.; Kundu, C.N.; Patil, C.R. Pentacyclic triterpenoids inhibit IKKβ mediated activation of NF-κB pathway: In silico and in vitro evidences. PLoS One, 2015, 10(5), e0125709.
[http://dx.doi.org/10.1371/journal.pone.0125709] [PMID: 25938234]
[121]
Hayes, J.D.; McMahon, M.; Chowdhry, S.; Dinkova-Kostova, A.T. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid. Redox Signal., 2010, 13(11), 1713-1748.
[http://dx.doi.org/10.1089/ars.2010.3221] [PMID: 20446772]
[122]
Yang, L.; Calingasan, N.Y.; Thomas, B.; Chaturvedi, R.K.; Kiaei, M.; Wille, E.J.; Liby, K.T.; Williams, C.; Royce, D.; Risingsong, R.; Musiek, E.S.; Morrow, J.D.; Sporn, M.; Beal, M.F. Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PLoS One, 2009, 4(6), e5757.
[http://dx.doi.org/10.1371/journal.pone.0005757] [PMID: 19484125]
[123]
Rein, M.J.; Renouf, M.; Cruz-Hernandez, C.; Actis-Goretta, L.; Thakkar, S.K.; da Silva Pinto, M. Bioavailability of bioactive food compounds: A challenging journey to bioefficacy. Br. J. Clin. Pharmacol., 2013, 75(3), 588-602.
[http://dx.doi.org/10.1111/j.1365-2125.2012.04425.x] [PMID: 22897361]

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