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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Mini-Review Article

Antitumor Effects of Triterpenes in Hepatocellular Carcinoma

Author(s): Antoni Sureda*, Miquel Martorell, Xavier Capó, Margalida Monserrat-Mesquida, Maria Magdalena Quetglas-Llabrés, Mahsa Rasekhian, Seyed M. Nabavi* and Silvia Tejada

Volume 28, Issue 13, 2021

Published on: 02 June, 2020

Page: [2465 - 2484] Pages: 20

DOI: 10.2174/0929867327666200602132000

Price: $65


Background: Triterpenes are a large group of secondary metabolites mainly produced by plants with a variety of biological activities, including potential antitumor effects. Hepatocellular carcinoma (HCC) is a very common primary liver disease spread worldwide. The treatment can consist of surgical intervention, radiotherapy, immunotherapy and chemotherapeutic drugs. These drugs mainly include tyrosine multikinase inhibitors, although their use is limited by the underlying liver disease and displays side effects. For that reason, the utility of natural compounds such as triterpenes to treat HCC is an interesting line of research. No clinical studies are reported in humans so far.

Objective: The aim of the present work is to review the knowledge about the effects of triterpenes as a possible coadjuvant tool to treat HCC.

Results: In vitro and xenograft models have pointed out the cytotoxic and anti-proliferative effects as well as improvements in tumor growth and development of many triterpenes. In addition, they have also shown to be chemosensitizing agents when co-administered with chemotherapeutic agents. The mechanisms of action are diverse and involve the participation of mitogen-activated protein kinases, including JNK, p38 MAPK and ERK, and the survival-associated PI3K / Akt signaling pathway. However, no clinical studies are still reported in humans.

Conclusion: Triterpenes could become a future strategy to address HCC or at least improve results when administered in combination with chemotherapeutic agents.

Keywords: Hepatocellular carcinoma, cancer, natural products, antitumor, triterpenes, tyrosine multikinase inhibitors.

Clark, T.; Maximin, S.; Meier, J.; Pokharel, S.; Bhargava, P. Hepatocellular carcinoma: review of epidemiology, screening, imaging diagnosis, response assessment and treatment. Curr. Probl. Diagn. Radiol., 2015, 44(6), 479-486.
[] [PMID: 25979220]
Wallace, M.C.; Preen, D.; Jeffrey, G.P.; Adams, L.A. The evolving epidemiology of hepatocellular carcinoma: a global perspective. Expert Rev. Gastroenterol. Hepatol., 2015, 9(6), 765-779.
[] [PMID: 25827821]
Forner, A.; Reig, M.; Bruix, J. Hepatocellular carcinoma. Lancet, 2018, 391(10127), 1301-1314.
[] [PMID: 29307467]
Sayiner, M.; Golabi, P.; Younossi, Z.M. Disease burden of hepatocellular carcinoma: a global perspective. Dig. Dis. Sci., 2019, 64(4), 910-917.
[] [PMID: 30835028]
Llovet, J.M.; Bustamante, J.; Castells, A.; Vilana, R. Ayuso, Mdel.C.; Sala, M.; Brú, C.; Rodés, J.; Bruix, J. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology, 1999, 29(1), 62-67.
[] [PMID: 9862851]
Chen, J.D.; Yang, H.I.; Iloeje, U.H.; You, S.L.; Lu, S.N.; Wang, L.Y.; Su, J.; Sun, C.A.; Liaw, Y.F.; Chen, C.J. Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (REVEAL-HBV) Study Group. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology, 2010, 138(5), 1747-1754.
[] [PMID: 20114048]
Gaddikeri, S.; McNeeley, M.F.; Wang, C.L.; Bhargava, P.; Dighe, M.K.; Yeh, M.M.; Dubinsky, T.J.; Kolokythas, O.; Lalwani, N. Hepatocellular carcinoma in the noncirrhotic liver. AJR Am. J. Roentgenol., 2014, 203(1),W34-47.
[] [PMID: 24951228]
Li, W.Q.; Park, Y.; McGlynn, K.A.; Hollenbeck, A.R.; Taylor, P.R.; Goldstein, A.M.; Freedman, N.D. Index-based dietary patterns and risk of incident hepatocellular carcinoma and mortality from chronic liver disease in a prospective study. Hepatology, 2014, 60(2), 588-597.
[] [PMID: 24715615]
Calle, E.E.; Rodriguez, C.; Walker-Thurmond, K.; Thun, M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med., 2003, 348(17), 1625-1638.
[] [PMID: 12711737]
El-Serag, H.B.; Kanwal, F. Obesity and hepatocellular carcinoma: hype and reality. Hepatology, 2014, 60(3), 779-781.
[] [PMID: 24753107]
Kasmari, A.J.; Welch, A.; Liu, G.; Leslie, D.; McGarrity, T.; Riley, T. Independent of cirrhosis, hepatocellular carcinoma risk is increased with diabetes and metabolic syndrome. Am. J. Med., 2017, 130(6), 746.e1-746.e7.
[]] [PMID: 28109969]
Marrero, J.A.; Fontana, R.J.; Fu, S.; Conjeevaram, H.S.; Su, G.L.; Lok, A.S. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J. Hepatol., 2005, 42(2), 218-224.
[] [PMID: 15664247]
Bravi, F.; Tavani, A.; Bosetti, C.; Boffetta, P.; La Vecchia, C. Coffee and the risk of hepatocellular carcinoma and chronic liver disease: a systematic review and meta-analysis of prospective studies. Eur. J. Cancer Prev., 2017, 26(5), 368-377.
[] [PMID: 27111112]
Thoppil, R.J.; Bishayee, A. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer. World J. Hepatol., 2011, 3(9), 228-249.
[] [PMID: 21969877]
Huang, M.; Lu, J.J.; Huang, M.Q.; Bao, J.L.; Chen, X.P.; Wang, Y.T. Terpenoids: natural products for cancer therapy. Expert Opin. Investig. Drugs, 2012, 21(12), 1801-1818.
[] [PMID: 23092199]
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.
[] [PMID: 25220842]
Bruix, J.; Gores, G.J.; Mazzaferro, V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut, 2014, 63(5), 844-855.
[] [PMID: 24531850]
Asahina, Y.; Tsuchiya, K.; Tamaki, N.; Hirayama, I.; Tanaka, T.; Sato, M.; Yasui, Y.; Hosokawa, T.; Ueda, K.; Kuzuya, T.; Nakanishi, H.; Itakura, J.; Takahashi, Y.; Kurosaki, M.; Enomoto, N.; Izumi, N. Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Hepatology, 2010, 52(2), 518-527.
[] [PMID: 20683951]
Petruzziello, A. Epidemiology of hepatitis B Virus (HBV) and hepatitis C virus (HCV) related hepatocellular carcinoma. Open Virol. J., 2018, 12, 26-32.
[] [PMID: 29541276]
El-Serag, H.B. Epidemiology of viral hepatitis and hepatocellular carcinoma., Gastroenterology, 2012, 142(6), 1264. e1-1273.e1..
[ ] [PMID: 22537432]
Arzumanyan, A.; Reis, H.M.; Feitelson, M.A. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat. Rev. Cancer, 2013, 13(2), 123-135.
[] [PMID: 23344543]
Morgan, T.R.; Mandayam, S.; Jamal, M.M. Alcohol and hepatocellular carcinoma., Gastroenterology, 2004, 127(5_ Suppl. 1), S87-S96..
[ ] [PMID: 15508108]
Degasperi, E.; Colombo, M. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease. Lancet Gastroenterol. Hepatol., 2016, 1(2), 156-164.
[] [PMID: 28404072]
Kao, J.H. Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract. Res. Clin. Gastroenterol., 2015, 29(6), 907-917.
[] [PMID: 26651252]
Schütte, K.; Balbisi, F.; Malfertheiner, P. Prevention of hepatocellular carcinoma. Gastrointest. Tumors, 2016, 3(1), 37-43.
[] [PMID: 27722155]
Lin, C.L.; Kao, J.H. Perspectives and control of hepatitis B virus infection in Taiwan. J. Formos. Med. Assoc., 2015, 114(10), 901-909.
[] [PMID: 26184565]
Ghasemi, F.; Rostami, S.; Meshkat, Z. Progress in the development of vaccines for hepatitis C virus infection. World J. Gastroenterol., 2015, 21(42), 11984-12002.
[] [PMID: 26576087]
Satapathy, S.K.; Sanyal, A.J. Epidemiology and natural history of nonalcoholic fatty liver disease. Semin. Liver Dis., 2015, 35(3), 221-235.
[] [PMID: 26378640]
Dusheiko, G. Towards the elimination and eradication of hepatitis B. J. Virus Erad., 2015, 1(1), 4-12.
[PMID: 27482390]
Wirth, T.C.; Manns, M.P. The impact of the revolution in hepatitis C treatment on hepatocellular carcinoma. Ann. Oncol., 2016, 27(8), 1467-1474.
[] [PMID: 27226385]
Díaz-González, Á.; Forner, A. Surveillance for hepatocellular carcinoma. Best Pract. Res. Clin. Gastroenterol., 2016, 30(6), 1001-1010.
[] [PMID: 27938779]
Chen, J.G.; Parkin, D.M.; Chen, Q.G.; Lu, J.H.; Shen, Q.J.; Zhang, B.C.; Zhu, Y.R. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J. Med. Screen., 2003, 10(4), 204-209.
[] [PMID: 14738659]
Toyoda, H.; Kumada, T.; Tada, T.; Kaneoka, Y.; Maeda, A.; Kanke, F.; Satomura, S. Clinical utility of highly sensitive Lens culinaris agglutinin-reactive alpha-fetoprotein in hepatocellular carcinoma patients with alpha-fetoprotein <20 ng/mL. Cancer Sci., 2011, 102(5), 1025-1031.
[] [PMID: 21244578]
Lok, A.S.; Sterling, R.K.; Everhart, J.E.; Wright, E.C.; Hoefs, J.C.; Di Bisceglie, A.M.; Morgan, T.R.; Kim, H.Y.; Lee, W.M.; Bonkovsky, H.L.; Dienstag, J.L. HALT-C Trial Group. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology, 2010, 138(2), 493-502.
[] [PMID: 19852963]
Ozer Etik, D.; Suna, N.; Boyacioglu, A.S. Management of hepatocellular carcinoma: prevention, surveillance, diagnosis and staging. Exp. Clin. Transplant., 2017, 15(Suppl. 2), 31-35.
[]] [PMID: 28301996]
Mayorga, C.; Yopp, A.C.; Singal, A.G. Hepatocellular carcinoma surveillance: all cirrhotic patients may not be equal. Gastroenterology, 2012, 143(5), 1393-1395.
[] [PMID: 23010303]
Chedid, M.F.; Kruel, C.R.P.; Pinto, M.A.; Grezzana-Filho, T.J.M.; Leipnitz, I.; Kruel, C.D.P.; Scaffaro, L.A.; Chedid, A.D. Hepatocellular carcinoma: diagnosis and operative management. Arq. Bras. Cir. Dig., 2017, 30(4), 272-278.
[] [PMID: 29340553]
Roskams, T. Anatomic pathology of hepatocellular carcinoma: impact on prognosis and response to therapy. Clin. Liver Dis., 2011, 15(2), 245-259. [vii-x.
[ ] [PMID: 21689611]
Grandhi, M.S.; Kim, A.K.; Ronnekleiv-Kelly, S.M.; Kamel, I.R.; Ghasebeh, M.A.; Pawlik, T.M. Hepatocellular carcinoma: from diagnosis to treatment. Surg. Oncol., 2016, 25(2), 74-85.
[] [PMID: 27312032]
Hartke, J.; Johnson, M.; Ghabril, M. The diagnosis and treatment of hepatocellular carcinoma. Semin. Diagn. Pathol., 2017, 34(2), 153-159.
[] [PMID: 28108047]
Llovet, J.M.; Burroughs, A.; Bruix, J. Hepatocellular carcinoma. Lancet, 2003, 362(9399), 1907-1917.
[] [PMID: 14667750]
Lurje, I.; Czigany, Z.; Bednarsch, J.; Roderburg, C.; Isfort, P.; Neumann, U.P.; Lurje, G. Treatment strategies for hepatocellular carcinoma - a multidisciplinary approach. Int. J. Mol. Sci., 2019, 20(6),E1465.
[] [PMID: 30909504]
Maurer, G.; Tarkowski, B.; Baccarini, M. Raf kinases in cancer-roles and therapeutic opportunities. Oncogene, 2011, 30(32), 3477-3488.
[] [PMID: 21577205 ]
Boland, P.; Wu, J. Systemic therapy for hepatocellular carcinoma: beyond sorafenib. Linchuang Zhongliuxue Zazhi, 2018, 7(5), 50.
[] [PMID: 30395717]
Ribeiro de Souza, A.; Reig, M.; Bruix, J. Systemic treatment for advanced hepatocellular carcinoma: the search of new agents to join sorafenib in the effective therapeutic armamentarium. Expert Opin. Pharmacother., 2016, 17(14), 1923-1936.
[] [PMID: 27598745]
Wilhelm, S.M.; Adnane, L.; Newell, P.; Villanueva, A.; Llovet, J.M.; Lynch, M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther., 2008, 7(10), 3129-3140.
[] [PMID: 18852116]
Rey, J.B.; Launay-Vacher, V.; Tournigand, C. Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists. Target. Oncol., 2015, 10(2), 199-213.
[] [PMID: 25213039]
Heo, Y.A.; Syed, Y.Y. Regorafenib: a review in hepatocellular carcinoma. Drugs, 2018, 78(9), 951-958.
[] [PMID: 29915898]
De Mattia, E.; Cecchin, E.; Guardascione, M.; Foltran, L.; Di Raimo, T.; Angelini, F.; D’Andrea, M.; Toffoli, G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J. Gastroenterol., 2019, 25(29), 3870-3896.
[] [PMID: 31413525]
Grüllich, C. Cabozantinib: Multi-kinase inhibitor of MET, AXL, RET and VEGFR2. Recent Results Cancer Res., 2018, 211, 67-75.
[] [PMID: 30069760]
Dhillon, S. Palbociclib: first global approval. Drugs, 2015, 75(5), 543-551.
[] [PMID: 25792301]
Li, S.; Yang, F.; Ren, X. Immunotherapy for hepatocellular carcinoma. Drug Discov. Ther., 2015, 9(5), 363-371.
[] [PMID: 26632545]
Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382), 1350-1355.
[]] [PMID: 29567705]
Na, Z.; Yeo, S.P.; Bharath, S.R.; Bowler, M.W.; Balıkçı, E.; Wang, C-I.; Song, H. Structural basis for blocking PD-1-mediated immune suppression by therapeutic antibody pembrolizumab. Cell Res., 2017, 27(1), 147-150.
[]] [PMID: 27325296]
Kim, H.C. Radioembolization for the treatment of hepatocellular carcinoma. Clin. Mol. Hepatol., 2017, 23(2), 109-114.
[] [PMID: 28494530]
Toskich, B.; Patel, T. Radioembolization for hepatocellular carcinoma: the time has come. Hepatology, 2018, 67(3), 820-822.
[] [PMID: 29023925]
Buckle, J. Clinical aromatherapy: Essential oils in healthcare, 3rd ed; Churchill Livingstone: St. Louis, 2015, p. 432.
Nazaruk, J.; Borzym-Kluczyk, M. The role of triterpenes in the management of diabetes mellitus and its complications. Phytochem. Rev., 2015, 14(4), 675-690.
[] [PMID: 26213526]
Phillips, D.R.; Rasbery, J.M.; Bartel, B.; Matsuda, S.P. Biosynthetic diversity in plant triterpene cyclization. Curr. Opin. Plant Biol., 2006, 9(3), 305-314.
[] [PMID: 16581287]
Rudolf, H.; Sticher, O. Pharmakognosie - Phytopharmazie; Springer-Verlag: Berlin, Heidelberg, 2010, p. 1451.
[ / 978-3-642-00963-1]
Sánchez-Quesada, C.; López-Biedma, A.; Warleta, F.; Campos, M.; Beltrán, G.; Gaforio, J.J. Bioactive properties of the main triterpenes found in olives, virgin olive oil and leaves of Olea europaea. J. Agric. Food Chem., 2013, 61(50), 12173-12182.
[] [PMID: 24279741]
Jeong, D.W.; Kim, Y.H.; Kim, H.H.; Ji, H.Y.; Yoo, S.D.; Choi, W.R.; Lee, S.M.; Han, C.K.; Lee, H.S. Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats. Biopharm. Drug Dispos., 2007, 28(2), 51-57.
[] [PMID: 17163409]
Song, M.; Hang, T.J.; Wang, Y.; Jiang, L.; Wu, X.L.; Zhang, Z.; Shen, J.; Zhang, Y. Determination of oleanolic acid in human plasma and study of its pharmacokinetics in Chinese healthy male volunteers by HPLC tandem mass spectrometry. J. Pharm. Biomed. Anal., 2006, 40(1), 190-196.
[] [PMID: 16126358]
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.
[] [PMID: 23003682]
Yin, M.C.; Lin, M.C.; Mong, M.C.; Lin, C.Y. Bioavailability, distribution, and antioxidative effects of selected triterpenes in mice. J. Agric. Food Chem., 2012, 60(31), 7697-7701.
[] [PMID: 22816768]
Cerga, O.; Borcan, F.; Ambrus, R.; Popovici, I. Syntheses of new cyclodextrin complexes with oleanolic and ursolic acids. J. Agroaliment. Proc. Technol., 2011, 17(4), 405-409.
Valdés, K.; Morales, J.; Rodríguez, L.; Günther, G. Potential use of nanocarriers with pentacyclic triterpenes in cancer treatments. Nanomedicine (Lond.), 2016, 11(23), 3139-3156.
[] [PMID: 27809705]
Fukushima, E.O.; Seki, H.; Ohyama, K.; Ono, E.; Umemoto, N.; Mizutani, M.; Saito, K.; Muranaka, T. CYP716A subfamily members are multifunctional oxidases in triterpenoid biosynthesis. Plant Cell Physiol., 2011, 52(12), 2050-2061.
[] [PMID: 22039103]
Csuk, R.; Deigner, H.P. The potential of click reactions for the synthesis of bioactive triterpenes. Bioorg. Med. Chem. Lett., 2019, 29(8), 949-958.
[] [PMID: 30799214]
Salazar, J.R.; Loza-Mejía, M.A.; Soto-Cabrera, D. Chemistry, biological activities and in silico bioprospection of sterols and triterpenes from mexican columnar Cactaceae. Molecules, 2020, 25(7), 1649.
[]] [PMID: 32260146]
Peron, G.; Marzaro, G.; Dall Acqua, S. Known triterpenes and their derivatives as scaffolds for the development of new therapeutic agents for cancer. Curr. Med. Chem., 2018, 25(10), 1259-1269.
[] [PMID: 28820068]
Amen, Y.M.; Zhu, Q.; Tran, H.B.; Afifi, M.S.; Halim, A.F.; Ashour, A.; Mira, A.; Shimizu, K. Lucidumol C, a new cytotoxic lanostanoid triterpene from Ganoderma lingzhi against human cancer cells. J. Nat. Med., 2016, 70(3), 661-666.
[] [PMID: 26899240]
Chuang, W.L.; Lin, P.Y.; Lin, H.C.; Chen, Y.L. The apoptotic effect of ursolic acid on SK-Hep-1 cells is regulated by the PI3K/Akt, p38 and JNK MAPK signaling pathways. Molecules, 2016, 21(4), 460.
[] [PMID: 27104510]
Li, Z.; You, K.; Li, J.; Wang, Y.; Xu, H.; Gao, B.; Wang, J. Madecassoside suppresses proliferation and invasiveness of HGF-induced human hepatocellular carcinoma cells via PKC-cMET-ERK1/2-COX-2-PGE2 pathway. Int. Immunopharmacol., 2016, 33, 24-32.
[] [PMID: 26851630]
Yang, H.; Kim, H.W.; Kim, Y.C.; Sung, S.H. Cytotoxic activities of naturally occurring oleanane-, ursane- and lupane-type triterpenes on HepG2 and AGS cells. Pharmacogn. Mag., 2017, 13(49), 118-122.
[] [PMID: 28216894]
Li, B.; Wu, G.L.; Dai, W.; Wang, G.; Su, H.Y.; Shen, X.P.; Zhan, R.; Xie, J.M.; Wang, Z.; Qin, Z.H.; Gao, Q.G.; Shen, G.H. Aescin-induced reactive oxygen species play a pro-survival role in human cancer cells via ATM/AMPK/ULK1-mediated autophagy. Acta Pharmacol. Sin., 2018, 39(12), 1874-1884.
[] [PMID: 29921885]
Yi, H.; Wang, K.; Du, B.; He, L.; Ho, H.; Qiu, M.; Zou, Y.; Li, Q.; Jin, J.; Zhan, Y.; Zhao, Z.; Liu, X. Aleuritolic acid impaired autophagic flux and induced apoptosis in hepatocellular carcinoma HepG2 cells. Molecules, 2018, 23(6)E1338
[] [PMID: 29865221]
Dasgupta, A.; Dey, D.; Ghosh, D.; Lai, T.K.; Bhuvanesh, N.; Dolui, S.; Velayutham, R.; Acharya, K. Astrakurkurone, a sesquiterpenoid from wild edible mushroom, targets liver cancer cells by modulating Bcl-2 family proteins. IUBMB Life, 2019, 71(7), 992-1002.
[] [PMID: 30977280]
Fontana, G.; Bruno, M.; Notarbartolo, M.; Labbozzetta, M.; Poma, P.; Spinella, A.; Rosselli, S. Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement. Bioorg. Chem., 2019, •••90103054
[] [PMID: 31212180]
He, H.; Shang, X.Y.; Liu, W.W.; Zhang, Y.; Song, S.J. Triterpenes from the fruit of Camptotheca acuminata suppress human hepatocellular carcinoma cell proliferation through apoptosis induction. Nat. Prod. Res., 2019, 33(24), 3527-3532.
[] [PMID: 29923429]
Li, Y.; Li, Z.; Jia, Y.; Ding, B.; Yu, J. In vitro anti-hepatoma activities of Notoginsenoside R1 through downregulation of tumor promoter miR-21. Dig. Dis. Sci., 2019.
[] [PMID: 31559550]
Wang, L.; Wang, J.; Cao, Y.; Li, W.; Wang, Y.; Xu, J.; Xu, G. Molecular evidence for better efficacy of hypocrellin A and oleanolic acid combination in suppression of HCC growth. Eur. J. Pharmacol., 2019, 842, 281-290.
[] [PMID: 30391347]
Yue, J.; Sun, Y.; Xu, J.; Cao, J.; Chen, G.; Zhang, H.; Zhang, X.; Zhao, Y. Cucurbitane triterpenoids from the fruit of Momordica charantia L. and their anti-hepatic fibrosis and anti-hepatoma activities. Phytochemistry, 2019, 157, 21-27.
[] [PMID: 30352327]
Kim, G.H.; Kan, S.Y.; Kang, H.; Lee, S.; Ko, H.M.; Kim, J.H.; Lim, J.H. Ursolic acid suppresses cholesterol biosynthesis and exerts anti-cancer effects in hepatocellular carcinoma cells. Int. J. Mol. Sci., 2019, 20(19)E4767
[] [PMID: 31561416]
Zhang, H.X.; Kang, Y.; Li, N.; Wang, H.F.; Bao, Y.R.; Li, Y.W.; Li, X.Z.; Jiang, Z.; Chen, G. Triterpenoids from Liquidambar Fructus induced cell apoptosis via a PI3K-AKT related signal pathway in SMMC7721 cancer cells. Phytochemistry, 2020, 171112228
[]] [PMID: 31911265]
Ayyad, S.E.; Abdel-Lateff, A.; Alarif, W.M.; Patacchioli, F.R.; Badria, F.A.; Ezmirly, S.T. In vitro and in vivo study of cucurbitacins-type triterpene glucoside from Citrullus colocynthis growing in Saudi Arabia against hepatocellular carcinoma. Environ. Toxicol. Pharmacol., 2012, 33(2), 245-251.
[] [PMID: 22245841]
Zhang, Z.; Wang, S.; Qiu, H.; Duan, C.; Ding, K.; Wang, Z. Waltonitone induces human hepatocellular carcinoma cells apoptosis in vitro and in vivo. Cancer Lett., 2009, 286(2), 223-231.
[] [PMID: 19539424]
Zhao, Q.; Xue, Y.; Wang, J.F.; Li, H.; Long, T.T.; Li, Z.; Wang, Y.M.; Dong, P.; Xue, C.H. In vitro and in vivo anti-tumour activities of echinoside A and ds-echinoside A from Pearsonothuria graeffei. J. Sci. Food Agric., 2012, 92(4), 965-974.
[] [PMID: 22012678]
He, Y.; Liu, F.; Zhang, L.; Wu, Y.; Hu, B.; Zhang, Y.; Li, Y.; Liu, H. Growth inhibition and apoptosis induced by lupeol, a dietary triterpene, in human hepatocellular carcinoma cells. Biol. Pharm. Bull., 2011, 34(4), 517-522.
[] [PMID: 21467639]
Lee, T.K.; Castilho, A.; Cheung, V.C.; Tang, K.H.; Ma, S.; Ng, I.O. Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation. Hepatology, 2011, 53(1), 160-170.
[] [PMID: 20979057]
Liu, F.; He, Y.; Liang, Y.; Wen, L.; Zhu, Y.; Wu, Y.; Zhao, L.; Li, Y.; Mao, X.; Liu, H. PI3-kinase inhibition synergistically promoted the anti-tumor effect of lupeol in hepatocellular carcinoma. Cancer Cell Int., 2013, 13(1), 108.
[] [PMID: 24176221]
Lu, X.L.; He, S.X.; Ren, M.D.; Wang, Y.L.; Zhang, Y.X.; Liu, E.Q. Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: involvement of CCAAT/enhancer binding protein β and cyclooxygenase-2. Mol. Med. Rep., 2012, 5(3), 637-644.
[]] [PMID: 22159471]
Kazmi, I.; Narooka, A.R.; Afzal, M.; Singh, R.; Al-Abbasi, F.A.; Ahmad, A.; Anwar, F. Anticancer effect of ursolic acid stearoyl glucoside in chemically induced hepatocellular carcinoma. J. Physiol. Biochem., 2013, 69(4), 687-695.
[] [PMID: 23512248]
Yang, J.; Qiu, B.; Li, X.; Zhang, H.; Liu, W. p53-p66(shc)/miR-21-Sod2 signaling is critical for the inhibitory effect of betulinic acid on hepatocellular carcinoma. Toxicol. Lett., 2015, 238(3), 1-10.
[] [PMID: 26222667]
Yang, F.; Gong, J.; Wang, G.; Chen, P.; Yang, L.; Wang, Z. Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway. Oncotarget, 2016, 7(46), 75165-75175.
[] [PMID: 27738335]
Ren, B.; Liu, H.; Gao, H.; Liu, S.; Zhang, Z.; Fribley, A.M.; Callaghan, M.U.; Xu, Z.; Zeng, Q.; Li, Y. Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR. Oncotarget, 2017, 8(54), 93039-93050.
[] [PMID: 29190976]
Liu, G.; Wang, K.; Kuang, S.; Cao, R.; Bao, L.; Liu, R.; Liu, H.; Sun, C. The natural compound GL22, isolated from Ganoderma mushrooms, suppresses tumor growth by altering lipid metabolism and triggering cell death. Cell Death Dis., 2018, 9(6), 689.
[] [PMID: 29880886]
Wakamatsu, T.; Nakahashi, Y.; Hachimine, D.; Seki, T.; Okazaki, K. The combination of glycyrrhizin and lamivudine can reverse the cisplatin resistance in hepatocellular carcinoma cells through inhibition of multidrug resistance-associated proteins. Int. J. Oncol., 2007, 31(6), 1465-1472.
[] [PMID: 17982673]
Wu, S.; Zhang, T.; Du, J. Ursolic acid sensitizes cisplatin-resistant HepG2/DDP cells to cisplatin via inhibiting Nrf2/ARE pathway. Drug Des. Devel. Ther., 2016, 10, 3471-3481.
[] [PMID: 27822011]
Lu, M.; Fei, Z.; Zhang, G. Synergistic anticancer activity of 20(S)-ginsenoside Rg3 and Sorafenib in hepatocellular carcinoma by modulating PTEN/Akt signaling pathway. Biomed. Pharmacother., 2018, 97, 1282-1288.
[] [PMID: 29156516]
Zhang, R.; Chen, Z.; Wu, S.S.; Xu, J.; Kong, L.C.; Wei, P. Celastrol enhances the anti-liver cancer activity of sorafenib. Med. Sci. Monit., 2019, 25, 4068-4075.
[] [PMID: 31152143]
Liese, J.; Hinrichs, T.M.; Lange, M.; Fulda, S. Cotreatment with sorafenib and oleanolic acid induces reactive oxygen species-dependent and mitochondrial-mediated apoptotic cell death in hepatocellular carcinoma cells. Anticancer Drugs, 2019, 30(3), 209-217.
[] [PMID: 30640794]
Hu, S.; Zhu, Y.; Xia, X.; Xu, X.; Chen, F.; Miao, X.; Chen, X. Ginsenoside Rg3 prolongs survival of the orthotopic hepatocellular carcinoma model by inducing apoptosis and inhibiting angiogenesis. Anal. Cell. Pathol. (Amst), 2019, 2019,3815786.
[]] [PMID: 31534898]
Lv, Y.; Li, J.; Chen, H.; Bai, Y.; Zhang, L. Glycyrrhetinic acid-functionalized mesoporous silica nanoparticles as hepatocellular carcinoma-targeted drug carrier. Int. J. Nanomedicine, 2017, 12, 4361-4370.
[] [PMID: 28652738]
Kumar, P.; Singh, A.K.; Raj, V.; Rai, A.; Keshari, A.K.; Kumar, D.; Maity, B.; Prakash, A.; Maiti, S.; Saha, S. Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations. Int. J. Nanomedicine, 2018, 13, 975-990.
[] [PMID: 29497292]
Zhang, J.; Wang, Y.; Jiang, Y.; Liu, T.; Luo, Y.; Diao, E.; Cao, Y.; Chen, L.; Zhang, L.; Gu, Q.; Zhou, J.; Sun, F.; Zheng, W.; Liu, J.; Li, X.; Hu, W. Enhanced cytotoxic and apoptotic potential in hepatic carcinoma cells of chitosan nanoparticles loaded with ginsenoside compound K. Carbohydr. Polym., 2018, 198, 537-545.
[] [PMID: 30093032]
Zhou, M.; Yi, Y.; Liu, L.; Lin, Y.; Li, J.; Ruan, J.; Zhong, Z. Polymeric micelles loading with ursolic acid enhancing anti-tumor effect on hepatocellular carcinoma. J. Cancer, 2019, 10(23), 5820-5831.
[] [PMID: 31737119]
Khan, M.W.; Zhao, P.; Khan, A.; Raza, F.; Raza, S.M.; Sarfraz, M.; Chen, Y.; Li, M.; Yang, T.; Ma, X.; Xiang, G. Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity. Int. J. Nanomedicine, 2019, 14, 3753-3771.
[] [PMID: 31239661]
Zhao, R.; Li, T.; Zheng, G.; Jiang, K.; Fan, L.; Shao, J. Simultaneous inhibition of growth and metastasis of hepatocellular carcinoma by co-delivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive chitosan-conjugated mesoporous silica nanocomplex. Biomaterials, 2017, 143, 1-16.
[] [PMID: 28755539]

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