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http://dx.doi.org/10.3831/KPI.201.22.007

Role of Pentacyclic Triterpenoids in Chemoprevention and Anticancer Treatment: An Overview on Targets and Underling Mechanisms  

Ghante, Mahavir H. (Centre for Research in Pharmaceutical Sciences, Sharda Bhavan Education Society's Nanded Pharmacy College)
Jamkhande, Prasad G. (Centre for Research in Pharmaceutical Sciences, Sharda Bhavan Education Society's Nanded Pharmacy College)
Publication Information
Journal of Pharmacopuncture / v.22, no.2, 2019 , pp. 55-67 More about this Journal
Abstract
The incidences of cancer are continuously increasing worldwide, affecting life of millions of people. Several factors associated with the internal and external environment are responsible for this deadly disease. The key internal determinants like abnormal hormonal regulation, genetic mutations and external determinants such as lifestyle and occupational factors enhances onset of cancer. From the ancient time, plants were remained as the most trusted source of medicine for the treatment of diverse disease conditions. Extensive studies have been performed for the discovery of effective anticancer agent from the plant and still it is going on. Pentacyclic triterpenoids are biologically active phytochemicals having a different range of activities such as anti-inflammatory, hepatoprotective, anti-hypertensive, antiulcerogenic and anti-tumor. These compounds generally contain ursane, oleanane, lupane and friedelane as a chief skeleton of pentacyclic triterpenoids which are generally present in higher plants. Isoprene unit, phytochemical, with good antitumor/anticancer activity is required for the biosynthesis of pentacyclic triterpenoids. Mechanisms such as cytotoxicity, DNA polymerase inhibition, regulation of apoptosis, change in signal transductions, interfere with angiogenesis and dedifferentiation, antiproliferative activity and metastasis inhibition are might be responsible for their anticancer effect. Present review spotlights diverse targets, mechanisms and pathways of pentacyclic triterpenoids responsible for anticancer effect.
Keywords
cancer; pentacyclic triterpenoids; apoptosis; anti-angiogenic; isoprene; antiproliferative;
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1 Martinez A, Rivas F, Perojil A, Parra A, Garcia-Granados A, Fernandez-Vivas A. Biotransformation of oleanolic and maslinic acids by Rhizomucor miehei. Phytochemistry. 2013;94:229-237.   DOI
2 Parmar S, Sharma T, Airao V, Bhatt R, Aghara R, Chavda S, Rabadiya SO, Gangwal AP. Neuropharmacological effects of triterpenoids. Phytopharmacology. 2013;4:354-372.
3 Pollier J, Goossens A. Oleanolic acid. Phytochemistry. 2012;77:10-15.   DOI
4 Maia JL, Lima-Junior RC, Melo CM, David JP, David JM, Campos AR, Santos FA, Rao VS. Oleanolic acid, a pentacyclic triterpene attenuates capsaicin-induced nociception in mice: possible mechanisms. Pharmacol Res. 2006;54:282-286.   DOI
5 Moreira DLF, de-Souza GHB, Rodrigues IV, Lopes NP, de Oliveira AR. A non-michaelian behavior of the in vitro metabolism of the pentacyclic triterpene alfa and beta amyrins by employing rat liver microsomes. J Pharm Biomed Anal. 2013;84:14-19.   DOI
6 Csuk R, Siewert B, Dressel C, Schafer R. Tormentic acid derivatives: synthesis and apoptic activity. Eur J Med Chem. 2012;56:237-245.   DOI
7 Mandal A, Ghosh S, Bothra AK, Nanda AK, Ghosh P. Synthesis of friedelan triterpenoid analogs with DNA topoisomerase $II{\alpha}$ inhibitory activity and their molecular docking studies. Eur J Med Chem. 2012;54:137-143.   DOI
8 American Cancer Society, Cancer Facts & Figures 2016, Atlanta: American Cancer Society; 2016.
9 International Agency for Research on Cancer and Cancer Research UK. World Cancer Factsheet, Cancer Research UK, London; 2012.
10 American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.
11 Ali I, Wani WA, Saleem K. Cancer scenario in India with future perspectives. Cancer Ther. 2011;8:56-70.
12 Hu Y, Fu L. Targeting cancer stem cells: a new therapy to cure cancer patients. Am J Cancer Res. 2012;2:340-356.
13 Ebner F, Schremmer-Danninger E, Rehbock J. The role of TP53 and p21 gene polymorphisms in breast cancer biology in a well specified and characterized German cohort. J Cancer Res Clin Oncol. 2010;136:1369-1375.   DOI
14 Mutai C, Abatis D, Vagias C, Moreau D, Roussakis C, Roussis V. Cytotoxic lupane-type triterpenoids from Acacia mellifera. Phytochemistry. 2004;65:1159-1164.   DOI
15 Ketron AC, Osheroff N. Phytochemicals as anticancer and chemopreventive topoisomerase II poisons. Phytochem Rev. 2013;13:19-35.   DOI
16 Sun H, Fang WS, Wang WZ, Hu C. Structure-activity relationships of oleanane-and ursane-type triterpenoids. Botanical Studies. 2006;47:339-368.
17 Chen Y, Williams V, Filippova M, Filippov V, Duerksen-Hughes P. Viral carcinogenesis: factors inducing DNA damage and virus integration. Cancers. 2014;6: 2155-2186.   DOI
18 Nath R, RoyS, De B, Choudhury MD. Anticancer and antioxidant activity of croton: a review. Int J Pharm Pharm Sci. 2013;5:63-70.
19 Ramachandran S, Prasad NR. Effect of ursolic acid, a triterpenoid antioxidant, on ultraviolet-B radiation-induced cytotoxicity, lipid peroxidation and DNA damage in human lymphocytes. Chem Biol Interact. 2008;176:99-107.   DOI
20 Pittayapan P. Health Insurance for Cancer Care in Asia: Thailand. Asia Pac J Oncol Nurs. 2016;3:54.   DOI
21 Sreedevi A, Javed R, Dinesh A. Epidemiology of cervical cancer with special focus on India. Int J Womens Health. 2015;7:405-414.
22 Dsouza ND, Murthy N, Aras R. Projection of cancer incident cases for India-till 2026. Asian Pac J Cancer Prev. 2013;14:4379-4386.   DOI
23 Dikshit R, Gupta PC, Ramasundarahettige C, Gajalakshmi V, Aleksandrowicz L, Badwe R, et al. Cancer mortality in India: a nationally representative survey. The Lancet. 2012;379:1807-1816.   DOI
24 James JT, Dubery IA. Pentacyclic triterpenoids from the medicinal herb, Centella asiatica (L.) Urban. Molecules. 2009;14:3922-3941.   DOI
25 Laszczyk MN. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta med. 2009;75:1549-1560.   DOI
26 Reyes CP, Nunez MJ, Jimenez IA, Busserolles J, Alcaraz MJ, Bazzocchi IL. Activity of lupane triterpenoids from Maytenus species as inhibitors of nitric oxide and prostaglandin E 2. Bioorg Med Chem. 2006;14:1573-1579.   DOI
27 Yan XJ, Gong LH, Zheng FY, Cheng KJ, Chen ZS, Shi Z. Triterpenoids as reversal agents for anticancer drug resistance treatment. Drug Discov Today. 2014;19:482-488.   DOI
28 Yan J, Sun L, Zhang X, Li Z, Zhou L, Qiu M. Serratene Triterpenoids from Palhinhaea cernua var. sikkimensis. Chem Pharm Bull (Tokyo). 2009;57:1381-1384.   DOI
29 Shanmugam MK, Dai X, Kumar AP, Tan BK, Sethi G, Bishayee A. Ursolic acid in cancer prevention and treatment:molecular targets, pharmacokinetics and clinical studies. Biochem Pharmacol. 2013;85:1579-1587.   DOI
30 Furtado RA, Rodrigues EP, Araujo FR, Oliveira WL, Furtado MA, Castro MB, et al. Ursolic acid and oleanolic acid suppress preneoplastic lesions induced by 1, 2-dimethylhydrazine in rat colon. Toxicol Pathol. 2008;36:576-580.   DOI
31 Salminen A, Lehtonen M, Suuronen T, Kaarniranta K, Huuskonen J. Terpenoids: natural inhibitors of NF-${\kappa}B$ signaling with anti-inflammatory and anticancer potential. Cell Mol Life Sci. 2008;65:2979-2999.   DOI
32 Wittayalai S, Sathalalai S, Thorroad S, Worawittayanon P, Ruchirawat S, Thasana N. Lycophlegmariols A-D: Cytotoxic serratene triterpenoids from the club moss Lycopodium phlegmaria L. Phytochemistry. 2012;76:117-123.   DOI
33 Lopez-Hortas L, Perez-Larran P, Gonzalez-Munoz MJ, Falque E, Dominguez H. Recent developments on the extraction and application of ursolic acid. A review. Food Research International. 2018;103:130-149.   DOI
34 Kangsamaksin T, Chaithongyot S, Wootthichairangsan C, Hanchaina R, Tangshewinsirikul C, Svasti J. Lupeol and stigmasterol suppress tumor angiogenesis and inhibit cholangiocarcinoma growth in mice via downregulation of tumor necrosis factor-$\alpha$. Plos One. 2017;12:1-16.
35 Turan I, Demir S, Kilinc K, Yaman SO, Misir S, Kara H, et al. Cytotoxic effect of Rosa canina extract on human colon cancer cells through repression of telomerase expression. Journal of Pharmaceutical Analysis. 2018;8(6):394-399.   DOI
36 Thoppil RJ, Bishayee A. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer. World J Hepatol. 2011;3:228-249.   DOI
37 Gauthier C, Legault J, Lebrun M, Dufour P, Pichette A. Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents. Bioorg Med Chem. 2006;14:6713-6725.   DOI
38 Feng JH, Chen W, Zhao Y, Ju XL. Anti-tumor activity of oleanolic, ursolic and glycyrrhetinic acid. The Open Natural Products Journal. 2009;2:48-52.   DOI
39 Soldi C, Pizzolatti MG, Luiz AP, Marcon R, Meotti FC, Mioto LA, et al. Synthetic derivatives of the $\alpha$-and $\beta$-amyrin triterpenes and their antinociceptive properties. Bioorg Med Chem. 2008;16:3377-3386.   DOI
40 Kvasnica M, Sarek J, Klinotova E, Dzubak P, Hajduch M. Synthesis of phthalates of betulinic acid and betulin with cytotoxic activity. Bioorg Med Chem. 2005;13:3447-3454.   DOI
41 Patocka J. Biologically active pentacyclic triterpenes and their current medicine signification. J Appl Biomed. 2003;1:7-12.   DOI
42 Bishayee A, Ahmed S, Brankov N, Perloff M. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Front Biosci. 2011;16:980.   DOI
43 Li ZJ, Yao C, Liu SF, Chen L, Xi YM, Zhang W, et al. Cytotoxic effect of icaritin and its mechanisms in inducing apoptosis in human burkitt lymphoma cell line. Biomed Res Int. 2014;1-7.
44 Andreeff M, Goodrich DW, Pardee AB. Cell proliferation, differentiation, and apoptosis. In: Kufe DW, Pollock RE, Weichselbaum RR editors. Holland-Frei Cancer Medicine. 6th edit. Hamilton (ON): BC Decker;2003.
45 Kaur J, Sharma M, Sharma P, Bansal MP. Antitumor activity of lantadenes in DMBA/TPA induced skin Tumors in mice: expression of transcription factors. Am J Biomed Sci. 2010;2:79-90.
46 Satomi Y, Nishino H, Shibata S. Glycyrrhetinic acid and related compounds induce G1 arrest and apoptosis in human hepatocellular carcinoma HepG2. Anticancer Res. 2005; 25:4043-4047.
47 Grace-Lynn C, Darah I, Chen Y, Latha LY, Jothy SL, Sasidharan S. In vitro antioxidant activity potential of lantadene A, a pentacyclic triterpenoid of Lantana plants. Molecules. 2012;17:11185-11198.   DOI
48 Patel S. A weed with multiple utility: Lantana camara. Reviews in Environmental Science and Bio/Technology. 2011;10:341-351.   DOI
49 Wang SR, Fang WS. Pentacyclic triterpenoids and their saponins with apoptosis-inducing activity. Curr Top Med Chem. 2009;9:1581-1596.   DOI
50 Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161:205-214.   DOI
51 Juan ME, Planas JM, Ruiz-Gutierrez V, Daniel H, Wenzel U. Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Br J Nutr. 2008;100:36-43.   DOI
52 Sharma M, Sharma P, Bansal M, Singh J. Lantadene A-induced apoptosis in human leukemia HL-60 cells. Indian J Pharmacol. 2007;39:140.   DOI
53 Wynendaele W, OosteromVA, Pawinski A, De Bruijn EA, Maesi RA. Angiogenesis: possibilities for therapeutic interventions. Pharm World Sci. 1998;20:225-235.   DOI
54 Prasad S, Kalra N, Shukla Y. Induction of apoptosis by lupeol and mango extract in mouse prostate and LNCaP cells. Nutr Cancer. 2008;60:120-130.   DOI
55 Mu X, Shi W, Sun L, Li H, Li H, Jiang Z, et al. Pristimerin, a triterpenoid, inhibits tumor angiogenesis by targeting VEGFR2 activation. Molecules. 2012;17:6854-6868.   DOI
56 Senese S, Lo Y, Huang D, Zangle TA, Gholkar AA, Robert L, et al. Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development. Cell Death Dis. 2014;5:e1462.   DOI
57 Janakiram NB, Indranie C, Malisetty SV, Jagan P, Steele VE, Rao CV. Chemoprevention of colon carcinogenesis by oleanolic acid and its analog in male F344 rats and modulation of COX-2 and apoptosis in human colon HT-29 cancer cells. Pharm Res. 2008;25:2151-2157.   DOI
58 Kanda T, Yokosuka O. The androgen receptor as an emerging target in hepatocellular carcinoma. J Hepatocell Carcinoma. 2015;2:91-99.   DOI
59 Fritz WA, Lin TM, Peterson RE. The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates. Carcinogenesis. 2008;29:1077-1082.   DOI
60 Lu JJ, Dang YY, Huang M, Xu WS, Chen XP, Wang YT. Anti-cancer properties of terpenoids isolated from Rhizoma Curcumae-A review. J Ethnopharmacol. 2012;143: 406-411.   DOI
61 Sun CC, Zhang YS, Xue X, Cheng YN, Liu HP, Zhao CR, et al. Inhibition of angiogenesis involves in anticancer activity of riccardin D, a macrocyclic bisbibenzyl, in human lung carcinoma. Eur J Pharmacol. 2011;667:136-143.   DOI
62 Swain SS, Rout KK, Chand PK. Production of triterpenoid anti-cancer compound taraxerol in Agrobacterium-transformed root cultures of butterfly pea (Clitoria ternatea L.). Appl Biochem Biotechnol. 2012;168:487-503.   DOI
63 Khanal P, Oh WK, Thuong PT, Cho SD, Choi HS. 24-Hydroxyursolic acid from the leaves of the Diospyros kaki (Persimmon) induces apoptosis by activation of AMP-activated protein kinase. Planta Med. 2010;76:689-693.   DOI
64 Neto CC. Ursolic acid and other pentacyclic triterpenoids: anticancer activities and occurrence in berries. Berries and Cancer Prevention. Springer New York; 2011.
65 Kim SS, Won SJ, Kim NJ, Cho SD, Choi HS. 3-Oxoolean-12-en-27-oic acid isolated from Aceriphyllum rossii induces caspase-8-dependent apoptosis in human promyelocytic leukemia HL-60 cells. Biol Pharm Bull. 2009;32:91-98.   DOI
66 Youn SH, Lee JS, Lee MS, Cha EY, Thuong PT, Kim JR, Chang ES. Anticancer properties of pomolic acid-induced AMP-activated protein kinase activation in MCF7 human breast cancer cells. Biol Pharm Bull. 2012;35:105-110.   DOI
67 Harsh M. Textbook of pathology. Jaypee Brothers Medical Publishers. New Delhi; 2010.
68 Singh MP, Kumar V, Agarwal A, Kumar R, Bhatt ML, Misra S. Clinico-epidemiological study of oral squamous cell carcinoma: A tertiary care centre study in North India. J Oral Biol Craniofac Res. 2016;6:32-35.   DOI
69 Loney T, Aw TC, Handysides DG Ali R, Blair I, Grivna M, Shah SM, et al. An analysis of the health status of the United Arab Emirates: the 'Big 4'public health issues. Global health action. 2013;6:1-8.   DOI
70 Dhanamani M, Devi SL, Kannan S. Ethnomedicinal plants for cancer therapy - a review. Hygeia JD Med. 2011;3:1-10.
71 Rang HP, Ritter JM, Flower RJ. Rang and Dale's Pharmacology: With student consult online access: Elsevier Health Sciences. 7th edition. Churchill Livingstone: Edinburgh; 2012.
72 Wang FZ, Yang NN, Zhao YL, Liu QQ, Fei HR, Zhang JG. PF-04691502 triggers cell cycle arrest, apoptosis and inhibits the angiogenesis in hepatocellular carcinoma cells. Toxicol Lett. 2013;220:150-156.   DOI
73 Niedzwiecki A, Roomi MW, Kalinovsky T, Rath M. Anticancer Efficacy of Polyphenols and Their Combinations. Nutrients. 2016;8:552.   DOI
74 Safarzadeh E, ShotorbaniSS, Baradaran B. Herbal medicine as inducers of apoptosis in cancer treatment. Adv Pharm Bull. 2014;4:421-427.
75 Fabio GD, Romanucci V, De Marco A, Zarrelli A. Triterpenoids from Gymnema sylvestre and their pharmacological activities. Molecules. 2014;19:10956-10981.   DOI
76 Pratheeshkumar P, Sreekala C, Zhang Z, Budhraja A, Ding S, Son YO, Wang X, Hitron A, Hyun-Jung K, Wang L, Lee JC. Cancer prevention with promising natural products: mechanisms of action and molecular targets. Anticancer Agents Med Chem. 2012;12:1159-1184.   DOI
77 Shu L, Cheung KL, Khor TO, Chen C, Kong AN. Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis. Cancer Metastasis Rev. 2010;29:483-502.   DOI
78 Muffler K, Leipold D, Scheller MC, Haas C, Steingroewer J, Bley T, Neuhaus HE, Mirata MA, Schrader J, Ulber R. Biotransformation of triterpenes. Process Biochemistry. 2011;46:1-15.   DOI