A Review on Anticancer Properties of Chebulagic Acid from Terminalia chebula

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DOI: 10.21522/TIJPH.2013.12.03.Art047

Authors : R. Satheesh Kumar, P. Amudha, R. Vidya, C.S. Kalpana, S. Sudhashini

Abstract:

This review aims to explore the potential of Chebulagic acid, a hydrolysable tannin derived from Terminalia chebula, in the treatment of cancer. Chebulagic acid boasts a myriad of medicinal and pharmacological benefits, including but not limited to antibacterial, antiviral, antioxidant, antidiabetic, antifungal, antiulcer, anticancer, antimutagenic, and wound healing properties. The objective of this review is to compile existing scientific literature on the anticancer attributes of Chebulagic acid. Numerous studies have elucidated its ability to regulate apoptosis and inhibit proliferation in various cancer cell lines and pathways. Nonetheless, further in vivo investigations are imperative to thoroughly dissect the mechanism-based pharmacological profile of Chebulagic acid. Such studies will furnish robust scientific evidence elucidating its anticancer efficacy across different cancer types and appraise its suitability for clinical trials.

References:

[1]. Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., Parkin, D. M., 2010. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer. 127(12), 2893–2917. https://doi.org/10.1002/ijc.25516.
[2]. Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., Bray, F., 2021, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 71(3):209-49. https://doi.org/10.3322/caac.21660.
[3]. Varshney, K., Mishra, K., 2022, Preclinical Research to Clinical Practice: A Review of Phytochemicals in Cancer Treatment. International Journal of Innovative Research in Engineering & Management. 9(1):147-51. DOI:10.55524/ijirem.2022.9.1.26.
[4]. Li, Q., Lei, X., Zhu, J., Zhong, Y., Yang, J., Wang, J., Tan, H., 2023, Radiotherapy/Chemotherapy‐Immunotherapy for Cancer Management: From Mechanisms to Clinical Implications. Oxidative Medicine and Cellular Longevity. 7530794. https://doi.org/10.1155/2023/7530794.
[5]. Di Gioia, F., Tzortzakis, N., Rouphael, Y., Kyriacou, M.C., Sampaio, S.L., CFR Ferreira, I., Petropoulos, S.A., 2020, Grown to be blue-antioxidant properties and health effects of colored vegetables. Part II: Leafy, fruit, and other vegetables. Antioxidants. 9(2):97. https://doi.org/10.3390/antiox9020097.
[6]. Kilit, A.C., Aydemir, E., 2023, Anticancer Effects of Punicalagin. Haydarpasa Numune Medical Journal. 63(1). DOI: 10.14744/hnhj.2021.77044.
[7]. Prathiba, S., Rajagopal, P., Selvaraj Jayaraman, M.K., Mahendra, J., Kasturi, R., 2021, A Review on Therapeutic Perspectives of Anticancer Properties of Chebulagic Acid. NVEO-NATURAL VOLATILES & ESSENTIAL OILS Journal| NVEO. 7598-612.https://www.researchgate.net/publication/356842524.
[8]. Rathinamoorthy, R., Thilagavathi, G., 2014, Terminalia chebula-review on pharmacological and biochemical studies. International Journal of PharmTech Research. 6(1):97-116. https://www.researchgate.net/publication/260132544.
[9]. Saini, N., Lather, V., Gahlawat, S.K., 2022, Exploring phytochemicals from himalayan medicinal plants as novel therapeutic agents. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). 22(9):1674-98. https://doi.org/10.2174/1871520621666211015141020.
[10]. Rao, N.K., Nammi, S., 2006, Antidiabetic and renoprotective effects of the chloroform extract of Terminalia chebula Retz. seeds in streptozotocin-induced diabetic rats. BMC complementary and alternative medicine. 6:1-6. https://doi.org/10.1186/1472-6882-6-17.
[11]. Kannan, P., Ramadevi, S.R., Hopper, W., 2009, Antibacterial activity of Terminalia chebula fruit extract. African Journal of Microbiology Research. 3(4):180-4. e http://www.academicjournals.org/ajmr.
[12]. Kim, T.G., Kang, S.Y., Jung, K.K., Kang, J.H., Lee, E., Han, H.M., Kim, S.H., 2001, Antiviral activities of extracts isolated from Terminalis chebula Retz., Sanguisorba officinalis L., Rubus coreanus Miq. and Rheum palmatum L. against hepatitis B virus. Phytotherapy research. 15(8):718-20. https://doi.org/10.1002/ptr.832.
[13]. Aher, V., Wahi, A., 2011, Immunomodulatory activity of alcohol extract of Terminalia chebula retz combretaceae. Tropical Journal of Pharmaceutical Research. 10(5):567-75. DOI:10.4314/tjpr.v10i5.5.
[14]. Thoithoisana Devi, S., Devika Chanu, K., Singh, N.B., Chaudhary, S.K., Keithellakpam, O.S., Singh, K.B., Mukherjee, P.K., Sharma, N., 2023, Chemical profiling and therapeutic evaluation of standardized hydroalcoholic extracts of Terminalia chebula fruits collected from different locations in Manipur against colorectal cancer. Molecules. 28(7):2901. https://doi.org/10.3390/molecules28072901.
[15]. Said Muhammad, S.M., Khan, B.A., Naveed Akhtar, N.A., Tariq Mahmood, T.M., Akhtar Rasul, A.R., Irshad Hussain, I.H., Haroon Khan, H.K., Amir Badshah, A.B., 2023, The morphology, extractions, chemical constituents and uses of Terminalia chebula: a review. 4772-4775. Publisher: Academic Journals.
[16]. Han QuanBin, H.Q., Song JingZheng, S.J., Qiao ChunFeng, Q.C., Wong Lina, W.L., Xu HongXi, X.H., 2006, Preparative isolation of hydrolysable tannins chebulagic acid and chebulinic acid from Terminalia chebula by high-speed counter-current chromatography. 1653-1657. DOI: 10.1002/jssc.200600089.
[17]. Bhatt, I.D., Rawat, S., Badhani, A., Rawal, R.S., 2017, Nutraceutical potential of selected wild edible fruits of the Indian Himalayan region. Food chemistry. 215:84-91. https://doi.org/10.1016/j.foodchem.2016.07.143.
[18]. Nutalapati, C., Chiranjeevi, U.K., Kishan, P.V., Kiran, K.K., Pingali, U., 2016, A randomized, double-blind, placebo-controlled, parallel group clinical study to evaluate the analgesic effect of aqueous extract of terminalia chebula, a proprietary chromium complex, and their combination in subjects with joint discomfort. Asian Journal of Pharmaceutical and Clinical Research. 9(3):264-9. https://doi.org/10.1007/s00408-022-00592-5.
[19]. Sheng, Z., Zhao, J., Muhammad, I., Zhang, Y., 2018, Optimization of total phenolic content from Terminalia chebula Retz. fruits using response surface methodology and evaluation of their antioxidant activities. PloS one. 13(8):e0202368. https://doi.org/10.1371/journal.pone.0202368.
[20]. Engels, C., KNOdler, M.A., Zhao, Y.Y., Carle, R., Gänzle, M.G., Schieber, A., 2009, Antimicrobial activity of gallotannins isolated from mango (Mangifera indica L.) kernels. Journal of agricultural and food chemistry. 57(17):7712-8. https://doi.org/10.1021/jf901621m.
[21]. Zhao, X., Sun, H., Hou, A., Zhao, Q., Wei, T., Xin, W., 2005, Antioxidant properties of two gallotannins isolated from the leaves of Pistacia weinmannifolia. Biochimica Et Biophysica Acta (BBA)-General Subjects. 1725(1):103-10. https://doi.org/10.1016/j.bbagen.2005.04.015.
[22]. Sangiovanni, E., Vrhovsek, U., Rossoni, G., Colombo, E., Brunelli, C., Brembati, L., Trivulzio, S., Gasperotti, M., Mattivi, F., Bosisio, E., Dell'Agli, M., 2013, Ellagitannins from Rubus berries for the control of gastric inflammation: in vitro and in vivo studies. PloS one. 8(8):e71762. https://doi.org/10.1371/journal.pone.0071762.
[23]. Hussein, R.H, Khalifa, F.K., 2014, The protective role of ellagitannins flavonoids pretreatment against N-nitrosodiethylamine induced-hepatocellular carcinoma. Saudi Journal of Biological Sciences. 21(6):589-96. https://doi.org/10.1016/j.sjbs.2014.03.004.
[24]. Lee, W., Lee, S.Y., Son, Y.J., Yun, J.M., 2015, Gallic acid decreases inflammatory cytokine secretion through histone acetyltransferase/histone deacetylase regulation in high glucose-induced human monocytes. Journal of medicinal food. 18(7):793-801. https://doi.org/10.1089/jmf.2014.3342.
[25]. Walia, H., Arora, S., 2013, Terminalia chebula—a pharmacognistic account. Journal of Medicinal Plants Research. 7(20):1351-61. DOI: 10.5897/JMPR12.050.
[26]. Priscilla, D.H., Prince, P.S., 2009, Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial infarction in Wistar rats. Chemico-biological interactions. 179(2-3):118-24. https://doi.org/10.1016/j.cbi.2008.12.012.
[27]. Ahmad, R.S., Hussain, M.B., Sultan, M.T., Arshad, M.S., Waheed, M., Shariati, M.A., Plygun, S., Hashempur, M.H., 2020, Biochemistry, safety, pharmacological activities, and clinical applications of turmeric: a mechanistic review. Evidence‐Based Complementary and Alternative Medicine. 2020(1):7656919. https://doi.org/10.1155/2020/7656919.
[28]. Ho, H.H., Chang, C.S., Ho, W.C., Liao, S.Y., Wu, C.H., Wang, C.J., 2010, Anti-metastasis effects of gallic acid on gastric cancer cells involves inhibition of NF-κB activity and downregulation of PI3K/AKT/small GTPase signals. Food and Chemical Toxicology. 48(8-9):2508-16. https://doi.org/10.1016/j.fct.2010.06.024.
[29]. Farag, M.A., Al‐Mahdy, D.A., Salah, El Dine, R., Fahmy, S., Yassin, A., Porzel, A., Brandt, W., 2015, Structure Activity Relationships of Antimicrobial Gallic Acid Derivatives from Pomegranate and Acacia Fruit Extracts against Potato Bacterial Wilt Pathogen. Chemistry & biodiversity. 12(6):955-62. https://doi.org/10.1002/cbdv.201400194.
[30]. Ibrahim, A., El Kareem, R., Sheir, M., 2015, Elucidation of acrylamide genotoxicity and neurotoxicity and the protective role of gallic acid and green tea. Journal of Forensic Toxicology & Pharmacology. 4(1). DOI:10.5281/zenodo.25849.
[31]. Hamada, S.I., Kataoka, T., Woo, J.T., Yamada, A., Yoshida, T., Nishimura, T., Otake, N., Nagai, K., 1997, Immunosuppressive effects of gallic acid and chebulagic acid on CTL-mediated cytotoxicity. Biological and Pharmaceutical Bulletin. 20(9):1017-9.  https://doi.org/10.1248/bpb.20.1017.
[32]. Sarkaki, A., Fathimoghaddam, H., Mansouri, S.M., Korrani, M.S., Saki, G., Farbood, Y., 2014, Gallic acid improves cognitive, hippocampal long-term potentiation deficits and brain damage induced by chronic cerebral hypoperfusion in rats. Pakistan Journal of Biological Sciences. 17(8):978-90. DOI: 10.3923/pjbs.2014.978.990.
[33]. Ajala, O.S., Jukov, A., Ma, C.M., 2014, Hepatitis C virus inhibitory hydrolysable tannins from the fruits of Terminalia chebula. Fitoterapia. 99:117-23. https://doi.org/10.1016/j.fitote.2014.09.014.
[34]. Pham, A.T., Malterud, K.E., Paulsen, B.S., Diallo, D., Wangensteen, H., 2014, α-Glucosidase inhibition, 15-lipoxygenase inhibition, and brine shrimp toxicity of extracts and isolated compounds from Terminalia macroptera leaves. Pharmaceutical Biology. 52(9):1166-9. https://doi.org/10.3109/13880209.2014.880486.
[35]. Lee, H.S., Jung, S.H., Yun, B.S., Lee, K.W., 2007, Isolation of chebulic acid from Terminalia chebula Retz. and its antioxidant effect in isolated rat hepatocytes. Archives of Toxicology. 81:211-8. https://doi.org/10.1007/s00204-006-0139-4.
[36]. Yang, Y., Xiu, J., Liu, J., Zhang, L., Li, X., Xu, Y., Qin, C., Zhang, L., 2013, Chebulagic acid, a hydrolyzable tannin, exhibited antiviral activity in vitro and in vivo against human enterovirus 71. International Journal of Molecular Sciences. 14(5):9618-27. https://doi.org/10.3390/ijms14059618.
[37]. Banerjee, R., Mukherjee, G., Patra, K.C., 2005, Microbial transformation of tannin-rich substrate to gallic acid through co-culture method. Bioresource Technology. 96(8):949-53. https://doi.org/10.1016/j.biortech.2004.08.004.
[38]. Reddy, D.B., Reddanna, P., 2009, Chebulagic acid (CA) attenuates LPS-induced inflammation by suppressing NF-κB and MAPK activation in RAW 264.7 macrophages. Biochemical and Biophysical Research Communications. 381(1):112-7. https://doi.org/10.1016/j.bbrc.2009.02.022.
[39]. Huang, Y.N., Zhao, D.D., Gao, B., Zhong, K., Zhu, R.X., Zhang, Y., Xie, W.J., Jia, L.R., Gao, H., 2012, Anti-hyperglycemic effect of chebulagic acid from the fruits of Terminalia chebula Retz. International Journal of Molecular Sciences. 13(5):6320-33. https://doi.org/10.3390/ijms13056320.
[40]. Kim, H.J., Kim, J., Kang, K.S., Lee, K.T., Yang, H.O., 2014, Neuroprotective effect of chebulagic acid via autophagy induction in SH-SY5Y cells. Biomolecules & therapeutics. 22(4):275. DOI: 10.4062/biomolther.2014.068.
[41]. Athira, A.P., Helen, A., Saja, K., Reddanna, P., Sudhakaran, P.R., 2013, Inhibition of Angiogenesis In Vitro by Chebulagic Acid: A COX‐LOX Dual Inhibitor. International Journal of Vascular Medicine. 2013;2013(1):843897. https://doi.org/10.1155/2013/843897.
[42]. Daniyal, M., Akram, M., Zainab, R., Munir, N., Sharif, A., Shah, S.M., Liu, B., Wang, W., 2019, Prevalence and current therapy in chronic liver disorders. Inflammopharmacology. 27:213-31. https://doi.org/10.1007/s10787-019-00562-z.
[43]. Mishra, V., Agrawal, M., Onasanwo, S.A., Madhur, G., Rastogi, P., Pandey, H.P., Palit, G., Narender, T., 2013, Anti-secretory and cyto-protective effects of chebulinic acid isolated from the fruits of Terminalia chebula on gastric ulcers. Phytomedicine. 20(6):506-11. https://doi.org/10.1016/j.phymed.2013.01.002.
[44]. Lu, K., Chakroborty, D., Sarkar, C., Lu, T., Xie, Z., Liu, Z., Basu, S., 2012. Triphala and its active constituent chebulinic acid are natural inhibitors of vascular endothelial growth factor-a mediated angiogenesis. e43934. https://doi.org/10.1371/journal.pone.0043934.
[45]. Yi, Z.C., Wang, Z., Li, H.X., Liu, M.J., Wu, R.C., Wang, X.H., 2004, Effects of chebulinic acid on differentiation of human leukemia K562 cells. Acta Pharmacologica Sinica. 25(2):231-8. PMID: 14769215
[46]. Tanaka, T., Kouno, I., Nonaka, G.I., 1996, Glutathione-mediated conversion of the ellagitannin geraniin into chebulagic acid. Chemical and pharmaceutical bulletin. 44(1), 34–40. https://doi.org/10.1248/cpb.44.34.
[47]. Mansouri, M.T., Hemmati, A.A., Naghizadeh, B., Mard, S.A., Rezaie, A., Ghorbanzadeh, B., 2015, A study of the mechanisms underlying the anti-inflammatory effect of ellagic acid in carrageenan-induced paw edema in rats. Indian journal of pharmacology. 47(3):292-8.
[48]. Goswami, S.K., Vishwanath, M., Gangadarappa, S.K., Razdan, R., Inamdar, M.N., 2014, Efficacy of ellagic acid and sildenafil in diabetes-induced sexual dysfunction. Pharmacognosy magazine. 10(Suppl 3):S581. DOI: 10.4103/0973-1296.139790.
[49]. García-Niño, W.R., Zazueta, C., 2015, Ellagic acid: Pharmacological activities and molecular mechanisms involved in liver protection. Pharmacological Research. 97:84-103. https://doi.org/10.1016/j.phrs.2015.04.008.
[50]. Dianat, M., Amini, N., Badavi, M., Farbood, Y., 2015, Ellagic acid improved arrhythmias induced by CaCL2 in the rat stress model. Avicenna Journal of Phytomedicine. 5(2):120. PMID: 25949953.
[51]. Dolatshahi, M., Farbood, Y., Sarkaki, A., Mansouri, S.M., Khodadadi, A., 2015, Ellagic acid improves hyperalgesia and cognitive deficiency in 6-hydroxidopamine induced rat model of Parkinson’s disease. Iranian journal of basic medical sciences. 18(1):38. PMID: 25810874.
[52]. Farbood, Y., Sarkaki, A., Dianat, M., Khodadadi, A., Haddad, M.K., Mashhadizadeh, S., 2015, Ellagic acid prevents cognitive and hippocampal long-term potentiation deficits and brain inflammation in rat with traumatic brain injury. Life Sciences. 124:120-7. https://doi.org/10.1016/j.lfs.2015.01.013.
[53]. Wang, C., Zhang, D., Ma, H., Liu, J., 2007, Neuroprotective effects of emodin-8-O-β-d-glucoside in vivo and in vitro. European Journal of Pharmacology. 577(1-3):58-63. https://doi.org/10.1016/j.ejphar.2007.08.033.
[54]. Xu, Y.L., Tang, L.Y., Zhou, X.D., Zhou, G.H., Wang, Z.J., 2015, Five new anthraquinones from the seed of Cassia obtusifolia. Archives of pharmacal research. 38:1054-8. https://doi.org/10.1007/s12272-014-0462-x.
[55]. Al-Harrasi, A., Bhatia, S., Aldawsari, M.F., Behl, T., 2022, Plant profile, phytochemistry, and ethnopharmacological uses of Terminalia bellirica, Terminalia chebula, and Terminalia arjuna. InRecent Advances in Natural Products Science (pp. 143-172). CRC Press.
[56]. Kumar, N., Gupta, G., Karnati, R., 2014, Chebulagic acid from Terminalia chebula causes G1 arrest, inhibits NFκB and induces apoptosis in retinoblastoma cells. BMC complementary and alternative medicine. 1-0. https://doi.org/10.1186/1472-6882-14-319 
[57]. Reddy, D.B., Reddy, T.C., Jyotsna, G., Sharan, S., Priya, N., Lakshmipathi, V., Reddanna, P., 2009, Chebulagic acid, a COX–LOX dual inhibitor isolated from the fruits of Terminalia chebula Retz., induces apoptosis in COLO-205 cell line. Journal of ethnopharmacology. 124(3):506-12.  https://doi.org/10.1016/j.jep.2009.05.022.
[58]. Ponnulakshmi, R., Shyamaladevi, B., Selvaraj, J., Valli, G., Purushothaman, V., Alsawalha, M., Mohan, S.K., 2019, Effect of chebulagic acid on apoptotic regulators in prostate cancer cell line-PC-3. Drug Invention Today. 12(2):281-5.
[59]. Morales, A., Miranda, M., Sánchez-Reyes, A., Biete, A., Fernández-Checa, J.C., 1998, Oxidative damage of mitochondrial and nuclear DNA induced by ionizing radiation in human hepatoblastoma cells. International Journal of Radiation Oncology* Biology* Physics. 42(1):191-203. https://doi.org/10.1016/S0360-3016(98)00185-0.
[60]. Achari, C., V Reddy, G., CM, Reddy, T., Reddanna P., 2011, Chebulagic acid synergizes the cytotoxicity of doxorubicin in human hepatocellular carcinoma through COX-2 dependant modulation of MDR-1. Medicinal Chemistry. 7(5):432-42. https://doi.org/10.2174/157340611796799087.
[61]. Zhao, J., Shi, Y., Ma, Y., Pan, L., Wang, Y., Yuan, L., Dong, J., Ying, J., 2023, Chebulagic acid suppresses gastric cancer by inhibiting the AURKA/β-catenin/Wnt pathway. Frontiers in Pharmacology. 14:1143427. https://doi.org/10.3389/fphar.2023.1143427