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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2014

Open Access 01-12-2014 | Research article

Chebulagic acid from Terminalia chebula causes G1 arrest, inhibits NFκB and induces apoptosis in retinoblastoma cells

Authors: Naresh Kumar, Gangappa D, Geetika Gupta, Roy Karnati

Published in: BMC Complementary Medicine and Therapies | Issue 1/2014

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Abstract

Background

Plants are the valuable source of natural products with important medicinal properties. Most of the approved anti cancer drugs have a natural product origin or are natural products. Retinoblastoma is the most common ocular cancer of children. Although chemotherapy is the preferred mode of therapy, a successful treatment for retinoblastoma requires enucleation. Chebulagic acid (CA) from Terminalia chebula was shown to have anti-proliferative properties in the studies on cancerous cell lines. Due to anti cancer properties of CA and due to limitation in treatment options for retinoblastoma, the present study is undertaken to understand the role of CA on the proliferation of retinoblastoma cells.

Methods

Anti proliferative potential of CA was determined by MTT assay. The expression levels of various cell death mediators in retinoblastoma cells with CA treatment were assessed by Western blotting. Flowcytometer analysis was used to estimate the mitochondrial membrane potential (MMP) and to determine the percentage of cells undergoing apoptosis.

Results

The present study showed CA inhibited the proliferation of retinoblastoma cells in a dose dependent manner. CA modulated MMP, induced release of Cytochrome c, activated caspase 3 and shifted the ratio of BAX and Bcl2 towards cell death. G1 arrest, noticed in CA treated cells, is mediated by the increase in the expression of CDK inhibitor p27. CA treatment also decreased the levels of NFκB in the nucleus. This decrease is mediated by suppression in degradation of IκBα.

Conclusion

CA has shown significant anti proliferative potential on retinoblastoma cells. Our findings clearly demonstrate that CA induces G1 arrest, inhibits NFκB and induces apoptosis of retinoblastoma cells.
Appendix
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Literature
1.
Butler MS: Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep. 2008, 25: 475-516. 10.1039/b514294f.CrossRefPubMed
2.
Newman DJ, Cragg GM: Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007, 70: 461-477. 10.1021/np068054v.CrossRefPubMed
3.
Pak RW, Lanteri VJ, Scheuch JR, Sawczuk IS: Review of vitamin E and selenium in the prevention of prostate cancer: implications of the selenium and vitamin E chemoprevention trial. Integr Cancer Ther. 2002, 1: 338-344. 10.1177/1534735402238186.CrossRefPubMed
4.
Vainio H, Weiderpass E: Fruit and vegetables in cancer prevention. Nutr Cancer. 2006, 54: 111-142. 10.1207/s15327914nc5401_13.CrossRefPubMed
5.
Nakahata N, Kutsuwa M, Kyo R, Kubo M, Hayashi K, Ohizumi Y: Analysis of inhibitory effects of scutellariae radix and baicalein on prostaglandin E2 production in rat C6 glioma cells. Am J Chin Med. 1998, 26: 311-323. 10.1142/S0192415X9800035X.CrossRefPubMed
6.
Paiva SA, Russell RM: Beta-carotene and other carotenoids as antioxidants. J Am Coll Nutr. 1999, 18: 426-433. 10.1080/07315724.1999.10718880.CrossRefPubMed
7.
Kale A, Gawande S, Kotwal S, Netke S, Roomi MW, Ivanov V, Niedzwiecki A, Rath M: A combination of green tea extract, specific nutrient mixture and quercetin: An effective intervention treatment for the regression of N-methyl-N-nitrosourea (MNU)-induced mammary tumors in Wistar rats. Oncol Lett. 2010, 1: 313-317.PubMedPubMedCentral
8.
Abdulla M, Gruber P: Role of diet modification in cancer prevention. Biofactors. 2000, 12: 45-51. 10.1002/biof.5520120108.CrossRefPubMed
9.
Zuzak TJ, Rist L, Eggenschwiler J, Grotzer MA, Viviani A: Pediatric medulloblastoma cells are susceptible to Viscum album (Mistletoe) preparations. Anticancer Res. 2006, 26: 3485-3492.PubMed
10.
Gul MZ, Bhakshu LM, Ahmad F, Kondapi AK, Qureshi IA, Ghazi IA: Evaluation of Abelmoschus moschatus extracts for antioxidant, free radical scavenging, antimicrobial and antiproliferative activities using in vitro assays. BMC Complement Altern Med. 2011, 11: 64-10.1186/1472-6882-11-64.CrossRefPubMedPubMedCentral
11.
Antczak C, Kloepping C, Radu C, Genski T, Müller-Kuhrt L, Siems K, de Stanchina E, Abramson DH, Djaballah H: Revisiting old drugs as novel agents for retinoblastoma: in vitro and in vivo antitumor activity of cardenolides. Invest Ophthalmol Vis Sci. 2009, 50: 3065-3073. 10.1167/iovs.08-3158.CrossRefPubMedPubMedCentral
12.
D'Anneo A, Augello G, Santulli A, Giuliano M, di Fiore R, Messina C, Tesoriere G, Vento R: Paclitaxel and beta-lapachone synergistically induce apoptosis in human retinoblastoma Y79 cells by downregulating the levels of phospho-Akt. J Cell Physiol. 2010, 222: 433-443. 10.1002/jcp.21983.CrossRefPubMed
13.
De Potter P: Current treatment of retinoblastoma. Curr Opin Ophthalmol. 2002, 13: 331-336. 10.1097/00055735-200210000-00007.CrossRefPubMed
14.
Abramson DH: Retinoblastoma in the 20th century: past success and future challenges the Weisenfeld lecture. Invest Ophthalmol Vis Sci. 2005, 46: 2683-2691. 10.1167/iovs.04-1067.CrossRefPubMed
15.
Brichard B, De Bruycker JJ, De Potter P, Neven B, Vermylen C, Cornu G: Combined chemotherapy and local treatment in the management of intraocular retinoblastoma. Med Pediatr Oncol. 2002, 38: 411-415. 10.1002/mpo.1355.CrossRefPubMed
16.
Benz MS, Scott IU, Murray TG, Kramer D, Toledano S: Complications of systemic chemotherapy as treatment of retinoblastoma. Arch Ophthalmol. 2000, 118: 577-578.PubMed
17.
Beck MN, Balmer A, Dessing C, Pica A, Munier F: First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol. 2000, 18: 2881-2887.PubMed
18.
Friedman DL, Himelstein B, Shields CL, Shields JA, Needle M, Miller D, Bunin GR, Meadows AT: Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol. 2000, 18: 12-17.PubMed
19.
Rizzuti AE, Dunkel IJ, Abramson DH: The adverse events of chemotherapy for retinoblastoma: what are they? Do we know?. Arch Ophthalmol. 2008, 126: 862-865. 10.1001/archopht.126.6.862.CrossRefPubMed
20.
Klein G, Michaelis J, Spix C, Wibbing R, Eggers G, Ritter J, Kaatsch P: Second malignant neoplasms after treatment of childhood cancer. Eur J Cancer. 2003, 39: 808-817. 10.1016/S0959-8049(02)00875-4.CrossRefPubMed
21.
Nishimura S, Sato T, Ueda H, Ueda K: Acute myeloblastic leukemia as a second malignancy in a patient with hereditary retinoblastoma. J Clin Oncol. 2001, 19: 4182-4183.PubMed
22.
Chantada G, Fandiño A, Casak S, Manzitti J, Raslawski E, Schvartzman E: Treatment of overt extraocular retinoblastoma. Med Pediatr Oncol. 2003, 40: 158-161. 10.1002/mpo.10249.CrossRefPubMed
23.
24.
Grossmann M, O'Reilly LA, Gugasyan R, Strasser A, Adams JM, Gerondakis S: The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J. 2000, 19: 6351-6360. 10.1093/emboj/19.23.6351.CrossRefPubMedPubMedCentral
25.
Schwartz GK, Shah MA: Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol. 2005, 23: 9408-9421. 10.1200/JCO.2005.01.5594.CrossRefPubMed
26.
Poulaki V, Mitsiades CS, Joussen AM, Lappas A, Kirchhof B, Mitsiades N: Constitutive nuclear factor-kappaB activity is crucial for human retinoblastoma cell viability. Am J Pathol. 2002, 161: 2229-2240. 10.1016/S0002-9440(10)64499-9.CrossRefPubMedPubMedCentral
27.
Sareen D, van Ginkel PR, Takach JC, Mohiuddin A, Darjatmoko SR, Albert DM, Polans AS: Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells. Invest Ophthalmol Vis Sci. 2006, 47: 3708-3716. 10.1167/iovs.06-0119.CrossRefPubMed
28.
Reddy DB, Reddanna P: Chebulagic acid (CA) attenuates LPS-induced inflammation by suppressing NF-kappaB and MAPK activation in RAW 264.7 macrophages. Biochem Biophys Res Commun. 2009, 381: 112-117. 10.1016/j.bbrc.2009.02.022.CrossRefPubMed
29.
Reddy DB, Reddy TC, Jyotsna G, Sharan S, Priya N, Lakshmipathi V, Reddanna P: Chebulagic acid, a COX-LOX dual inhibitor isolated from the fruits of Terminalia chebula Retz., induces apoptosis in COLO-205 cell line. J Ethnopharmacol. 2009, 124: 506-512. 10.1016/j.jep.2009.05.022.CrossRefPubMed
30.
Cheng HY, Lin TC, Yu KH, Yang CM, Lin CC: Antioxidant and free radical scavenging activities of Terminalia chebula. Biol Pharm Bull. 2003, 26: 1331-1335. 10.1248/bpb.26.1331.CrossRefPubMed
31.
Iason G: The role of plant secondary metabolites in mammalian herbivory: ecological perspectives. Proc Nutr Soc. 2005, 64: 123-131. 10.1079/PNS2004415.CrossRefPubMed
32.
33.
Lee SI, Hyun PM, Kim SH, Kim KS, Lee SK, Kim BS, Maeng PJ, Lim JS: Suppression of the onset and progression of collagen-induced arthritis by chebulagic acid screened from a natural product library. Arthritis Rheum. 2005, 52: 345-353. 10.1002/art.20715.CrossRefPubMed
34.
Huang YN, Zhao DD, Gao B, Zhong K, Zhu RX, Zhang Y, Xie WJ, Jia LR, Gao H: Anti-Hyperglycemic Effect of Chebulagic Acid from the Fruits of Terminalia chebula Retz. Int J Mol Sci. 2012, 13: 6320-6333. 10.3390/ijms13056320.CrossRefPubMedPubMedCentral
35.
Kinoshita S, Inoue Y, Nakama S, Ichiba T, Aniya Y: Antioxidant and hepatoprotective actions of medicinal herb, Terminalia catappa L. from Okinawa Island and its tannin corilagin. Phytomedicine. 2007, 14: 755-762. 10.1016/j.phymed.2006.12.012.CrossRefPubMed
36.
Murakami A, Ishida H, Kobo K, Furukawa I, Ikeda Y, Yonaha M, Aniya Y, Ohigashi H: Suppressive effects of Okinawan food items on free radical generation from stimulated leukocytes and identification of some active constituents: implications for the prevention of inflammation-associated carcinogenesis. Asian Pac J Cancer Prev. 2005, 6: 437-448.PubMed
37.
Lin LT, Chen TY, Chung CY, Noyce RS, Grindley TB, McCormick C, Lin TC, Wang GH, Lin CC, Richardson CD: Hydrolyzable tannins (chebulagic acid and punicalagin) target viral glycoprotein-glycosaminoglycan interactions to inhibit herpes simplex virus 1 entry and cell-to-cell spread. J Virol. 2011, 85: 4386-4398. 10.1128/JVI.01492-10.CrossRefPubMedPubMedCentral
38.
Roy KR, Arunasree KM, Reddy NP, Dheeraj B, Reddy GV, Reddanna P: Alteration of mitochondrial membrane potential by Spirulina platensis C-phycocyanin induces apoptosis in the doxorubicin resistant human hepatocellular-carcinoma cell line HepG2. Biotechnol Appl Biochem. 2007, 47: 159-167. 10.1042/BA20060206.CrossRefPubMed
39.
Roy KR, Arunasree KM, Dhoot A, Aparna R, Reddy GV, Vali S, Reddanna P: C-Phycocyanin inhibits 2-acetylaminofluorene-induced expression of MDR1 in mouse macrophage cells: ROS mediated pathway determined via combination of experimental and In silico analysis. Arch Biochem Biophys. 2007, 459: 169-177. 10.1016/j.abb.2007.01.006.CrossRefPubMed
40.
Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72: 248-254. 10.1016/0003-2697(76)90527-3.CrossRefPubMed
41.
Harvey A: Strategies for discovering drugs from previously unexplored natural products. Drug Discov Today. 2000, 5: 294-300. 10.1016/S1359-6446(00)01511-7.CrossRefPubMed
42.
Baker DD, Chu M, Oza U, Rajgarhia V: The value of natural products to future pharmaceutical discovery. Nat Prod Rep. 2007, 24: 1225-1244. 10.1039/b602241n.CrossRefPubMed
43.
Sunazuka T, Hirose T, Omura S: Efficient total synthesis of novel bioactive microbial metabolites. Acc Chem Res. 2008, 41: 302-314. 10.1021/ar6000044.CrossRefPubMed
44.
Nishanth RP, Ramakrishna BS, Jyotsna RG, Roy KR, Reddy GV, Reddy PK, Reddanna P: C-Phycocyanin inhibits MDR1 through reactive oxygen species and cyclooxygenase-2 mediated pathways in human hepatocellular carcinoma cell line. Eur J Pharmacol. 2010, 649: 74-83. 10.1016/j.ejphar.2010.09.011.CrossRefPubMed
45.
Roy KR, Nishanth RP, Sreekanth D, Reddy GV, Reddanna P: C-Phycocyanin ameliorates 2-acetylaminofluorene induced oxidative stress and MDR1 expression in the liver of albino mice. Hepatol Res. 2008, 38: 511-520. 10.1111/j.1872-034X.2007.00290.x.CrossRefPubMed
46.
Sreekanth D, Arunasree MK, Roy KR, Chandramohan Reddy T, Reddy GV, Reddanna P: Betanin a betacyanin pigment purified from fruits of Opuntia ficus-indica induces apoptosis in human chronic myeloid leukemia Cell line-K562. Phytomedicine. 2007, 14: 739-746. 10.1016/j.phymed.2007.03.017.CrossRefPubMed
47.
48.
Yeh CC, Yang JI, Lee JC, Tseng CN, Chan YC, Hseu YC, Tang JY, Chuang LY, Huang HW, Chang FR, Chang HW: Anti-proliferative effect of methanolic extract of Gracilaria tenuistipitata on oral cancer cells involves apoptosis, DNA damage, and oxidative stress. BMC Complement Altern Med. 2012, 12: 142-10.1186/1472-6882-12-142.CrossRefPubMedPubMedCentral
49.
Tasyriq M, Najmuldeen IA, In LL, Mohamad K, Awang K, Hasima N: 7α-Hydroxy-β-Sitosterol from Chisocheton tomentosus Induces Apoptosis via Dysregulation of Cellular Bax/Bcl-2 Ratio and Cell Cycle Arrest by Downregulating ERK1/2 Activation. Evid Based Complement Alternat Med. 2012, 2012: 765316-CrossRefPubMedPubMedCentral
50.
Deeb D, Jiang H, Gao X, Hafner MS, Wong H, Divine G, Chapman RA, Dulchavsky SA, Gautam SC: Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-kappaB through suppression of IkappaBalpha phosphorylation. Mol Cancer Ther. 2004, 3: 803-812.PubMed
51.
Lopes FC, Rocha A, Pirraco A, Regasini LO, Silva DH, Bolzani VS, Azevedo I, Carlos IZ, Soares R: Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa. BMC Complement Altern Med. 2009, 9: 15-10.1186/1472-6882-9-15.CrossRefPubMedPubMedCentral
52.
Metadata
Title
Chebulagic acid from Terminalia chebula causes G1 arrest, inhibits NFκB and induces apoptosis in retinoblastoma cells
Authors
Naresh Kumar
Gangappa D
Geetika Gupta
Roy Karnati
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2014
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/1472-6882-14-319

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