Welcome to International Network for Natural Sciences | INNSpub

Gallic acid mitigates apoptotic cell death induced by the anticancer drug tamoxifen in female rats

Research Paper | March 1, 2018

| Download 6

Eman M. Saleh, Germine M. Hamdy, Dina M. Seoudi

Key Words:

Int. J. Biosci.12( 3), 70-86, March 2018

DOI: http://dx.doi.org/10.12692/ijb/12.3.70-86


IJB 2018 [Generate Certificate]


Tamoxifen (TAM),the anti-estrogenic agentwas used for advanced breast cancer management. Despite its benefits, a number of clinical reports have demonstrated many side effects. Therefore, this study was designed to assess the possible hepatoprotective effects of Gallic acid (GA) against TAM-induced abnormalities in female rats. Fifty adult female Sprague dawleyrats were divided into 5 groups. Group I: normal control, Group II: TAM group, Group III: GA group, Group IV:prophylactic group of GA, Group V:prophylactic group of silymarin. Blood and liver tissues were collected for biochemical, and histopathological studies. Group II; rats receiving TAM, showed significant increases in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, E-cadherin, and Caspase-3 and decreases in albumin and Na+/K+ ATPase activity. The Prophylactic group of GA; group IV, significantly reduced the elevated levels of the previously mentioned biochemical markers, as well as increased the levels of serum albumin and liver Na+/K+ ATPase. Histopathology of liver and spleen also confirmed the protective effective of GA. The results confirm that administration of GA showed better results than that of the standard drug silymarin. Therefore, GA assumes to be a promising hepatoprotective agent that ameliorates the side effects induced by TAM therapy.


Copyright © 2018
By Authors and International Network for
Natural Sciences (INNSPUB)
This article is published under the terms of the Creative
Commons Attribution Liscense 4.0

Gallic acid mitigates apoptotic cell death induced by the anticancer drug tamoxifen in female rats

Abdel-Moneim AM, Al-Kahtani MA, El-Kersh MA, Al-Omair MA. 2015. Free Radical-Scavenging, Anti-Inflammatory/Anti-Fibrotic and Hepatoprotective Actions of Taurine and Silymarin against CCl4 Induced Rat Liver Damage. PLoS One 10(12), e0144509. http://dx.doi.org/10.1371/journal.pone.0144509.

Aglan HA, Ahmed HH, El-Toumy SA, Mahmoud NS. 2017. Gallic acid against hepatocellular carcinoma: An integrated scheme of the potential mechanisms of action from in vivo study. Tumor Biology 39(6), http://dx.doi.org/10.1177/1010428317699127.

Athukuri BL, Neerati P. 2016. Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition. Drug Metabolism and Personalized Therapy 31(4), 229-234. http://dx.doi.org/10.1515/dmpt-2016-0029.

Baker Bechmann M, Rotoli D, Morales M, Maeso Mdel C, Garcia Mdel P, Avila J, Mobasheri A, Martin-Vasallo P. 2016. Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases. Frontiers in Physiology 7(9). http://dx.doi.org/10.3389/fphys.2016.00009.

Bancroft JD, Stevens A. 1990. Theory and practice of histological techniques, 3rd ed. Churchill Livingstone, Edinburgh ; New York.

Belfield A, Goldberg D. 1971. Colorimetric determination of alkaline phosphatase activity. Enzyme 12, 561-566.

Chang BY, Kim SA, Malla B, Kim SY. 2011. The Effect of Selective Estrogen Receptor Modulators (SERMs) on the Tamoxifen Resistant Breast Cancer Cells. Toxicology Research 27(2), 85-93. http://dx.doi.org/10.5487/TR.2011.27.2.085.

Cheng CH, Cheng YP, Chang IL, Chen HY, Wu CC, Hsieh CP. 2016. Dodecyl gallate induces apoptosis by upregulating the caspase-dependent apoptotic pathway and inhibiting the expression of anti-apoptotic Bcl-2 family proteins in human osteosarcoma cells. Molecular Medicine Reports 13(2), 1495-1500. http://dx.doi.org/10.3892/mmr.2015.4717.

Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Muller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrutia G, Valentini M, Wang Y, Peto R. 2013. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381(9869), 805-816. https://doi.org/10.1016/S0140-6736(12)619631.

Dorniani D, Saifullah B, Barahuie F, Arulselvan P, Hussein MZ, Fakurazi S, Twyman LJ. 2016. Graphene Oxide-Gallic Acid Nanodelivery System for Cancer Therapy. Nanoscale Research Letters11(1), 491. https://doi.org/10.1186/s11671-016-1712-2.

Doumas B, Watson W, Biggs H. 1971. Albumin standards and the measurement of serum albumin with bromcresol green. Clinica Chimica Acta31(1), 87-96. PMID: 9049440.

El-Beshbishy HA. 2005. The effect of dimethyl dimethoxy biphenyl dicarboxylate (DDB) against tamoxifen-induced liver injury in rats: DDB use is curative or protective. Journal of Biochemistry and Molecular Biology 38(3), 300-306. http://dx.doi.org/10.5483/BMBRep.2005.38.3.300.

Floren LC, Hebert MF, Venook AP, Jordan VC, Cisneros A, Somberg KA. 1998. Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction. Annals of Oncology9(10), 1123-1126. PMID: 9834826.

Gao FF, Lv JW, Wang Y, Fan R, Li Q, Zhang Z, Wei L. 2016. Tamoxifen induces hepatotoxicity and changes to hepatocyte morphology at the early stage of endocrinotherapy in mice. Biomedical Reports 4(1), 102-106. http://dx.doi.org/10.3892/br.2015.536.

Gonçalves-de-Albuquerque CF, Silva AR, Ignácio da Silva C, Castro-Faria-Neto HC, Burth P. 2017. Na/K Pump and Beyond: Na/K-ATPase as a Modulator of Apoptosis and Autophagy. Molecules 22, 578-595. http://dx.doi.org/10.3390/molecules22040578.

Gornall AG, Bardawill CJ, David MM. 1949. Determination of serum proteins by means of the biuret reaction. Journal of Biological Chemistry 177(2), 751-766.PMID: 18110453.

Grenman S, Shapira A, Carey TE. 1988. In vitro response of cervical cancer cell lines CaSki, HeLa, and ME-180 to the antiestrogen tamoxifen. Gynecologic Oncology30(2), 228-238. https://doi.org/10.1016/0090-8258(88)90029-7.

Grigorian A, O’Brien CB. 2014. Hepatotoxicity Secondary to Chemotherapy. Journal of Clinical and Translational Hepatology 2(2), 95-102. http://dx.doi.org/10.14218/JCTH.2014.00011.

Guimaraes TA, Farias LC, Fraga CA, Feltenberger JD, Melo GA, Coletta RD, Souza Santos SH, de Paula AM, Guimaraes AL. 2016. Evaluation of the antineoplastic activity of gallic acid in oral squamous cell carcinoma under hypoxic conditions. Anticancer Drugs 27(5), 407-416. http://dx.doi.org/10.1097/CAD.0000000000000342.

Han NN, Zhou Q, Huang Q, Liu KJ. 2017. Carnosic acid cooperates with tamoxifen to induce apoptosis associated with Caspase-3 activation in breast cancer cells in vitro and in vivo. Biomedicine & Pharmacotherapy89, 827-837. http://dx.doi.org/10.1016/j.biopha.2017.01.084.

Hard G, MJ I, K J, L R, OP K, AR I, GM. W. 1993. Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats. Cancer Research53(19), 4534-4541.PMID: 8402624.

Jatoba CA, de Rezende AA, de Paiva Rodrigues SJ, de Almeida Camara MM, das Gracas Almeida M, Freire-Neto F, da Rocha LR, da Medeiros AC, Brandao-Neto J, de Carvalho Formiga MC, de Azevedo IM, de Oliveira Ramos AM. 2008. Liver iron overload induced by tamoxifen in diabetic and non-diabetic female Wistar rats. Biometals 21(2), 171-178. http://dx.doi.org/10.1007/s10534-007-9105-8.

Jin L, Piao ZH, Sun S, Liu B, Ryu Y, Choi SY, Kim GR, Kim HS, Kee HJ, Jeong MH. 2017. Gallic acid attenuates pulmonary fibrosis in a mouse model of transverse aortic contraction-induced heart failure. Vascular pharmacology. 99, 74-82. http://dx.doi.org/10.1016/j.vph.2017.10.007.

Karimi-Khouzani O, Heidarian E, Amini SA. 2017. Anti-inflammatory and ameliorative effects of gallic acid on fluoxetine-induced oxidative stress and liver damage in rats. Pharmacological Reports69(4), 830-835. http://dx.doi.org/10.1016/j.pharep.2017.03.011.

Katayama M, Hirai S, Kamihagi K, Nakagawa K, Yasumoto M, Kato I. 1994. Soluble E-cadherin fragments increased in circulation of cancer patients. British Journal of Cancer69(3), 580-585.PMID: 8123491.

Kim SJ, Lee JH, Kim BS, So HS, Park R, Myung NY, Um JY, Hong SH. 2012. (-)-Epigallocatechin-3-gallate protects against NO-induced ototoxicity through the regulation of caspase- 1, caspase-3, and NF-kappaB activation. PLoS One 7(9), e43967. http://dx.doi.org/10.1371/journal.pone.0043967.

Kiyotani K, Mushiroda T, Nakamura Y, Zembutsu H. 2012. Pharmacogenomics of tamoxifen: roles of drug metabolizing enzymes and transporters. Drug Metab Pharmacokinet 27(1), 122-131. https://doi.org/10.2133/dmpk.DMPK-11-RV-084.

Krishnappa P, Venkatarangaiah K, Venkatesh, Shivamogga Rajanna SK, Kashi Prakash Gupta R. 2014. Antioxidant and prophylactic effects of Delonix elata L., stem bark extracts, and flavonoid isolated quercetin against carbon tetrachloride-induced hepatotoxicity in rats. BioMed Research International2014, 507851. http://dx.doi.org/10.1155/2014/507851.

Latief U, Husain H, Mukherjee D, Ahmad R. 2016. Hepatoprotective efficacy of gallic acid during Nitrosodiethylamine-induced liver inflammation in Wistar rats. The Journal of Basic and Applied Zoology 76, 31-41. https://doi.org/10.1016/j.jobaz.2016.07.002.

Lefranc F, Kiss R. 2008. The Sodium Pump α1 Subunit as a Potential Target to Combat Apoptosis-Resistant Glioblastomas. Neoplasia 10 (3), 198–206. https://doi.org/10.1593/neo.07928.

Liu W, Dong M, Bo L, Li C, Liu Q, Li Z, Jin F. 2016. Epigallocatechin-3-gallate suppresses alveolar epithelial cell apoptosis in seawater aspiration-induced acute lung injury via inhibiting STAT1-caspase-3/p21 associated pathway. Molecular Medicine Reports13(1), 829-836. http://dx.doi.org/10.3892/mmr.2015.4617.

Lo C, Lai TY, Yang JS, Yang JH, Ma YS, Weng SW, Lin HY, Chen HY, Lin JG, Chung JG. 2011. Gallic acid inhibits the migration and invasion of A375.S2 human melanoma cells through the inhibition of matrix metalloproteinase-2 and Ras. Melanoma Research21(4): 267-273. http://dx.doi.org/10.1097/CMR.0b013e3283414444.

Lopez-Lopez E, Sedeno-Diaz JE, Soto C, Favari L. 2011. Responses of antioxidant enzymes, lipid peroxidation, and Na+/K+-ATPase in liver of the fish Goodea atripinnis exposed to Lake Yuriria water. Fish Physiology and Biochemistry37(3), 511-522. http://dx.doi.org/10.1007/s10695-010-9453-0.

Mard SA, Mojadami S, Farbood Y, Gharib Naseri MK. 2015. The anti-inflammatory and anti-apoptotic effects of gallic acid against mucosal inflammation and erosions-induced by gastric ischemia-reperfusion in rats. Veterinary Research Forum 6(4), 305-311.PMID: 26973766.

Nallagangula KS, Nagaraj SK, Venkataswamy L, Chandrappa M. 2018. Liver fibrosis: a compilation on the biomarkers status and their significance during disease progression. Future Science OA 4(1), FSO250. http://dx.doi.org/10.4155/fsoa-2017-0083

Oropesa-Avila M, Fernandez-Vega A, de la Mata M, Maraver JG, Cordero MD, Cotan D, de Miguel M, Calero CP, Paz MV, Pavon AD, Sanchez MA, Zaderenko AP, Ybot-Gonzalez P, Sanchez-Alcazar JA. 2013. Apoptotic microtubules delimit an active caspase free area in the cellular cortex during the execution phase of apoptosis. Cell Death & Disease 4, e527. http://dx.doi.org/10.1038/cddis.2013.58

Pan HJ, Chang HT, Lee CH. 2016. Association between tamoxifen treatment and the development of different stages of nonalcoholic fatty liver disease among breast cancer patients. Journal of the Formosan Medical Association 115(6), 411-417. http://dx.doi.org/10.1016/j.jfma.2015.05.006.

Perazzoli MR, Perondi CK, Baratto CM, Winter E, Creczynski-Pasa TB, Locatelli C. 2017. Gallic Acid and Dodecyl Gallate Prevents Carbon Tetrachloride-Induced Acute and Chronic Hepatotoxicity by Enhancing Hepatic Antioxidant Status and Increasing p53 Expression. Biological and Pharmaceutical Bulletin40(4), 425-434. http://dx.doi.org/10.1248/bpb.b16-00782.

Perry RR, Kang Y, Greaves B. 1995. Effects of tamoxifen on growth and apoptosis of estrogen-dependent and -independent human breast cancer cells. Annals of Surgical Oncology 2(3), 238-245.PMID: 7641021.

Rabinowich L, Shibolet O. 2015. Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease. BioMed Research International 2015, 168905. http://dx.doi.org/10.1155/2015/168905.

Raj PV, Nitesh K, Chandrashekhar HR, Mallikarjuna Rao C, Venkata Rao J, Udupa N. 2010. Effect of Lecithin and silymarin on D-galactosamine induced toxicity in isolated hepatocytes and rats. Indian Journal of Clinical Biochemistry 25(2), 169-174. http://dx.doi.org/10.1007/s12291-010-0031-0.

Reitman S, Frankel S. 1957. A colorimetric method for determination of serum glutamate oxaloacetate and glutamic pyruvate transaminase. American Journal of Clinical Pathology 28, 56-63. PMID: 13458125.

Repetto O, De Paoli P, De Re V, Canzonieri V, Cannizzaro R. 2014. Levels of soluble E-cadherin in breast, gastric, and colorectal cancers. BioMed Research International 2014, 408047. http://dx.doi.org/10.1155/2014/408047.

Repke KR, Matthes E. 1994. Tamoxifen is a Na(+)-antagonistic inhibitor of Na+/K(+)-transporting ATPase from tumour and normal cells. Journal of Enzyme Inhibition 8(3), 207-212. https://doi.org/10.3109/14756369409020202.

Sewpaul A, French JJ, Khoo TK, Kernohan M, Kirby JA, Charnley RM. 2009. Soluble E-cadherin: an early marker of severity in acute pancreatitis. HPB Surg 2009, 397375. http://dx.doi.org/10.1155/2009/397375.

Soyama A, Eguchi S, Takatsuki M, Kawashita Y, Hidaka M, Tokai H, Nagayoshi S, Mochizuki S, Matsumoto S, Hamasaki K, Tajima Y, Kanematsu T. 2008. Significance of the serum level of soluble E-cadherin in patients with HCC. Hepatogastroenterology 55(85), 1390-1393.PMID: 18795696.

Suddek GM. 2014. Protective role of thymoquinone against liver damage induced by tamoxifen in female rats. Canadian Journal of Physiology and Pharmacology92(8), 640-644. http://dx.doi.org/10.1139/cjpp-2014-0148.

Sun G, Zhang S, Xie Y, Zhang Z, Zhao W. 2016. Gallic acid as a selective anticancer agent that induces apoptosis in SMMC-7721 human hepatocellular carcinoma cells. Oncology letters 11, 150-158. http://dx.doi.org/10.3892/ol.2015.3845

Sundfeldt K, Ivarsson K, Rask K, Haeger M, Hedin L, Brannstrom M. 2001. Higher levels of soluble E-cadherin in cyst fluid from malignant ovarian tumours than in benign cysts. Anticancer Research21(1A), 65-70.PMID: 11299791.

Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, Costantini P, Ferri KF, Irinopoulou T, Prevost MC, Brothers G, Mak TW, Penninger J, Earnshaw WC, Kroemer G. 2000. Two distinct pathways leading to nuclear apoptosis. Journal of Experimental Medicine 192(4), 571-580. http://dx.doi.org/10.1084/jem.192.4.571.

Symowicz J, Adley BP, Gleason KJ, Johnson JJ, Ghosh S, Fishman DA, Hudson LG, Stack MS. 2007. Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res 67(5), 2030-2039. http://dx.doi.org/10.1158/0008-5472.CAN-06-2808

Tryndyak VP, Muskhelishvili L, Kovalchuk O, Rodriguez-Juarez R, Montgomery B, Churchwell MI, Ross SA, Beland FA, Pogribny IP. 2006. Effect of long-term tamoxifen exposure on genotoxic and epigenetic changes in rat liver: implications for tamoxifen-induced hepatocarcinogenesis. Carcinogenesis 27(8), 1713-1720. http://dx.doi.org/10.1093/carcin/bgl050

Umakumar G, Ali MN, John KS, Tabassum H.. 2012. Bio-conversion studies on gallic acid production from Chebulic myrobalan and Emblic myrobalan by Aspergillus niger MTCC 281 and Rhizopus oryzae MTCC 1987. International Journal of Pharma and Bio Sciences 3(2), 146-155.

Verma RJ, Chakraborty BS, Patel C, Mathuria N. 2008. Curcumin ameliorates aflatoxin-induced changes in SDH and ATPase activities in liver and kidney of mice. Acta Poloniae Pharmaceutica65(4), 415-419.PMID: 19051581.

Wang XQ, Yu SP. 2005. Novel regulation of Na, K-ATPase by Src tyrosine kinases in cortical neurons. Journal of Neurochemistry93(6), 1515-1523. http://dx.doi.org/10.1111/j.1471-4159.2005.03147.x

Wickramage I, Tennekoon KH, Ariyaratne MA, Hewage AS, Sundralingam T. 2017. CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study. Breast Cancer (Dove Med Press) 9, 111-120. http://dx.doi.org/10.2147/BCTT.S126557.

Yakubu MT, Adesokan AA, Akanji MA. 2006. Biochemical changes in the Liver, Kidney and Serum of rat following chronic administration of cimetidine. African Journal of Biomedical Research 9, 213-218.

Yamaguchi N, Nakayama Y. 2017. Down-regulation of Forkhead box protein A1 (FOXA1) leads to cancer stem cell-like properties in tamoxifen-resistant breast cancer cells through induction of interleukin-6. Journal of Biological Chemistry 292(20), 8136-8148. http://dx.doi.org/10.1074/jbc.M116.763276.

Yang R-M, Zhang X-L, Wang L, Huang J-P, Yang J, Yan Y-J, Luo J-Y, Wang X-T, Huang S-X. 2017a.α-Pyrone Derivatives from a Streptomyces Strain Resensitize Tamoxifen Resistance in Breast Cancer Cells. Natural Products and Bioprospecting 7(4), 329-334. http://dx.doi.org/10.1007/s13659-017-0136-8.

Yang Y, Pan W, Tang X, Wu S, Sun X. 2017b. A meta-analysis of randomized controlled trials comparing the efficacy and safety of anastrozole versus tamoxifen for breast cancer. Oncotarget 8(29), 48362-48374. http://dx.doi.org/10.18632/oncotarget.16466.

Yang YH, Wang Z, Zheng J, Wang R. 2015. Protective effects of gallic acid against spinal cord injury-induced oxidative stress. Molecular Medicine Reports12(2), 3017-3024. http://dx.doi.org/10.3892/mmr.2015.3738.

Yeh C-T, Yen G-C. 2006. Induction of Hepatic Antioxidant Enzymes by Phenolic Acids in Rats Is Accompanied by Increased Levels of Multidrug Resistance–Associated Protein 3 mRNA Expression. The journal of Nutrition 136, 11-15. http://dx.doi.org/10.1093/jn/136.1.11.

Zartman JK, Foreman NK, Donson AM, Fleitz JM. 2004. Measurement of tamoxifen-induced apoptosis in glioblastoma by cytometric bead analysis of active caspase-3. Journal of Neuro-Oncology67(1-2), 3-7. https://doi.org/10.1023/B:NEON.000.

Zembutsu H, Nakamura S, Akashi-Tanaka S, Kuwayama T, Watanabe C, Takamaru T, Takei H, Ishikawa T, Miyahara K, Matsumoto H, Hasegawa Y, Kutomi G, Shima H, Satomi F, Okazaki M, Zaha H, Onomura M, Matsukata A, Sagara Y, Baba S, Yamada A, Shimada K, Shimizu D, Tsugawa K, Shimo A, Tan EY, Hartman M, Chan CW, Lee SC, Nakamura Y. 2017. Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study. Clinical Cancer Research 23(8), 2019-2026. http://dx.doi.org/10.1158/1078-0432.CCR-16-1779.