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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

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Review Article

Plant Polyphenolic Compounds Potentiates Therapeutic Efficiency of Anticancer Chemotherapeutic Drugs: A Review

Author(s): Lokanatha Oruganti and Balaji Meriga*

Volume 21, Issue 2, 2021

Published on: 07 August, 2020

Page: [246 - 252] Pages: 7

DOI: 10.2174/1871530320666200807115647

Price: $65

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Abstract

Background: Scientific research continues to develop more efficacious drugs to treat and cure cancer, the dreadful disease threatening the human race. Chemotherapy is an essential means in cancer therapy, however, plant drugs having pharmacological safety, can be used alone or as additions to current chemotherapeutic agents to enhance therapeutic efficacy and minimize chemotherapyinduced adverse effects.

Objective: A combination therapy where the synergistic effect on multiple targets is possible has gained significance because a one-drug one-target approach fails to yield the desired therapeutic effect. Therefore, a detailed description of important plant polyphenolic compounds with anticancer activity and their role in potentiating chemotherapeutic efficiency of existing anticancer drugs is provided in this review. Systematically screening combinations of active pharmaceutical ingredients for potential synergy with plant compounds may be especially valuable in cancer therapy.

Methods: We extensively have gone through reviews and research articles available in the literature. We made use of databases such as Google Scholar, Research Gate, PubMed, Science Direct, etc. The following keywords were used in our literature search: “Chemotherapy, drug development, cancer drugs, plant-derived polyphenolics, synergistic studies, combination therapy, diagnosis and genetics.”

Conclusion: Systematic research studies on screening combinations of plant phytochemicals with potential chemotherapeutic pharmaceuticals shed light on their synergistic effects, mechanisms of actions paving the way to develop more efficient anticancer therapeutics to treat and cure the cancer menace, to nullify chemotherapy-induced adverse effects and our review substantially contributes in this direction.

Keywords: Cancer drugs, drug development, chemotherapy, combinational studies, natural anticancer compounds, plantderived polyphenolics, multi target, synergistic effects.

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[1]
Baylin, S.B.; Ohm, J.E. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat. Rev. Cancer, 2006, 6(2), 107-116.
[http://dx.doi.org/10.1038/nrc1799] [PMID: 16491070]
[2]
Release, S. Maestro, version 9.8; Schrödinger, LLC: New York, NY, 2014.
[3]
Ehrlich, P. Address in pathology, on chemiotherapy: delivered before the Seventeenth International Congress of Medicine. BMJ, 1913, 2(2746), 353-359.
[http://dx.doi.org/10.1136/bmj.2.2746.353] [PMID: 20766753]
[4]
Albert, A. Quantitative studies of the avidity of naturally occurring substances for trace metals; amino-acids having only two ionizing groups. Biochem. J., 1950, 47(5), 531-538.
[http://dx.doi.org/10.1042/bj0470531] [PMID: 14800966]
[5]
Tobert, J.A. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat. Rev. Drug Discov., 2003, 2(7), 517-526.
[http://dx.doi.org/10.1038/nrd1112] [PMID: 12815379]
[6]
Krause, D.S.; Van Etten, R.A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med., 2005, 353(2), 172-187.
[http://dx.doi.org/10.1056/NEJMra044389] [PMID: 16014887]
[7]
Hopkins, A.L.; Groom, C.R. The druggable genome. Nat. Rev. Drug Discov., 2002, 1(9), 727-730.
[http://dx.doi.org/10.1038/nrd892] [PMID: 12209152]
[8]
Aggarwal, B.B.; Sethi, G.; Baladandayuthapani, V.; Krishnan, S.; Shishodia, S. Targeting cell signaling pathways for drug discovery: an old lock needs a new key. J. Cell. Biochem., 2007, 102(3), 580-592.
[http://dx.doi.org/10.1002/jcb.21500] [PMID: 17668425]
[9]
Borisy, A.A.; Elliott, P.J.; Hurst, N.W.; Lee, M.S.; Lehár, J.; Price, E.R.; Serbedzija, G.; Zimmermann, G.R.; Foley, M.A.; Stockwell, B.R.; Keith, C.T. Systematic discovery of multicomponent therapeutics. Proc. Natl. Acad. Sci. USA, 2003, 100(13), 7977-7982.
[http://dx.doi.org/10.1073/pnas.1337088100] [PMID: 12799470]
[10]
Keith, C.T.; Borisy, A.A.; Stockwell, B.R. Multicomponent therapeutics for networked systems. Nat. Rev. Drug Discov., 2005, 4(1), 71-78.
[http://dx.doi.org/10.1038/nrd1609] [PMID: 15688074]
[11]
Sharma, V.; Hupp, C.D.; Tepe, J.J. Enhancement of chemotherapeutic efficacy by small molecule inhibition of NF-kappaB and checkpoint kinases. Curr. Med. Chem., 2007, 14(10), 1061-1074.
[http://dx.doi.org/10.2174/092986707780362844] [PMID: 17456020]
[12]
Banerjee, S.; Zhang, Y.; Wang, Z.; Che, M.; Chiao, P.J.; Abbruzzese, J.L.; Sarkar, F.H. In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int. J. Cancer, 2007, 120(4), 906-917.
[http://dx.doi.org/10.1002/ijc.22332] [PMID: 17131310]
[13]
McDonnell, C.O.; Holden, G.; Sheridan, M.E.; Foley, D.; Moriarty, M.; Walsh, T.N.; Bouchier-Hayes, D.J. Improvement in efficacy of chemoradiotherapy by addition of an antiangiogenic agent in a murine tumor model. J. Surg. Res., 2004, 116(1), 19-23.
[http://dx.doi.org/10.1016/j.jss.2003.09.014] [PMID: 14732345]
[14]
Hwang, J.T.; Ha, J.; Park, O.J. Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways. Biochem. Biophys. Res. Commun., 2005, 332(2), 433-440.
[http://dx.doi.org/10.1016/j.bbrc.2005.04.143] [PMID: 15896711]
[15]
Sánchez, Y.; Amrán, D.; Fernández, C.; de Blas, E.; Aller, P. Genistein selectively potentiates arsenic trioxide-induced apoptosis in human leukemia cells via reactive oxygen species generation and activation of reactive oxygen species-inducible protein kinases (p38-MAPK, AMPK). Int. J. Cancer, 2008, 123(5), 1205-1214.
[http://dx.doi.org/10.1002/ijc.23639] [PMID: 18546268]
[16]
Jiang, H.; Ma, Y.; Chen, X.; Pan, S.; Sun, B.; Krissansen, G.W.; Sun, X. Genistein synergizes with arsenic trioxide to suppress human hepatocellular carcinoma. Cancer Sci., 2010, 101(4), 975-983.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01464.x] [PMID: 20219070]
[17]
Lim, H.A.; Kim, J.H.; Kim, J.H.; Sung, M.K.; Kim, M.K.; Park, J.H.; Kim, J.S. Genistein induces glucose-regulated protein 78 in mammary tumor cells. J. Med. Food, 2006, 9(1), 28-32.
[http://dx.doi.org/10.1089/jmf.2006.9.28] [PMID: 16579725]
[18]
Banerjee, S.; Zhang, Y.; Ali, S.; Bhuiyan, M.; Wang, Z.; Chiao, P.J.; Philip, P.A.; Abbruzzese, J.; Sarkar, F.H. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res., 2005, 65(19), 9064-9072.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1330] [PMID: 16204081]
[19]
Ortega, N.; Romero, M.P.; Macià, A.; Reguant, J.; Anglès, N.; Morelló, J.R.; Motilva, M.J. Obtention and characterization of phenolic extracts from different cocoa sources. J. Agric. Food Chem., 2008, 56(20), 9621-9627.
[http://dx.doi.org/10.1021/jf8014415] [PMID: 18821769]
[20]
Wang, Y.; Wang, H.; Zhang, W.; Shao, C.; Xu, P.; Shi, C.H.; Shi, J.G.; Li, Y.M.; Fu, Q.; Xue, W.; Lei, Y.H.; Gao, J.Y.; Wang, J.Y.; Gao, X.P.; Li, J.Q.; Yuan, J.L.; Zhang, Y.T. Genistein sensitizes bladder cancer cells to HCPT treatment in vitro and in vivo via ATM/NF-κB/IKK pathway-induced apoptosis. PLoS One, 2013, 8(1), 1-9.
[http://dx.doi.org/10.1371/journal.pone.0050175]
[21]
Ali, S.; Varghese, L.; Pereira, L.; Tulunay-Ugur, O.E.; Kucuk, O.; Carey, T.E.; Wolf, G.T.; Sarkar, F.H. Sensitization of squamous cell carcinoma to cisplatin induced killing by natural agents. Cancer Lett., 2009, 278(2), 201-209.
[http://dx.doi.org/10.1016/j.canlet.2009.01.009] [PMID: 19231069]
[22]
Du, B.; Jiang, L.; Xia, Q.; Zhong, L. Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29. Chemotherapy, 2006, 52(1), 23-28.
[http://dx.doi.org/10.1159/000090238] [PMID: 16340194]
[23]
Montopoli, M.; Ragazzi, E.; Froldi, G.; Caparrotta, L. Cell-cycle inhibition and apoptosis induced by curcumin and cisplatin or oxaliplatin in human ovarian carcinoma cells. Cell Prolif., 2009, 42(2), 195-206.
[http://dx.doi.org/10.1111/j.1365-2184.2009.00585.x] [PMID: 19236381]
[24]
Dhandapani, K.M.; Mahesh, V.B.; Brann, D.W. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. J. Neurochem., 2007, 102(2), 522-538.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04633.x] [PMID: 17596214]
[25]
Zhang, Q.; Wei, D.; Liu, J. In vivo reversal of doxorubicin resistance by (-)-epigallocatechin gallate in a solid human carcinoma xenograft. Cancer Lett., 2004, 208(2), 179-186.
[http://dx.doi.org/10.1016/j.canlet.2004.01.033] [PMID: 15142676]
[26]
Lang, M.; Henson, R.; Braconi, C.; Patel, T. Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells. Liver Int., 2009, 29(5), 670-677.
[http://dx.doi.org/10.1111/j.1478-3231.2009.01984.x] [PMID: 19226332]
[27]
Chan, M.M.; Soprano, K.J.; Weinstein, K.; Fong, D. Epigallocatechin-3-gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility. J. Cell. Physiol., 2006, 207(2), 389-396.
[http://dx.doi.org/10.1002/jcp.20569] [PMID: 16402374]
[28]
Zanini, C.; Giribaldi, G.; Mandili, G.; Carta, F.; Crescenzio, N.; Bisaro, B.; Doria, A.; Foglia, L.; di Montezemolo, L.C.; Timeus, F.; Turrini, F. Inhibition of heat shock proteins (HSP) expression by quercetin and differential doxorubicin sensitization in neuroblastoma and Ewing’s sarcoma cell lines. J. Neurochem., 2007, 103(4), 1344-1354.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04835.x] [PMID: 17680992]
[29]
Du, G.; Lin, H.; Yang, Y.; Zhang, S.; Wu, X.; Wang, M.; Ji, L.; Lu, L.; Yu, L.; Han, G. Dietary quercetin combining intratumoral doxorubicin injection synergistically induces rejection of established breast cancer in mice. Int. Immunopharmacol., 2010, 10(7), 819-826.
[http://dx.doi.org/10.1016/j.intimp.2010.04.018] [PMID: 20447470]
[30]
Kuhar, M.; Imran, S.; Singh, N. Curcumin and quercetin combined with cisplatin to induce apoptosis in human laryngeal carcinoma Hep-2 cells through the mitochondrial pathway. J. Cancer Mol., 2007, 3(4), 121-128.
[31]
Ramos, A.M.; Aller, P. Quercetin decreases intracellular GSH content and potentiates the apoptotic action of the antileukemic drug arsenic trioxide in human leukemia cell lines. Biochem. Pharmacol., 2008, 75(10), 1912-1923.
[http://dx.doi.org/10.1016/j.bcp.2008.02.007] [PMID: 18359480]
[32]
Jakubowicz-Gil, J.; Langner, E.; Wertel, I.; Piersiak, T.; Rzeski, W. Temozolomide, quercetin and cell death in the MOGGCCM astrocytoma cell line. Chem. Biol. Interact., 2010, 188(1), 190-203.
[http://dx.doi.org/10.1016/j.cbi.2010.07.015] [PMID: 20654599]
[33]
Do Amaral, C.L.; Francescato, H.D.; Coimbra, T.M.; Costa, R.S.; Darin, J.D.; Antunes, L.M. Bianchi, Mde.L. Resveratrol attenuates cisplatin-induced nephrotoxicity in rats. Arch. Toxicol., 2008, 82(6), 363-370.
[http://dx.doi.org/10.1007/s00204-007-0262-x] [PMID: 18026934]
[34]
Wang, J.; He, D.; Zhang, Q.; Han, Y.; Jin, S.; Qi, F. Resveratrol protects against Cisplatin-induced cardiotoxicity by alleviating oxidative damage. Cancer Biother. Radiopharm., 2009, 24(6), 675-680.
[http://dx.doi.org/10.1089/cbr.2009.0679] [PMID: 20025547]
[35]
Kweon, S.H.; Song, J.H.; Kim, T.S. Resveratrol-mediated reversal of doxorubicin resistance in acute myeloid leukemia cells via downregulation of MRP1 expression. Biochem. Biophys. Res. Commun., 2010, 395(1), 104-110.
[http://dx.doi.org/10.1016/j.bbrc.2010.03.147] [PMID: 20350534]
[36]
Rasul, A.; Yu, B.; Zhong, L.; Khan, M.; Yang, H.; Ma, T. Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy. Oncol. Rep., 2012, 27(5), 1481-1487.
[PMID: 22367117]
[37]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod., 2007, 70(3), 461-477.
[http://dx.doi.org/10.1021/np068054v] [PMID: 17309302]
[38]
Aggarwal, B.B. Nuclear factor-kappaB: the enemy within. Cancer Cell, 2004, 6(3), 203-208.
[http://dx.doi.org/10.1016/j.ccr.2004.09.003] [PMID: 15380510]
[39]
Aggarwal, B.B.; Shishodia, S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol., 2006, 71(10), 1397-1421.
[http://dx.doi.org/10.1016/j.bcp.2006.02.009] [PMID: 16563357]
[40]
Stiborova, M.; Manhartova, Z.; Hodek, P.; Adam, V.; Kizek, R.; Frei, E. Formation of DNA adducts by ellipticine and its micellar form in rats – a comparative study. Sensors (Basel), 2014, 14(12), 22982-22997.
[http://dx.doi.org/10.3390/s141222982] [PMID: 25479328]
[41]
Siu, D. Activity-dependent hepatocyte growth factor expression and its role in organogenesis and cancer growth suppression. Med. Hypotheses, 2004, 63(1), 62-70.
[http://dx.doi.org/10.1016/j.mehy.2004.01.031] [PMID: 15193349]
[42]
Fernandez, E.J.; Lolis, E. Structure, function, and inhibition of chemokines. Annu. Rev. Pharmacol. Toxicol., 2002, 42(1), 469-499.
[http://dx.doi.org/10.1146/annurev.pharmtox.42.091901.115838] [PMID: 11807180]
[43]
Hu, M.L. Dietary polyphenols as antioxidants and anticancer agents: more questions than answers. Chang Gung Med. J., 2011, 34(5), 449-460.
[PMID: 22035889]
[44]
Ramos, S. Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Mol. Nutr. Food Res., 2008, 52(5), 507-526.
[http://dx.doi.org/10.1002/mnfr.200700326] [PMID: 18435439]
[45]
Kim, Y.J.; Park, M.Y.; Chang, N.; Kwon, O. Intake and major sources of dietary flavonoid in Korean adults: Korean national health and nutrition examination survey 2010-2012. Asia Pac. J. Clin. Nutr., 2015, 24(3), 456-463.
[PMID: 26420187]
[46]
Chun, O.K.; Chung, S.J.; Song, W.O. Estimated dietary flavonoid intake and major food sources of U.S. adults. J. Nutr., 2007, 137(5), 1244-1252.
[http://dx.doi.org/10.1093/jn/137.5.1244] [PMID: 17449588]
[47]
Ovaskainen, M.L.; Törrönen, R.; Koponen, J.M.; Sinkko, H.; Hellström, J.; Reinivuo, H.; Mattila, P. Dietary intake and major food sources of polyphenols in Finnish adults. J. Nutr., 2008, 138(3), 562-566.
[http://dx.doi.org/10.1093/jn/138.3.562] [PMID: 18287367]
[48]
Li, L.; Zhang, M.; Holman, C.D.A.J. Population versus hospital controls in the assessment of dietary intake of isoflavone for case-control studies on cancers in China. Nutr. Cancer, 2013, 65(3), 390-397.
[http://dx.doi.org/10.1080/01635581.2013.767915] [PMID: 23530638]
[49]
Singh, S.; Aggarwal, B.B. Activation of transcription factor NF-κ B is suppressed by curcumin (diferuloylmethane). J. Biol. Chem., 1995, 270(42), 24995-25000.
[http://dx.doi.org/10.1074/jbc.270.42.24995] [PMID: 7559628]
[50]
Estrov, Z.; Shishodia, S.; Faderl, S.; Harris, D.; Van, Q.; Kantarjian, H.M.; Talpaz, M.; Aggarwal, B.B. Resveratrol blocks interleukin-1β-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. Blood, 2003, 102(3), 987-995.
[http://dx.doi.org/10.1182/blood-2002-11-3550] [PMID: 12689943]
[51]
Hong, J.; Lambert, J.D.; Lee, S.H.; Sinko, P.J.; Yang, C.S. Involvement of multidrug resistance-associated proteins in regulating cellular levels of (-)-epigallocatechin-3-gallate and its methyl metabolites. Biochem. Biophys. Res. Commun., 2003, 310(1), 222-227.
[http://dx.doi.org/10.1016/j.bbrc.2003.09.007] [PMID: 14511674]
[52]
Manna, S.K.; Mukhopadhyay, A.; Van, N.T.; Aggarwal, B.B. Silymarin suppresses TNF-induced activation of NF-κ B, c-Jun N-terminal kinase, and apoptosis. J. Immunol., 1999, 163(12), 6800-6809.
[PMID: 10586080]
[53]
Ashikawa, K.; Majumdar, S.; Banerjee, S.; Bharti, A.C.; Shishodia, S.; Aggarwal, B.B. Piceatannol inhibits TNF-induced NF-kappaB activation and NF-kappaB-mediated gene expression through suppression of IκBα kinase and p65 phosphorylation. J. Immunol., 2002, 169(11), 6490-6497.
[http://dx.doi.org/10.4049/jimmunol.169.11.6490] [PMID: 12444159]
[54]
Bode, A.M.; Ma, W.Y.; Surh, Y.J.; Dong, Z. Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by [6]-gingerol. Cancer Res., 2001, 61(3), 850-853.
[PMID: 11221868]
[55]
Yasunari, T.; Bharat, B.A. Flavopiridol inhibits NF-κB activation induced by various carcinogens and inflammatory agents through inhibition of IκBα kinase and p65 phosphorylation: abrogation of cyclin D1, cyclooxygenase-2, and matrix metalloprotease-9. J. Biol. Chem., 2004, 279(6), 4750-4759.
[http://dx.doi.org/10.1074/jbc.M304546200] [PMID: 14630924]
[56]
Chen, W.; Zhao, Z.; Li, L.; Wu, B.; Chen, S.F.; Zhou, H.; Wang, Y.; Li, Y.Q. Hispolon induces apoptosis in human gastric cancer cells through a ROS-mediated mitochondrial pathway. Free Radic. Biol. Med., 2008, 45(1), 60-72.
[http://dx.doi.org/10.1016/j.freeradbiomed.2008.03.013] [PMID: 18423410]
[57]
Niero, E.L.D.O.; Machado-Santelli, G.M. Cinnamic acid induces apoptotic cell death and cytoskeleton disruption in human melanoma cells. J. Exp. Clin. Cancer Res., 2013, 32(1), 31.
[http://dx.doi.org/10.1186/1756-9966-32-31]
[58]
Majumdar, A.P.; Banerjee, S.; Nautiyal, J.; Patel, B.B.; Patel, V.; Du, J.; Yu, Y.; Elliott, A.A.; Levi, E.; Sarkar, F.H. Curcumin synergizes with resveratrol to inhibit colon cancer. Nutr. Cancer, 2009, 61(4), 544-553.
[http://dx.doi.org/10.1080/01635580902752262] [PMID: 19838927]
[59]
Mertens-Talcott, S.U.; Talcott, S.T.; Percival, S.S. Low concentrations of quercetin and ellagic acid synergistically influence proliferation, cytotoxicity and apoptosis in MOLT-4 human leukemia cells. J. Nutr., 2003, 133(8), 2669-2674.
[http://dx.doi.org/10.1093/jn/133.8.2669] [PMID: 12888656]
[60]
Mertens-Talcott, S.U.; Percival, S.S. Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells. Cancer Lett., 2005, 218(2), 141-151.
[http://dx.doi.org/10.1016/j.canlet.2004.06.007] [PMID: 15670891]
[61]
Kowalczyk, M.C.; Kowalczyk, P.; Tolstykh, O.; Hanausek, M.; Walaszek, Z.; Slaga, T.J. Synergistic effects of combined phytochemicals and skin cancer prevention in SENCAR mice. Cancer Prev. Res. (Phila.), 2010, 3(2), 170-178.
[http://dx.doi.org/10.1158/1940-6207.CAPR-09-0196] [PMID: 20103723]
[62]
Shimizu, M.; Deguchi, A.; Lim, J.T.; Moriwaki, H.; Kopelovich, L.; Weinstein, I.B. (-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin. Cancer Res., 2005, 11(7), 2735-2746.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-2014] [PMID: 15814656]
[63]
Morré, D.J.; Morré, D.M.; Sun, H.; Cooper, R.; Chang, J.; Janle, E.M. Tea catechin synergies in inhibition of cancer cell proliferation and of a cancer specific cell surface oxidase (ECTO-NOX). Pharmacol. Toxicol., 2003, 92(5), 234-241.
[http://dx.doi.org/10.1034/j.1600-0773.2003.920506.x] [PMID: 12753411]

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