Research article Topical Sections

In vitro activity of some flavonoid derivatives on human leukemic myeloid cells: evidence for aminopeptidase-N (CD13) inhibition, antiproliferative and cell death properties

  • Received: 17 May 2016 Accepted: 28 July 2016 Published: 25 January 2016
  • Leukemia cells from patients with acute myeloid leukemia (AML) display high proliferative capacity and are resistant to death. Membrane-anchored aminopeptidase-N/CD13 is a potential drug target in AML. Clinical research efforts are currently focusing on targeted therapies that induce death in AML cells. We previously developed a non-cytotoxic APN/CD13 inhibitor based on flavone-8-acetic acid scaffold, the 2',3-dinitroflavone-8-acetic acid (1). In this context, among the variously substituted 113 compounds further synthesized and tested for evaluation of their effects on APN/CD13 activity, proliferation and survival in human AML U937 cells, eight flavonoid derivatives emerged: 2',3-dinitro-6-methoxy-flavone-8-acetic acid (2), four compounds (36) with the 3-chloro-2,3-dihydro-3-nitro-2-phenyl-4H-1-benzopyran-4-one structure, and three (79) with the 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2H-1-benzopyran framework. Different structure-activity relationships were observed between APN/CD13 activity and growth/survival processes. We showed that compound 2, but not benzopyran derivatives 39, inhibited APN activity (although to a less degree than 1). Both 1 and 2 did not affect AML cell proliferation and survival, indicating that CD13’s APN activity is not required for these processes. In contrast, benzopyran compounds 39 inhibited in a concentration-dependent manner the growth of U937 cells by inducing death as evidenced by phosphatidylserine externalization. Cell death was associated with the presence of geminal nitro group and chlorine at the 3-position of the 2H-1-benzopyran scaffold. The presence of other substituents such as CH2COOH or CH2CH=CH2 groups at the 8-position, NO2 or I substituents at the 2'- or 3'-position, OCH3 or OCH2C6H5 groups at the 4'-position did not affect cell death. Importantly, the inhibitory effects evidenced with compounds 79 were not due to their potential decomposition into the corresponding (Z)-(2chloro-2-nitroethenyl)benzene and salicylaldehyde. Based on these preliminary data, the 3-chloro,3-nitro-2H-1-benzopyran derivatives could be classified as a new group of compounds with promising antitumor properties; this study therefore provides the opportunity to explore their potential efficiency in AML patients’ cells ex vivo.

    Citation: Sandrine Bouchet, Marion Piedfer, Santos Susin, Daniel Dauzonne, Brigitte Bauvois. In vitro activity of some flavonoid derivatives on human leukemic myeloid cells: evidence for aminopeptidase-N (CD13) inhibition, antiproliferative and cell death properties[J]. AIMS Molecular Science, 2016, 3(3): 368-385. doi: 10.3934/molsci.2016.3.368

    Related Papers:

  • Leukemia cells from patients with acute myeloid leukemia (AML) display high proliferative capacity and are resistant to death. Membrane-anchored aminopeptidase-N/CD13 is a potential drug target in AML. Clinical research efforts are currently focusing on targeted therapies that induce death in AML cells. We previously developed a non-cytotoxic APN/CD13 inhibitor based on flavone-8-acetic acid scaffold, the 2',3-dinitroflavone-8-acetic acid (1). In this context, among the variously substituted 113 compounds further synthesized and tested for evaluation of their effects on APN/CD13 activity, proliferation and survival in human AML U937 cells, eight flavonoid derivatives emerged: 2',3-dinitro-6-methoxy-flavone-8-acetic acid (2), four compounds (36) with the 3-chloro-2,3-dihydro-3-nitro-2-phenyl-4H-1-benzopyran-4-one structure, and three (79) with the 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2H-1-benzopyran framework. Different structure-activity relationships were observed between APN/CD13 activity and growth/survival processes. We showed that compound 2, but not benzopyran derivatives 39, inhibited APN activity (although to a less degree than 1). Both 1 and 2 did not affect AML cell proliferation and survival, indicating that CD13’s APN activity is not required for these processes. In contrast, benzopyran compounds 39 inhibited in a concentration-dependent manner the growth of U937 cells by inducing death as evidenced by phosphatidylserine externalization. Cell death was associated with the presence of geminal nitro group and chlorine at the 3-position of the 2H-1-benzopyran scaffold. The presence of other substituents such as CH2COOH or CH2CH=CH2 groups at the 8-position, NO2 or I substituents at the 2'- or 3'-position, OCH3 or OCH2C6H5 groups at the 4'-position did not affect cell death. Importantly, the inhibitory effects evidenced with compounds 79 were not due to their potential decomposition into the corresponding (Z)-(2chloro-2-nitroethenyl)benzene and salicylaldehyde. Based on these preliminary data, the 3-chloro,3-nitro-2H-1-benzopyran derivatives could be classified as a new group of compounds with promising antitumor properties; this study therefore provides the opportunity to explore their potential efficiency in AML patients’ cells ex vivo.


    加载中
    [1] King ME, Rowe JM (2007) Recent developments in acute myelogenous leukemia therapy. Oncologist 12 Suppl 2: 14-21.
    [2] Robak T, Wierzbowska A (2009) Current and emerging therapies for acute myeloid leukemia. Clin Ther 31 Pt 2: 2349-2370.
    [3] Steele VE, Boone CW, Dauzonne D, et al. (2002) Correlation between electron-donating ability of a series of 3-nitroflavones and their efficacy to inhibit the onset and progression of aberrant crypt foci in the rat colon. Cancer Res 62: 6506-6509.
    [4] Cardenas M, Marder M, Blank VC, et al. (2006) Antitumor activity of some natural flavonoids and synthetic derivatives on various human and murine cancer cell lines. Bioorg Med Chem 14: 2966-2971. doi: 10.1016/j.bmc.2005.12.021
    [5] Li Y, Fang H, Xu W (2007) Recent advance in the research of flavonoids as anticancer agents. Mini Rev Med Chem 7: 663-678. doi: 10.2174/138955707781024463
    [6] Singh M, Kaur M, Silakari O (2014) Flavones: an important scaffold for medicinal chemistry. Eur J Med Chem 84: 206-239. doi: 10.1016/j.ejmech.2014.07.013
    [7] Chabot GG, Touil YS, Pham MH, et al. (2010) Flavonoids in cancer prevention and therapy: chemistry, pharamcology, mechanisms of action, and perspectives for cancer drugdiscovery. In: Moulay A, editor. Alternative and complementary therapies for cancer. Springer US, 583-612.
    [8] Hou DX, Kumamoto T (2010) Flavonoids as protein kinase inhibitors for cancer chemoprevention: direct binding and molecular modeling. Antioxid Redox Signal 13: 691-719. doi: 10.1089/ars.2009.2816
    [9] Ravishankar D, Rajora AK, Greco F, et al. (2013) Flavonoids as prospective compounds for anti-cancer therapy. Int J Biochem Cell Biol 45: 2821-2831. doi: 10.1016/j.biocel.2013.10.004
    [10] Li-Weber M (2009) New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat Rev 35: 57-68. doi: 10.1016/j.ctrv.2008.09.005
    [11] Liesveld JL, Abboud CN, Lu C, et al. (2003) Flavonoid effects on normal and leukemic cells. Leuk Res 27: 517-527. doi: 10.1016/S0145-2126(02)00265-5
    [12] Newcomb EW (2004) Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity. Anticancer Drugs 15: 411-419. doi: 10.1097/01.cad.0000127332.06439.47
    [13] Cheng S, Gao N, Zhang Z, et al. (2010) Quercetin induces tumor-selective apoptosis through downregulation of Mcl-1 and activation of Bax. Clin Cancer Res 16: 5679-5691. doi: 10.1158/1078-0432.CCR-10-1565
    [14] Fathi AT, Karp JE (2009) New agents in acute myeloid leukemia: beyond cytarabine and anthracyclines. Curr Oncol Rep 11: 346-352. doi: 10.1007/s11912-009-0047-x
    [15] Blum W, Phelps MA, Klisovic RB, et al. (2010) Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias. Haematologica 95: 1098-1105. doi: 10.3324/haematol.2009.017103
    [16] Karp JE, Smith BD, Resar LS, et al. (2011) Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood 117: 3302-3310. doi: 10.1182/blood-2010-09-310862
    [17] Zeidner JF, Foster MC, Blackford AL, et al. (2015) Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica 100: 1172-1179. doi: 10.3324/haematol.2015.125849
    [18] Bauvois B, Puiffe ML, Bongui JB, et al. (2003) Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13. J Med Chem 46: 3900-3913. doi: 10.1021/jm021109f
    [19] Quiney C, Dauzonne D, Kern C, et al. (2004) Flavones and polyphenols inhibit the NO pathway during apoptosis of leukemia B-cells. Leuk Res 28: 851-861. doi: 10.1016/j.leukres.2003.12.003
    [20] Piedfer M, Bouchet S, Tang R, et al. (2013) p70S6 kinase is a target of the novel proteasome inhibitor 3,3'-diamino-4'-methoxyflavone during apoptosis in human myeloid tumor cells. Biochim Biophys Acta 1833: 1316-1328. doi: 10.1016/j.bbamcr.2013.02.016
    [21] Bauvois B, Dauzonne D (2006) Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: chemistry, biological evaluations, and therapeutic prospects. Med Res Rev 26: 88-130.
    [22] Bouchet S, Tang R, Fava F, et al. (2016) The CNGRC-GG-D(KLAKLAK)2 peptide induces a caspase-independent, Ca2+-dependent death in human leukemic myeloid cells by targeting surface aminopeptidase N/CD13. Oncotarget 7: 19445-19467.
    [23] Klobusicka M, Kusenda J, Babusikova O (2005) Myeloid enzymes profile related to the immunophenotypic characteristics of blast cells from patients with acute myeloid leukemia (AML) at diagnosis. Neoplasma 52: 211-218.
    [24] Taussig DC, Pearce DJ, Simpson C, et al. (2005) Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106: 4086-4092. doi: 10.1182/blood-2005-03-1072
    [25] Piedfer M, Dauzonne D, Tang R, et al. (2011) Aminopeptidase-N/CD13 is a potential proapoptotic target in human myeloid tumor cells. Faseb J 25: 2831-2842. doi: 10.1096/fj.11-181396
    [26] Wickstrom M, Larsson R, Nygren P, et al. (2011) Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci 102: 501-508. doi: 10.1111/j.1349-7006.2010.01826.x
    [27] Dauzonne D, Folléas B, Martinez L, et al. (1997) Synthesis and in vitro cytotoxicity of a series of 3-aminoflavones. . Eur J Med Chem 32: 71-82. doi: 10.1016/S0223-5234(97)84363-2
    [28] Dauzonne D, Demerseman P (1990) A convenient synthesis of 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-p henyl-2H-1-benzopyrans. Synthesis 1: 66-70.
    [29] Dauzonne D, Grandjean C (1992) Synthesis of 2-Aryl-3-nitro-4H-1-benzopyran-4-ones. Synthesis 7: 677-680.
    [30] Pham MH, Auzeil N, Regazzetti A, et al. (2007) Identification of new flavone-8-acetic acid metabolites using mouse microsomes and comparison with human microsomes. Drug Metab Dispos 35: 2023-2034. doi: 10.1124/dmd.107.017012
    [31] Ceccaldi A, Rajavelu A, Champion C, et al. (2011) C5-DNA methyltransferase inhibitors: from screening to effects on zebrafish embryo development. Chembiochem 12: 1337-1345. doi: 10.1002/cbic.201100130
    [32] Lanotte M, Martin-Thouvenin V, Najman S, et al. (1991) NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). Blood 77: 1080-1086.
    [33] Laouar A, Wietzerbin J, Bauvois B (1993) Divergent regulation of cell surface protease expression in HL-60 cells differentiated into macrophages with granulocyte macrophage colony stimulating factor or neutrophils with retinoic acid. Int Immunol 5: 965-973. doi: 10.1093/intimm/5.8.965
    [34] Laouar A, Villiers C, Sanceau J, et al. (1993) Inactivation of interleukin-6 in vitro by monoblastic U937 cell plasma membranes involves both protease and peptidyl-transferase activities. Eur J Biochem 215: 825-831. doi: 10.1111/j.1432-1033.1993.tb18098.x
    [35] Broker LE, Kruyt FA, Giaccone G (2005) Cell death independent of caspases: a review. Clin Cancer Res 11: 3155-3162. doi: 10.1158/1078-0432.CCR-04-2223
    [36] Wang ZB, Liu YQ, Cui YF (2005) Pathways to caspase activation. Cell Biol Int 29: 489-496. doi: 10.1016/j.cellbi.2005.04.001
    [37] Antczak C, De Meester I, Bauvois B (2001) Transmembrane proteases as disease markers and targets for therapy. J Biol Regul Homeost Agents 15: 130-139.
    [38] Bauvois B (2001) Transmembrane proteases in focus: diversity and redundancy? J Leukoc Biol 70: 11-17.
    [39] Bauvois B (2004) Transmembrane proteases in cell growth and invasion: new contributors to angiogenesis? Oncogene 23: 317-329. doi: 10.1038/sj.onc.1207124
    [40] Mina-Osorio P (2008) The moonlighting enzyme CD13: old and new functions to target. Trends Mol Med 14: 361-371. doi: 10.1016/j.molmed.2008.06.003
    [41] Antczak C, De Meester I, Bauvois B (2001) Ectopeptidases in pathophysiology. Bioessays 23: 251-260.
    [42] Grujic M, Renko M (2002) Aminopeptidase inhibitors bestatin and actinonin inhibit cell proliferation of myeloma cells predominantly by intracellular interactions. Cancer Lett 182: 113-119. doi: 10.1016/S0304-3835(02)00086-1
    [43] Winnicka B, O'Conor C, Schacke W, et al. (2010) CD13 is dispensable for normal hematopoiesis and myeloid cell functions in the mouse. J Leukoc Biol 88: 347-359. doi: 10.1189/jlb.0210065
    [44] Scaffidi C, Schmitz I, Zha J, et al. (1999) Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 274: 22532-22538. doi: 10.1074/jbc.274.32.22532
    [45] Galluzzi L, Vitale I, Abrams JM, et al. (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19: 107-120. doi: 10.1038/cdd.2011.96
    [46] Galluzzi L, Kepp O, Krautwald S, et al. (2014) Molecular mechanisms of regulated necrosis. Semin Cell Dev Biol 35: 24-32. doi: 10.1016/j.semcdb.2014.02.006
    [47] Pasparakis M, Vandenabeele P (2015) Necroptosis and its role in inflammation. Nature 517: 311-320. doi: 10.1038/nature14191
    [48] Baritaud M, Boujrad H, Lorenzo HK, et al. (2010) Histone H2AX: The missing link in AIF-mediated caspase-independent programmed necrosis. Cell Cycle 9: 3166-3173. doi: 10.4161/cc.9.16.12887
    [49] Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, et al. (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 15: 135-147.
    [50] Bonora M, Wieckowski MR, Chinopoulos C, et al. (2015) Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 34: 1475-1486. doi: 10.1038/onc.2014.96
    [51] Yuan Z, Long C, Junming T, et al. (2012) Quercetin-induced apoptosis of HL-60 cells by reducing PI3K/Akt. Mol Biol Rep 39: 7785-7793. doi: 10.1007/s11033-012-1621-0
    [52] Lee WJ, Hsiao M, Chang JL, et al. (2015) Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft. Arch Toxicol 89: 1103-1117. doi: 10.1007/s00204-014-1300-0
    [53] Chen YC, Shen SC, Lee WR, et al. (2002) Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. Arch Toxicol 76: 351-359. doi: 10.1007/s00204-002-0346-6
    [54] Hu C, Xu M, Qin R, et al. (2015) Wogonin induces apoptosis and endoplasmic reticulum stress in HL-60 leukemia cells through inhibition of the PI3K-AKT signaling pathway. Oncol Rep 33: 3146-3154.
    [55] Hsiao PC, Lee WJ, Yang SF, et al. (2014) Nobiletin suppresses the proliferation and induces apoptosis involving MAPKs and caspase-8/-9/-3 signals in human acute myeloid leukemia cells. Tumour Biol 35: 11903-11911. doi: 10.1007/s13277-014-2457-0
    [56] Budhraja A, Gao N, Zhang Z, et al. (2012) Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo. Mol Cancer Ther 11: 132-142. doi: 10.1158/1535-7163.MCT-11-0343
    [57] Ruela-de-Sousa RR, Fuhler GM, Blom N, et al. (2010) Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy. Cell Death Dis 1: e19. doi: 10.1038/cddis.2009.18
    [58] Park C, Lee WS, Go SI, et al. (2014) Morin, a flavonoid from moraceae, induces apoptosis by induction of BAD protein in human leukemic cells. Int J Mol Sci 16: 645-659. doi: 10.3390/ijms16010645
    [59] Gao H, Liu Y, Li K, et al. (2016) Hispidulin induces mitochondrial apoptosis in acute myeloid leukemia cells by targeting extracellular matrix metalloproteinase inducer. Am J Transl Res 8: 1115-1132.
    [60] Cardenas MG, Blank VC, Marder MN, et al. (2012) 2'-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells. Anticancer Drugs 23: 815-826. doi: 10.1097/CAD.0b013e328353f947
    [61] Chang H, Lin H, Yi L, et al. (2010) 3,6-Dihydroxyflavone induces apoptosis in leukemia HL-60 cell via reactive oxygen species-mediated p38 MAPK/JNK pathway. Eur J Pharmacol 648: 31-38. doi: 10.1016/j.ejphar.2010.08.020
    [62] Rosato RR, Dai Y, Almenara JA, et al. (2004) Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation. Leukemia 18: 1780-1788. doi: 10.1038/sj.leu.2403491
    [63] Delmulle L, Vanden Berghe T, Keukeleire DD, et al. (2008) Treatment of PC-3 and DU145 prostate cancer cells by prenylflavonoids from hop (Humulus lupulus L.) induces a caspase-independent form of cell death. Phytother Res 22: 197-203.
    [64] Wu PP, Kuo SC, Huang WW, et al. (2009) (-)-Epigallocatechin gallate induced apoptosis in human adrenal cancer NCI-H295 cells through caspase-dependent and caspase-independent pathway. Anticancer Res 29: 1435-1442.
    [65] Zhang Y, Yang ND, Zhou F, et al. (2012) (-)-Epigallocatechin-3-gallate induces non-apoptotic cell death in human cancer cells via ROS-mediated lysosomal membrane permeabilization. PLoS One 7: e46749. doi: 10.1371/journal.pone.0046749
    [66] Wang G, Wang JJ, Yang GY, et al. (2012) Effects of quercetin nanoliposomes on C6 glioma cells through induction of type III programmed cell death. Int J Nanomedicine 7: 271-280. doi: 10.2217/nnm.11.186
    [67] Liao H, Bao X, Zhu J, et al. (2015) O-Alkylated derivatives of quercetin induce apoptosis of MCF-7 cells via a caspase-independent mitochondrial pathway. Chem Biol Interact 242: 91-98. doi: 10.1016/j.cbi.2015.09.022
    [68] Lindsay CK, Gomez DE, Thorgeirsson UP (1996) Effect of flavone acetic acid on endothelial cell proliferation: evidence for antiangiogenic properties. Anticancer Res 16: 425-431.
    [69] Granci V, Dupertuis YM, Pichard C (2010) Angiogenesis as a potential target of pharmaconutrients in cancer therapy. Curr Opin Clin Nutr Metab Care 13: 417-422. doi: 10.1097/MCO.0b013e3283392656
    [70] Prasad S, Phromnoi K, Yadav VR, et al. (2010) Targeting inflammatory pathways by flavonoids for prevention and treatment of cancer. Planta Med 76: 1044-1063. doi: 10.1055/s-0030-1250111
    [71] Asensi M, Ortega A, Mena S, et al. (2011) Natural polyphenols in cancer therapy. Crit Rev Clin Lab Sci 48: 197-216. doi: 10.3109/10408363.2011.631268
    [72] Pham MH, Dauzonne D, Chabot GG (2016) Not flavone-8-acetic acid (FAA) but its murine metabolite 6-OH-FAA exhibits remarkable antivascular activities in vitro. Anti-Cancer Drugs 27: 398-406. doi: 10.1097/CAD.0000000000000341
    [73] Granja A, Pinheiro M, Reis S (2016) Epigallocatechin Gallate Nanodelivery Systems for Cancer Therapy. Nutrients 8: 307. doi: 10.3390/nu8050307
    [74] Bauvois B (2012) New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 1825: 29-36.
    [75] Trujillo A, McGee C, Cogle CR (2012) Angiogenesis in acute myeloid leukemia and opportunities for novel therapies. J Oncol 2012: 128608.
    [76] Haouas H (2014) Angiogenesis and acute myeloid leukemia. Hematology 19: 311-323. doi: 10.1179/1607845413Y.0000000139
    [77] Klein G, Vellenga E, Fraaije MW, et al. (2004) The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia. Crit Rev Oncol Hematol 50: 87-100. doi: 10.1016/j.critrevonc.2003.09.001
    [78] Bouchet S, Tang R, Fava F, et al. (2014) Targeting CD13 (aminopeptidase-N) in turn downregulates ADAM17 by internalization in acute myeloid leukaemia cells. Oncotarget 5: 8211-8222. doi: 10.18632/oncotarget.1788
    [79] Bouchet S, Bauvois B (2014) Neutrophil Gelatinase-Associated Lipocalin (NGAL), Pro-Matrix Metalloproteinase-9 (pro-MMP-9) and Their Complex Pro-MMP-9/NGAL in Leukaemias. Cancers (Basel) 6: 796-812. doi: 10.3390/cancers6020796
  • Reader Comments
  • © 2016 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(4889) PDF downloads(1076) Cited by(3)

Article outline

Figures and Tables

Figures(7)  /  Tables(1)

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog