Phytochemical-Mediated Glioma Targeted Treatment: Drug Resistance and Novel Delivery Systems

Hang      Cao; Xuejun      Li; Feiyifan      Wang; Yueqi      Zhang; Yi      Xiong; Qi      Yang
doi:10.2174/0929867326666190809221332
Abstract

Glioma, especially its most malignant type, Glioblastoma (GBM), is the most common and the most aggressive malignant tumour in the central nervous system. Currently, we have no specific therapies that can significantly improve its dismal prognosis. Recent studies have reported promising in vitro experimental results of several novel glioma-targeting drugs; these studies are encouraging to both researchers and patients. However, clinical trials have revealed that novel compounds that focus on a single, clear glioma genetic alteration may not achieve a satisfactory outcome or have side effects that are unbearable. Based on this consensus, phytochemicals that exhibit multiple bioactivities have recently attracted much attention. Traditional Chinese medicine and traditional Indian medicine (Ayurveda) have shown that phytocompounds inhibit glioma angiogenesis, cancer stem cells and tumour proliferation; these results suggest a novel drug therapeutic strategy. However, single phytocompounds or their direct usage may not reverse comprehensive malignancy due to poor histological penetrability or relatively unsatisfactory in vivo efficiency. Recent research that has employed temozolomide combination treatment and Nanoparticles (NPs) with phytocompounds has revealed a powerful dual-target therapy and a high blood-brain barrier penetrability, which is accompanied by low side effects and strong specific targeting. This review is focused on major phytocompounds that have contributed to glioma-targeting treatment in recent years and their role in drug resistance inhibition, as well as novel drug delivery systems for clinical strategies. Lastly, we summarize a possible research strategy for the future.
Keywords: Phytochemical, glioma, glioblastoma, drug resistance, drug delivery system, nanoparticles.
« Previous Next »
[1] 
Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.B.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; Curschmann, J.; Janzer, R.C.; Ludwin, S.K.; Gorlia, T.; Allgeier, A.; Lacombe, D.; Cairncross, J.G.; Eisenhauer, E.; Mirimanoff, R.O. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med.,  2005, 352(10), 987-996.
[http://dx.doi.org/10.1056/NEJMoa043330] [PMID:  15758009] 
[2] 
Cao, H.; Wang, F.; Li, X.J. Future strategies on glioma research: from big data to the clinic. Genomics Proteomics Bioinformatics,  2017, 15(4), 263-265.
[http://dx.doi.org/10.1016/j.gpb.2017.07.001] [PMID:  28797870] 
[3] 
Wang, F.Y.; Kang, C.S.; Wang-Gou, S.Y.; Huang, C.H.; Feng, C.Y.; Li, X.J. EGFL7 is an intercellular EGFR signal messenger that plays an oncogenic role in glioma. Cancer Lett.,  2017, 384, 9-18.
[http://dx.doi.org/10.1016/j.canlet.2016.10.009] [PMID:  27725228] 
[4] 
Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.B.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; Hau, P.; Brandes, A.A.; Gijtenbeek, J.; Marosi, C.; Vecht, C.J.; Mokhtari, K.; Wesseling, P.; Villa, S.; Eisenhauer, E.; Gorlia, T.; Weller, M.; Lacombe, D.; Cairncross, J.G.; Mirimanoff, R.O. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol.,  2009, 10(5), 459-466.
[http://dx.doi.org/10.1016/S1470-2045(09)70025-7] [PMID:  19269895] 
[5] 
Wanggou, S.; Feng, C.; Xie, Y.; Ye, L.; Wang, F.; Li, X. Sample level enrichment analysis of KEGG pathways identifies clinically relevant subtypes of glioblastoma. J. Cancer,  2016, 7(12), 1701-1710.
[http://dx.doi.org/10.7150/jca.15486] [PMID:  27698907] 
[6] 
Yi, X.; Cao, H.; Tang, H.; Gong, G.; Hu, Z.; Liao, W.; Sun, L.; Chen, B.T.; Li, X. Gliosarcoma: a clinical and radiological analysis of 48 cases. Eur. Radiol.,  2019, 29(1), 429-438.
[http://dx.doi.org/10.1007/s00330-018-5398-y] [PMID:  29948068] 
[7] 
Zhao, Y.Z.; Lin, Q.; Wong, H.L.; Shen, X.T.; Yang, W.; Xu, H.L.; Mao, K.L.; Tian, F.R.; Yang, J.J.; Xu, J.; Xiao, J.; Lu, C.T. Glioma-targeted therapy using Cilengitide nanoparticles combined with UTMD enhanced delivery. J. Control. Release,  2016, 224, 112-125.
[http://dx.doi.org/10.1016/j.jconrel.2016.01.015] [PMID:  26792571] 
[8] 
Louis, D.N.; Ohgaki, H.; Wiestler, O.D.; Cavenee, W.K.; Burger, P.C.; Jouvet, A.; Scheithauer, B.W.; Kleihues, P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol.,  2007, 114(2), 97-109.
[http://dx.doi.org/10.1007/s00401-007-0243-4] [PMID:  17618441] 
[9] 
Stupp, R.; Hegi, M.E.; Gilbert, M.R.; Chakravarti, A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J. Clin. Oncol.,  2007, 25(26), 4127-4136.
[http://dx.doi.org/10.1200/JCO.2007.11.8554] [PMID:  17827463] 
[10] 
Stupp, R.; Hegi, M.E.; Gorlia, T.; Erridge, S.C.; Perry, J.; Hong, Y-K.; Aldape, K.D.; Lhermitte, B.; Pietsch, T.; Grujicic, D.; Steinbach, J.P.; Wick, W.; Tarnawski, R.; Nam, D.H.; Hau, P.; Weyerbrock, A.; Taphoorn, M.J.; Shen, C.C.; Rao, N.; Thurzo, L.; Herrlinger, U.; Gupta, T.; Kortmann, R.D.; Adamska, K.; McBain, C.; Brandes, A.A.; Tonn, J.C.; Schnell, O.; Wiegel, T.; Kim, C.Y.; Nabors, L.B.; Reardon, D.A.; van den Bent, M.J.; Hicking, C.; Markivskyy, A.; Picard, M.; Weller, M. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol.,  2014, 15(10), 1100-1108.
[http://dx.doi.org/10.1016/S1470-2045(14)70379-1] [PMID:  25163906] 
[11] 
Stupp, R.; Newlands, E. Seminars in oncology,  Elsevier, 2001; Vol. 28(Suppl. 12), pp 19-23.
[http://dx.doi.org/10.1016/S0093-7754(01)90067-3] 
[12] 
Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol.,  2016, 131(6), 803-820.
[http://dx.doi.org/10.1007/s00401-016-1545-1] [PMID:  27157931] 
[13] 
Johannessen, T.C.A.; Bjerkvig, R. Molecular mechanisms of temozolomide resistance in glioblastoma multiforme. Expert Rev. Anticancer Ther.,  2012, 12(5), 635-642.
[http://dx.doi.org/10.1586/era.12.37] [PMID:  22594898] 
[14] 
Lee, S.Y. Temozolomide resistance in glioblastoma multiforme. Genes Dis.,  2016, 3(3), 198-210.
[http://dx.doi.org/10.1016/j.gendis.2016.04.007] [PMID:  30258889] 
[15] 
Kitange, G.J.; Carlson, B.L.; Schroeder, M.A.; Grogan, P.T.; Lamont, J.D.; Decker, P.A.; Wu, W.; James, C.D.; Sarkaria, J.N. Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro-oncol.,  2009, 11(3), 281-291.
[http://dx.doi.org/10.1215/15228517-2008-090] [PMID:  18952979] 
[16] 
Bao, S.; Wu, Q.; McLendon, R.E.; Hao, Y.; Shi, Q.; Hjelmeland, A.B.; Dewhirst, M.W.; Bigner, D.D.; Rich, J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,  2006, 444(7120), 756-760.
[http://dx.doi.org/10.1038/nature05236] [PMID:  17051156] 
[17] 
Eramo, A.; Ricci-Vitiani, L.; Zeuner, A.; Pallini, R.; Lotti, F.; Sette, G.; Pilozzi, E.; Larocca, L.M.; Peschle, C.; De Maria, R. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ.,  2006, 13(7), 1238-1241.
[http://dx.doi.org/10.1038/sj.cdd.4401872] [PMID:  16456578] 
[18] 
Kim, S.S.; Harford, J.B.; Pirollo, K.F.; Chang, E.H. Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine. Biochem. Biophys. Res. Commun.,  2015, 468(3), 485-489.
[http://dx.doi.org/10.1016/j.bbrc.2015.06.137] [PMID:  26116770] 
[19] 
Vidal, S.J.; Rodriguez-Bravo, V.; Galsky, M.; Cordon-Cardo, C.; Domingo-Domenech, J. Targeting cancer stem cells to suppress acquired chemotherapy resistance. Oncogene,  2014, 33(36), 4451-4463.
[http://dx.doi.org/10.1038/onc.2013.411] [PMID:  24096485] 
[20] 
Miller, J.J.; Wen, P.Y. Emerging targeted therapies for glioma. Expert Opin. Emerg. Drugs,  2016, 21(4), 441-452.
[http://dx.doi.org/10.1080/14728214.2016.1257609] [PMID:  27809598] 
[21] 
Touat, M.; Idbaih, A.; Sanson, M.; Ligon, K.L. Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann. Oncol.,  2017, 28(7), 1457-1472.
[http://dx.doi.org/10.1093/annonc/mdx106] [PMID:  28863449] 
[22] 
Weller, M.; Butowski, N.; Tran, D.D.; Recht, L.D.; Lim, M.; Hirte, H.; Ashby, L.; Mechtler, L.; Goldlust, S.A.; Iwamoto, F.; Drappatz, J.; O’Rourke, D.M.; Wong, M.; Hamilton, M.G.; Finocchiaro, G.; Perry, J.; Wick, W.; Green, J.; He, Y.; Turner, C.D.; Yellin, M.J.; Keler, T.; Davis, T.A.; Stupp, R.; Sampson, J.H. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol.,  2017, 18(10), 1373-1385.
[http://dx.doi.org/10.1016/S1470-2045(17)30517-X] [PMID:  28844499] 
[23] 
Balaña, C.; Gil, M.J.; Perez, P.; Reynes, G.; Gallego, O.; Ribalta, T.; Capellades, J.; Gonzalez, S.; Verger, E. Sunitinib administered prior to radiotherapy in patients with non-resectable glioblastoma: results of a phase II study. Target. Oncol.,  2014, 9(4), 321-329.
[http://dx.doi.org/10.1007/s11523-014-0305-1] [PMID:  24424564] 
[24] 
Scott, B.J.; Quant, E.C.; McNamara, M.B.; Ryg, P.A.; Batchelor, T.T.; Wen, P.Y. Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors. Neuro-oncol.,  2010, 12(6), 603-607.
[http://dx.doi.org/10.1093/neuonc/nop073] [PMID:  20156808] 
[25] 
Huang, T.T.; Sarkaria, S.M.; Cloughesy, T.F.; Mischel, P.S. Targeted therapy for malignant glioma patients: lessons learned and the road ahead. Neurotherapeutics,  2009, 6(3), 500-512.
[http://dx.doi.org/10.1016/j.nurt.2009.04.008] [PMID:  19560740] 
[26] 
Siegelin, M.D.; Habel, A.; Gaiser, T. Epigalocatechin-3-gallate (EGCG) downregulates PEA15 and thereby augments TRAIL-mediated apoptosis in malignant glioma. Neurosci. Lett.,  2008, 448(1), 161-165.
[http://dx.doi.org/10.1016/j.neulet.2008.10.036] [PMID:  18948169] 
[27] 
Zhang, Y.; Wang, S.X.; Ma, J.W.; Li, H.Y.; Ye, J.C.; Xie, S.M.; Du, B.; Zhong, X.Y. EGCG inhibits properties of glioma stem-like cells and synergizes with temozolomide through downregulation of P-glycoprotein inhibition. J. Neurooncol.,  2015, 121(1), 41-52.
[http://dx.doi.org/10.1007/s11060-014-1604-1] [PMID:  25173233] 
[28] 
Shi, L.; Wang, Z.; Sun, G. Curcumin induces glioma stem-like cell formation. Neuroreport,  2015, 26(3), 167-172.
[http://dx.doi.org/10.1097/WNR.0000000000000320] [PMID:  25602852] 
[29] 
Wang, X.; Deng, J.; Yuan, J.; Tang, X.; Wang, Y.; Chen, H.; Liu, Y.; Zhou, L. Curcumin exerts its tumor suppressive function via inhibition of NEDD4 oncoprotein in glioma cancer cells. Int. J. Oncol.,  2017, 51(2), 467-477.
[http://dx.doi.org/10.3892/ijo.2017.4037] [PMID:  28627598] 
[30] 
Zhang, Z.; Li, C.; Tan, Q.; Xie, C.; Yang, Y.; Zhan, W.; Han, F.; Shanker Sharma, H.; Sharma, A. Curcumin suppresses tumor growth and angiogenesis in human glioma cells through modulation of vascular endothelial growth factor/angiopoietin-2/thrombospondin-1 signaling. CNS Neurol. Disord. Drug Targets,  2017, 16(3), 346-350.
[http://dx.doi.org/10.2174/1871527315666160902144513] [PMID:  27592626] 
[31] 
Zhuang, W.; Long, L.; Zheng, B.; Ji, W.; Yang, N.; Zhang, Q.; Liang, Z. Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Sci.,  2012, 103(4), 684-690.
[http://dx.doi.org/10.1111/j.1349-7006.2011.02198.x] [PMID:  22192169] 
[32] 
Ahmad, Z.; Hassan, S.S.; Azim, S. A therapeutic connection between dietary phytochemicals and ATP synthase. Curr. Med. Chem.,  2017, 24(35), 3894-3906.
[http://dx.doi.org/10.2174/0929867324666170823125330] [PMID:  28831918] 
[33] 
Ahmad, Z.; Okafor, F.; Azim, S.; Laughlin, T.F. ATP synthase: a molecular therapeutic drug target for antimicrobial and antitumor peptides. Curr. Med. Chem.,  2013, 20(15), 1956-1973.
[http://dx.doi.org/10.2174/0929867311320150003] [PMID:  23432591] 
[34] 
Amini, A.; Liu, M.; Ahmad, Z. Understanding the link between antimicrobial properties of dietary olive phenolics and bacterial ATP synthase. Int. J. Biol. Macromol.,  2017, 101, 153-164.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.03.087] [PMID:  28322962] 
[35] 
Chinnam, N.; Dadi, P.K.; Sabri, S.A.; Ahmad, M.; Kabir, M.A.; Ahmad, Z. Dietary bioflavonoids inhibit Escherichia coli ATP synthase in a differential manner. Int. J. Biol. Macromol.,  2010, 46(5), 478-486.
[http://dx.doi.org/10.1016/j.ijbiomac.2010.03.009] [PMID:  20346967] 
[36] 
Liu, M.; Amini, A.; Ahmad, Z. Safranal and its analogs inhibit Escherichia coli ATP synthase and cell growth. Int. J. Biol. Macromol.,  2017, 95, 145-152.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.11.038] [PMID:  27865956] 
[37] 
Ahmad, Z.; Laughlin, T.F.; Kady, I.O. Thymoquinone inhibits Escherichia coli ATP synthase and cell growth. PLoS One,  2015, 10(5), e0127802
[http://dx.doi.org/10.1371/journal.pone.0127802] [PMID:  25996607] 
[38] 
Matés, J.M.; Segura, J.A.; Alonso, F.J.; Márquez, J. Anticancer antioxidant regulatory functions of phytochemicals. Curr. Med. Chem.,  2011, 18(15), 2315-2338.
[http://dx.doi.org/10.2174/092986711795656036] [PMID:  21517750] 
[39] 
Erices, J.I.; Torres, Á.; Niechi, I.; Bernales, I.; Quezada, C. Current natural therapies in the treatment against glioblastoma. Phytother. Res.,  2018, 32(11), 2191-2201.
[http://dx.doi.org/10.1002/ptr.6170] [PMID:  30109743] 
[40] 
Epriliati, I. Phytochemicals-A Global Perspective of Their Role in Nutrition and Health; IntechOpen, 2012. 
[http://dx.doi.org/10.5772/1387] 
[41] 
Gupta, S.C.; Patchva, S.; Aggarwal, B.B. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J.,  2013, 15(1), 195-218.
[http://dx.doi.org/10.1208/s12248-012-9432-8] [PMID:  23143785] 
[42] 
Harrison, T.S.; Lyseng-Williamson, K.A. Vincristine sulfate liposome injection: a guide to its use in refractory or relapsed acute lymphoblastic leukemia. BioDrugs,  2013, 27(1), 69-74.
[http://dx.doi.org/10.1007/s40259-012-0002-5] [PMID:  23329395] 
[43] 
Akram, M.; Shahab-Uddin, A.A.; Usmanghani, K.; Hannan, A.; Mohiuddin, E.; Asif, M. Curcuma longa and curcumin: a review article. Rom. J. Biol. Plant Biol.,  2010, 55(2), 65-70.
[44] 
Cabrera, C.; Artacho, R.; Giménez, R. Beneficial effects of green tea - a review. J. Am. Coll. Nutr.,  2006, 25(2), 79-99.
[http://dx.doi.org/10.1080/07315724.2006.10719518] [PMID:  16582024] 
[45] 
Venditto, V.J.; Simanek, E.E. Cancer therapies utilizing the camptothecins: a review of the in vivo literature. Mol. Pharm.,  2010, 7(2), 307-349.
[http://dx.doi.org/10.1021/mp900243b] [PMID:  20108971] 
[46] 
Hosseini, A.; Ghorbani, A. Cancer therapy with phytochemicals: evidence from clinical studies. Avicenna J. Phytomed.,  2015, 5(2), 84-97.
[http://dx.doi.org/10.22038/ajp.2015.3872] [PMID:  25949949] 
[47] 
Shahani, K.; Swaminathan, S.K.; Freeman, D.; Blum, A.; Ma, L.; Panyam, J. Injectable sustained release microparticles of curcumin: a new concept for cancer chemoprevention. Cancer Res.,  2010, 70(11), 4443-4452.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-4362] [PMID:  20460537] 
[48] 
Chowdhury, R.; Nimmanapalli, R.; Graham, T.; Reddy, G. Curcumin attenuation of lipopolysaccharide induced cardiac hypertrophy in rodents. ISRN Inflamm.,  2013, 2013(31), 539305
[http://dx.doi.org/10.1155/2013/539305] [PMID:  24236240] 
[49] 
Anand, P.; Kunnumakkara, A.B.; Newman, R.A.; Aggarwal, B.B. Bioavailability of curcumin: problems and promises. Mol. Pharm.,  2007, 4(6), 807-818.
[http://dx.doi.org/10.1021/mp700113r] [PMID:  17999464] 
[50] 
Meskin, M.S.; Randolph, R.K.; Davies, A.J.; Lewis, D.S.; Bidlack, W.R. Phytochemicals: Mechanisms of action; CRC Press, 2003. 
[http://dx.doi.org/10.1201/9780203506332] 
[51] 
Wahlström, B.; Blennow, G. A study on the fate of curcumin in the rat. Acta Pharmacol. Toxicol. (Copenh.),  1978, 43(2), 86-92.
[http://dx.doi.org/10.1111/j.1600-0773.1978.tb02240.x] [PMID:  696348] 
[52] 
Lampe, J.W.; Chang, J.L. Interindividual differences in phytochemical metabolism and deposition. Semin. Cancer Biol.,  2007, 17(5), 347-353.
[http://dx.doi.org/10.1016/j.semcancer.2007.05.003] [PMID:  17588771] 
[53] 
Farooqui, T.; Farooqui, A.A. Neuroprotective effects of phytochemicals in neurological disorders; John Wiley & Sons, 2017. 
[http://dx.doi.org/10.1002/9781119155195] 
[54] 
Upadhyay, S.; Dixit, M. Role of polyphenols and other phytochemicals on molecular signaling. Oxid. Med. Cell. Longev.,  2015, 2015(Suppl. 3), 504253
[http://dx.doi.org/10.1155/2015/504253] [PMID:  26180591] 
[55] 
Walle, T.; Hsieh, F.; DeLegge, M.H.; Oatis, J.E., Jr; Walle, U.K. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos.,  2004, 32(12), 1377-1382.
[http://dx.doi.org/10.1124/dmd.104.000885] [PMID:  15333514] 
[56] 
Goldin, B.R. In situ bacterial metabolism and colon mutagens. Annu. Rev. Microbiol.,  1986, 40(1), 367-393.
[http://dx.doi.org/10.1146/annurev.mi.40.100186.002055] [PMID:  3535648] 
[57] 
Keppler, K.; Humpf, H-U. Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorg. Med. Chem.,  2005, 13(17), 5195-5205.
[http://dx.doi.org/10.1016/j.bmc.2005.05.003] [PMID:  15963727] 
[58] 
Rechner, A.R.; Smith, M.A.; Kuhnle, G.; Gibson, G.R.; Debnam, E.S.; Srai, S.K.S.; Moore, K.P.; Rice-Evans, C.A. Colonic metabolism of dietary polyphenols: influence of structure on microbial fermentation products. Free Radic. Biol. Med.,  2004, 36(2), 212-225.
[http://dx.doi.org/10.1016/j.freeradbiomed.2003.09.022] [PMID:  14744633] 
[59] 
Ronis, M.J.; Little, J.M.; Barone, G.W.; Chen, G.; Radominska-Pandya, A.; Badger, T.M. Sulfation of the isoflavones genistein and daidzein in human and rat liver and gastrointestinal tract. J. Med. Food,  2006, 9(3), 348-355.
[http://dx.doi.org/10.1089/jmf.2006.9.348] [PMID:  17004897] 
[60] 
Marín, L.; Miguélez, E.M.; Villar, C.J.; Lombó, F. Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. BioMed Res. Int.,  2015, 2015, 905215
[http://dx.doi.org/10.1155/2015/905215] [PMID:  25802870] 
[61] 
de Santi, C.; Pietrabissa, A.; Mosca, F.; Pacifici, G.M. Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver. Xenobiotica,  2000, 30(11), 1047-1054.
[http://dx.doi.org/10.1080/00498250010002487] [PMID: 11197066] 
[62] 
Donovan, J.L.; Crespy, V.; Manach, C.; Morand, C.; Besson, C.; Scalbert, A.; Rémésy, C. Catechin is metabolized by both the small intestine and liver of rats. J. Nutr.,  2001, 131(6), 1753-1757.
[http://dx.doi.org/10.1093/jn/131.6.1753] [PMID:  11385063] 
[63] 
Gang, D.R. Phytochemicals, Plant Growth, and the Environment; Springer Science & Business Media, 2012. 
[64] 
Medina-Remón, A.; Tresserra-Rimbau, A.; Arranz, S.; Estruch, R.; Lamuela-Raventos, R.M. Polyphenols excreted in urine as biomarkers of total polyphenol intake. Bioanalysis,  2012, 4(22), 2705-2713.
[http://dx.doi.org/10.4155/bio.12.249] [PMID:  23210653] 
[65] 
Conaway, C.C.; Jiao, D.; Kohri, T.; Liebes, L.; Chung, F.L. Disposition and pharmacokinetics of phenethyl isothiocyanate and 6-phenylhexyl isothiocyanate in F344 rats. Drug Metab. Dispos.,  1999, 27(1), 13-20.
[PMID:  9884304] 
[66] 
Kumar, G.P.; Khanum, F. Neuroprotective potential of phytochemicals. Pharmacogn. Rev.,  2012, 6(12), 81-90.
[http://dx.doi.org/10.4103/0973-7847.99898] [PMID:  23055633] 
[67] 
Abbott, N.J.; Patabendige, A.A.K.; Dolman, D.E.M.; Yusof, S.R.; Begley, D.J. Structure and function of the blood-brain barrier. Neurobiol. Dis.,  2010, 37(1), 13-25.
[http://dx.doi.org/10.1016/j.nbd.2009.07.030] [PMID:  19664713] 
[68] 
Pardridge, W.M. Blood-brain barrier delivery. Drug Discov. Today,  2007, 12(1-2), 54-61.
[http://dx.doi.org/10.1016/j.drudis.2006.10.013] [PMID:  17198973] 
[69] 
Pardridge, W.M. Drug transport across the blood-brain barrier. J. Cereb. Blood Flow Metab.,  2012, 32(11), 1959-1972.
[http://dx.doi.org/10.1038/jcbfm.2012.126] [PMID:  22929442] 
[70] 
Wolburg, H.; Lippoldt, A. Tight junctions of the blood-brain barrier: development, composition and regulation. Vascul. Pharmacol.,  2002, 38(6), 323-337.
[http://dx.doi.org/10.1016/S1537-1891(02)00200-8] [PMID:  12529927] 
[71] 
Oldendorf, W.H. Lipid solubility and drug penetration of the blood brain barrier. Proc. Soc. Exp. Biol. Med.,  1974, 147(3), 813-815.
[http://dx.doi.org/10.3181/00379727-147-38444] [PMID:  4445171] 
[72] 
Mishra, S.; Palanivelu, K. The effect of curcumin (turmeric) on Alzheimer’s disease: an overview. Ann. Indian Acad. Neurol.,  2008, 11(1), 13-19.
[http://dx.doi.org/10.4103/0972-2327.40220] [PMID:  19966973] 
[73] 
Ireson, C.R.; Jones, D.J.L.; Orr, S.; Coughtrie, M.W.H.; Boocock, D.J.; Williams, M.L.; Farmer, P.B.; Steward, W.P.; Gescher, A.J. Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol. Biomarkers Prev.,  2002, 11(1), 105-111.
[PMID:  11815407] 
[74] 
Rankovic, Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J. Med. Chem.,  2015, 58(6), 2584-2608.
[http://dx.doi.org/10.1021/jm501535r] [PMID:  25494650] 
[75] 
Pajouhesh, H.; Lenz, G.R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx,  2005, 2(4), 541-553.
[http://dx.doi.org/10.1602/neurorx.2.4.541] [PMID:  16489364] 
[76] 
Gupta, S.P. QSAR studies on drugs acting at the central nervous system. Chem. Rev.,  1989, 89(8), 1765-1800.
[http://dx.doi.org/10.1021/cr00098a007] 
[77] 
Goodwin, J.T.; Conradi, R.A.; Ho, N.F.H.; Burton, P.S. Physicochemical determinants of passive membrane permeability: role of solute hydrogen-bonding potential and volume. J. Med. Chem.,  2001, 44(22), 3721-3729.
[http://dx.doi.org/10.1021/jm010253i] [PMID:  11606137] 
[78] 
Fischer, H.; Gottschlich, R.; Seelig, A. Blood-brain barrier permeation: molecular parameters governing passive diffusion. J. Membr. Biol.,  1998, 165(3), 201-211.
[http://dx.doi.org/10.1007/s002329900434] [PMID:  9767674] 
[79] 
Hansch, C.; Leo, A. Substituent constants for correlation analysis in chemistry and biology; Wiley, 1979. 
[80] 
Atkinson, F.; Cole, S.; Green, C.; Van de Waterbeemd, H. Lipophilicity and other parameters affecting brain penetration. Curr. Med. Chem. Cent. Nerv. Syst. Agents,  2002, 2(3), 229-240.
[http://dx.doi.org/10.2174/1568015023358058] 
[81] 
Leeson, P.D.; Davis, A.M. Time-related differences in the physical property profiles of oral drugs. J. Med. Chem.,  2004, 47(25), 6338-6348.
[http://dx.doi.org/10.1021/jm049717d] [PMID:  15566303] 
[82] 
Österberg, T.; Norinder, U. Prediction of polar surface area and drug transport processes using simple parameters and PLS statistics. J. Chem. Inf. Comput. Sci.,  2000, 40(6), 1408-1411.
[http://dx.doi.org/10.1021/ci000065l] [PMID:  11128099] 
[83] 
Russo, S.; De Azevedo, W.F. Advances in the understanding of the cannabinoid receptor 1-focusing on the inverse agonists interactions. Curr. Med. Chem.,  2019, 26(10), 1908-1919.
[http://dx.doi.org/10.2174/0929867325666180417165247] [PMID:  29667549] 
[84] 
Kelder, J.; Grootenhuis, P.D.J.; Bayada, D.M.; Delbressine, L.P.C.; Ploemen, J.P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm. Res.,  1999, 16(10), 1514-1519.
[http://dx.doi.org/10.1023/A:1015040217741] [PMID:  10554091] 
[85] 
van de Waterbeemd, H.; Camenisch, G.; Folkers, G.; Chretien, J.R.; Raevsky, O.A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target.,  1998, 6(2), 151-165.
[http://dx.doi.org/10.3109/10611869808997889] [PMID:  9886238] 
[86] 
Clark, D.E. In silico prediction of blood-brain barrier permeation. Drug Discov. Today,  2003, 8(20), 927-933.
[http://dx.doi.org/10.1016/S1359-6446(03)02827-7] [PMID:  14554156] 
[87] 
Mobley, D.L.; Bannan, C.C.; Rizzi, A.; Bayly, C.I.; Chodera, J.D.; Lim, V.T.; Lim, N.M.; Beauchamp, K.A.; Slochower, D.R.; Shirts, M.R.; Gilson, M.K.; Eastman, P.K. Escaping Atom Types in Force Fields Using Direct Chemical Perception. J. Chem. Theory Comput.,  2018, 14(11), 6076-6092.
[http://dx.doi.org/10.1021/acs.jctc.8b00640] [PMID:  30351006] 
[88] 
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res.,  2019, 47(D1), D1102-D1109.
[http://dx.doi.org/10.1093/nar/gky1033] [PMID:  30371825] 
[89] 
Amaral, M.E.A.; Nery, L.R.; Leite, C.E.; de Azevedo Junior, W.F.; Campos, M.M. Pre-clinical effects of metformin and aspirin on the cell lines of different breast cancer subtypes. Invest. New Drugs,  2018, 36(5), 782-796.
[http://dx.doi.org/10.1007/s10637-018-0568-y] [PMID:  29392539] 
[90] 
Levin, N.M.B.; Pintro, V.O.; Bitencourt-Ferreira, G.; de Mattos, B.B.; de Castro Silvério, A.; de Azevedo, W.F., Jr Development of CDK-targeted scoring functions for prediction of binding affinity. Biophys. Chem.,  2018, 235, 1-8.
[http://dx.doi.org/10.1016/j.bpc.2018.01.004] [PMID:  29407904] 
[91] 
de Ávila, M.B.; Xavier, M.M.; Pintro, V.O.; de Azevedo, W.F., Jr Supervised machine learning techniques to predict binding affinity. A study for cyclin-dependent kinase 2. Biochem. Biophys. Res. Commun.,  2017, 494(1-2), 305-310.
[http://dx.doi.org/10.1016/j.bbrc.2017.10.035] [PMID:  29017921] 
[92] 
Levin, N.M.B.; Pintro, V.O.; de Avila, M.B.; de Mattos, B.B.; De Azevedo, W.F., Jr Understanding the structural basis for inhibition of cyclindependent kinases. New pieces in the molecular puzzle. Curr. Drug Targets,  2017, 18(9), 1104-1111.
[http://dx.doi.org/10.2174/1389450118666161116130155] [PMID:  27848884] 
[93] 
de Azevedo, W.F. Opinion paper: targeting multiple cyclin-dependent kinases (CDKs): a new strategy for molecular docking studies. Curr. Drug Targets,  2016, 17(1), 2-2.
[http://dx.doi.org/10.2174/138945011701151217100907] [PMID:  26687602] 
[94] 
Borowska, S.; Brzoska, M.M.; Tomczyk, M. Complexation of bioelements and toxic metals by polyphenolic compounds - implications for health. Curr. Drug Targets,  2018, 19(14), 1612-1638.
[http://dx.doi.org/10.2174/1389450119666180403101555] [PMID:  29611487] 
[95] 
Noda, Y.; Kaneyuki, T.; Mori, A.; Packer, L. Antioxidant activities of pomegranate fruit extract and its anthocyanidins: delphinidin, cyanidin, and pelargonidin. J. Agric. Food Chem.,  2002, 50(1), 166-171.
[http://dx.doi.org/10.1021/jf0108765] [PMID:  11754562] 
[96] 
Hou, D-X.; Fujii, M.; Terahara, N.; Yoshimoto, M. Molecular mechanisms behind the chemopreventive effects of anthocyanidins. J. Biomed. Biotechnol.,  2004, 2004(5), 321-325.
[http://dx.doi.org/10.1155/S1110724304403040] [PMID:  15577196] 
[97] 
Hou, D-X.; Yanagita, T.; Uto, T.; Masuzaki, S.; Fujii, M. Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: structure-activity relationship and molecular mechanisms involved. Biochem. Pharmacol.,  2005, 70(3), 417-425.
[http://dx.doi.org/10.1016/j.bcp.2005.05.003] [PMID:  15963474] 
[98] 
Miguel, M.G. Anthocyanins: Antioxidant and/or antiinflammatory activities. J. Appl. Pharm. Sci.,  2011, 1(6), 715.
[99] 
Nabavi, S.F.; Habtemariam, S.; Daglia, M.; Shafighi, N.; Barber, A.J.; Nabavi, S.M. Anthocyanins as a potential therapy for diabetic retinopathy. Curr. Med. Chem.,  2015, 22(1), 51-58.
[http://dx.doi.org/10.2174/0929867321666140815123852] [PMID:  25139396] 
[100] 
Putta, S.; Yarla, N.S.; Kumar, K. E.; Lakkappa, D.B.; Kamal, M.A.; Scotti, L.; Scotti, M.T.; Ashraf, G.M.; Rao, B.S.B.; D, S.K.; Reddy, G.V.; Tarasov, V.V.; Imandi, S.B.; Aliev, G. Preventive and therapeutic potentials of anthocyanins in diabetes and associated complications. Curr. Med. Chem.,  2018, 25(39), 5347-5371.
[http://dx.doi.org/10.2174/0929867325666171206101945] [PMID:  29210634] 
[101] 
Wang, L.S.; Stoner, G.D. Anthocyanins and their role in cancer prevention. Cancer Lett.,  2008, 269(2), 281-290.
[http://dx.doi.org/10.1016/j.canlet.2008.05.020] [PMID:  18571839] 
[102] 
Bulgakov, V.P.; Vereshchagina, Y.V.; Veremeichik, G.N. Anticancer polyphenols from cultured plant cells: production and new bioengineering strategies. Curr. Med. Chem.,  2018, 25(36), 4671-4692.
[http://dx.doi.org/10.2174/0929867324666170609080357] [PMID:  28595545] 
[103] 
Zhang, Y.; Vareed, S.K.; Nair, M.G. Human tumor cell growth inhibition by nontoxic anthocyanidins, the pigments in fruits and vegetables. Life Sci.,  2005, 76(13), 1465-1472.
[http://dx.doi.org/10.1016/j.lfs.2004.08.025] [PMID:  15680311] 
[104] 
Kaur, C.; Kapoor, H.C. Anti-oxidant activity and total phenolic content of some Asian vegetables. Int. J. Food Sci. Technol.,  2002, 37(2), 153-161.
[http://dx.doi.org/10.1046/j.1365-2621.2002.00552.x] 
[105] 
Hou, D-X.; Tong, X.; Terahara, N.; Luo, D.; Fujii, M. Delphinidin 3-sambubioside, a Hibiscus anthocyanin, induces apoptosis in human leukemia cells through reactive oxygen species-mediated mitochondrial pathway. Arch. Biochem. Biophys.,  2005, 440(1), 101-109.
[http://dx.doi.org/10.1016/j.abb.2005.06.002] [PMID:  16018963] 
[106] 
Lamy, S.; Lafleur, R.; Bédard, V.; Moghrabi, A.; Barrette, S.; Gingras, D.; Béliveau, R. Anthocyanidins inhibit migration of glioblastoma cells: structure-activity relationship and involvement of the plasminolytic system. J. Cell. Biochem.,  2007, 100(1), 100-111.
[http://dx.doi.org/10.1002/jcb.21023] [PMID:  16823770] 
[107] 
Abdullah Thani, N.A.; Sallis, B.; Nuttall, R.; Schubert, F.R.; Ahsan, M.; Davies, D.; Purewal, S.; Cooper, A.; Rooprai, H.K.; Rooprai, H.K. Induction of apoptosis and reduction of MMP gene expression in the U373 cell line by polyphenolics in Aronia melanocarpa and by curcumin. Oncol. Rep.,  2012, 28(4), 1435-1442.
[http://dx.doi.org/10.3892/or.2012.1941] [PMID:  22842701] 
[108] 
Chakrabarti, M.; Ray, S.K. Direct transfection of miR-137 mimics is more effective than DNA demethylation of miR-137 promoter to augment anti-tumor mechanisms of delphinidin in human glioblastoma U87MG and LN18 cells. Gene,  2015, 573(1), 141-152.
[http://dx.doi.org/10.1016/j.gene.2015.07.034] [PMID:  26187071] 
[109] 
Ouanouki, A.; Lamy, S.; Annabi, B. Anthocyanidins inhibit epithelial-mesenchymal transition through a TGFβ/Smad2 signaling pathway in glioblastoma cells. Mol. Carcinog.,  2017, 56(3), 1088-1099.
[http://dx.doi.org/10.1002/mc.22575] [PMID:  27649384] 
[110] 
Kocaadam, B.; Şanlier, N. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit. Rev. Food Sci. Nutr.,  2017, 57(13), 2889-2895.
[http://dx.doi.org/10.1080/10408398.2015.1077195] [PMID:  26528921] 
[111] 
Uzzan, B.; Benamouzig, R. Is curcumin a chemopreventive agent for colorectal cancer? Curr. Colorectal Cancer Rep.,  2016, 12(1), 35-41.
[http://dx.doi.org/10.1007/s11888-016-0307-8] 
[112] 
Ghazimoradi, M.; Saberi-Karimian, M.; Mohammadi, F.; Sahebkar, A.; Tavallaie, S.; Safarian, H.; Ferns, G.A.; Ghayour-Mobarhan, M.; Moohebati, M.; Esmaeili, H.; Ahmadinejad, M. The effects of curcumin and curcumin-phospholipid complex on the serum pro-oxidant-antioxidant balance in subjects with metabolic syndrome. Phytother. Res.,  2017, 31(11), 1715-1721.
[http://dx.doi.org/10.1002/ptr.5899] [PMID:  28840615] 
[113] 
Putteeraj, M.; Lim, W.L.; Teoh, S.L.; Yahaya, M.F. Flavonoids and its neuroprotective effects on brain ischemia and neurodegenerative diseases. Curr. Drug Targets,  2018, 19(14), 1710-1720.
[http://dx.doi.org/10.2174/1389450119666180326125252] [PMID:  29577854] 
[114] 
Syarifah-Noratiqah, S.B.; Naina-Mohamed, I.; Zulfarina, M.S.; Qodriyah, H.M.S. Natural polyphenols in the treatment of alzheimer’s disease. Curr. Drug Targets,  2018, 19(8), 927-937.
[http://dx.doi.org/10.2174/1389450118666170328122527] [PMID:  28356027] 
[115] 
Boadas-Vaello, P.; Vela, J.M.; Verdu, E. New pharmacological approaches using polyphenols on the physiopathology of neuropathic pain. Curr. Drug Targets,  2017, 18(2), 160-173.
[http://dx.doi.org/10.2174/1389450117666160527142423] [PMID:  27231108] 
[116] 
Mandal, S. Curcumin, a promising anti-cancer therapeutic: its bioactivity and development of drug delivery vehicles. Int. J. Drug Res. Technol.,  2017, 6(2), 14.
[117] 
Ghosh, S.; Banerjee, S.; Sil, P.C. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: a recent update. Food Chem. Toxicol.,  2015, 83, 111-124.
[http://dx.doi.org/10.1016/j.fct.2015.05.022] [PMID:  26066364] 
[118] 
Chandran, B.; Goel, A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother. Res.,  2012, 26(11), 1719-1725.
[http://dx.doi.org/10.1002/ptr.4639] [PMID:  22407780] 
[119] 
Wang, Y.; Lu, Z.; Wu, H.; Lv, F. Study on the antibiotic activity of microcapsule curcumin against foodborne pathogens. Int. J. Food Microbiol.,  2009, 136(1), 71-74.
[http://dx.doi.org/10.1016/j.ijfoodmicro.2009.09.001] [PMID:  19775769] 
[120] 
Appendino, G.; Belcaro, G.; Cornelli, U.; Luzzi, R.; Togni, S.; Dugall, M.; Cesarone, M.R.; Feragalli, B.; Ippolito, E.; Errichi, B.M.; Pellegrini, L.; Ledda, A.; Ricci, A.; Bavera, P.; Hosoi, M.; Stuard, S.; Corsi, M.; Errichi, S.; Gizzi, G. Potential role of Curcumin phytosome (Meriva) in controlling the evolution of diabetic microangiopathy. A pilot study. Panminerva Med.,  2011, 53(3)(Suppl. 1), 43-49.
[PMID:  22108476] 
[121] 
Chen, L.X.; He, Y.J.; Zhao, S.Z.; Wu, J.G.; Wang, J.T.; Zhu, L.M.; Lin, T.T.; Sun, B.C.; Li, X.R. Inhibition of tumor growth and vasculogenic mimicry by curcumin through down-regulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model. Cancer Biol. Ther.,  2011, 11(2), 229-235.
[http://dx.doi.org/10.4161/cbt.11.2.13842] [PMID:  21084858] 
[122] 
Choi, B.H.; Kim, C.G.; Lim, Y.; Shin, S.Y.; Lee, Y.H. Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NF kappa B pathway. Cancer Lett.,  2008, 259(1), 111-118.
[http://dx.doi.org/10.1016/j.canlet.2007.10.003] [PMID:  18006147] 
[123] 
Han, S-S.; Chung, S-T.; Robertson, D.A.; Ranjan, D.; Bondada, S. Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. Clin. Immunol.,  1999, 93(2), 152-161.
[http://dx.doi.org/10.1006/clim.1999.4769] [PMID:  10527691] 
[124] 
Han, S.S.; Keum, Y.S.; Seo, H.J.; Surh, Y.J. Curcumin suppresses activation of NF-kappaB and AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells. J. Biochem. Mol. Biol.,  2002, 35(3), 337-342.
[http://dx.doi.org/10.5483/bmbrep.2002.35.3.337] [PMID:  12297018] 
[125] 
Li, M.; Zhang, Z.; Hill, D.L.; Wang, H.; Zhang, R. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res.,  2007, 67(5), 1988-1996.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3066] [PMID:  17332326] 
[126] 
Qiao, Q.; Jiang, Y.; Li, G. Inhibition of the PI3K/AKT-NF-κB pathway with curcumin enhanced radiation-induced apoptosis in human Burkitt’s lymphoma. J. Pharmacol. Sci.,  2013, 121(4), 247-256.
[http://dx.doi.org/10.1254/jphs.12149FP] [PMID:  23603894] 
[127] 
Yu, T.; Ji, J.; Guo, Y.L. MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells. Biochem. Biophys. Res. Commun.,  2013, 441(1), 53-58.
[http://dx.doi.org/10.1016/j.bbrc.2013.10.008] [PMID:  24134840] 
[128] 
Hatcher, H.; Planalp, R.; Cho, J.; Torti, F.M.; Torti, S.V. Curcumin: from ancient medicine to current clinical trials. Cell. Mol. Life Sci.,  2008, 65(11), 1631-1652.
[http://dx.doi.org/10.1007/s00018-008-7452-4] [PMID:  18324353] 
[129] 
Bisht, S.; Maitra, A. Systemic delivery of curcumin: 21st century solutions for an ancient conundrum. Curr. Drug Discov. Technol.,  2009, 6(3), 192-199.
[http://dx.doi.org/10.2174/157016309789054933] [PMID:  19496751] 
[130] 
Manzo, F.; Tambaro, F.P.; Mai, A.; Altucci, L. Histone acetyltransferase inhibitors and preclinical studies. Expert Opin. Ther. Pat.,  2009, 19(6), 761-774.
[http://dx.doi.org/10.1517/13543770902895727] [PMID:  19473103] 
[131] 
Lahiff, C.; Moss, A.C. Curcumin for clinical and endoscopic remission in ulcerative colitis. Inflamm. Bowel Dis.,  2011, 17(7), E66
[http://dx.doi.org/10.1002/ibd.21710] [PMID:  21484966] 
[132] 
S. Vadhan-Raj, D.M. Weber, M. Wang, S.A. Giralt, S.K.
Thomas, R. Alexanian, X. Zhou, P. Patel, C.E. Bueso-
Ramos, R.A. Newman, Curcumin downregulatesNF-kB and
related genes in patients with multiple myeloma: results of
aphase I/II study Am. Soc. Hematology, 2007.https://ashpublications.org/blood/article/110/11/1177/73784/Curcumin-Downregulates-NF-kB-and-Related-Genes-in
[133] 
Du, W.Z.; Feng, Y.; Wang, X.F.; Piao, X.Y.; Cui, Y.Q.; Chen, L.C.; Lei, X.H.; Sun, X.; Liu, X.; Wang, H.B.; Li, X.F.; Yang, D.B.; Sun, Y.; Zhao, Z.F.; Jiang, T.; Li, Y.L.; Jiang, C.L. Curcumin suppresses malignant glioma cells growth and induces apoptosis by inhibition of SHH/GLI1 signaling pathway in vitro and vivo. CNS Neurosci. Ther.,  2013, 19(12), 926-936.
[http://dx.doi.org/10.1111/cns.12163] [PMID:  24165291] 
[134] 
Cheng, C.; Jiao, J.T.; Qian, Y.; Guo, X.Y.; Huang, J.; Dai, M.C.; Zhang, L.; Ding, X.P.; Zong, D.; Shao, J.F. Curcumin induces G2/M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells. Mol. Med. Rep.,  2016, 13(5), 3763-3770.
[http://dx.doi.org/10.3892/mmr.2016.5037] [PMID:  27035875] 
[135] 
Ramalingam, P.; Ko, Y.T. Enhanced oral delivery of curcumin from N-trimethyl chitosan surface-modified solid lipid nanoparticles: pharmacokinetic and brain distribution evaluations. Pharm. Res.,  2015, 32(2), 389-402.
[http://dx.doi.org/10.1007/s11095-014-1469-1] [PMID:  25082210] 
[136] 
Valcic, S.; Muders, A.; Jacobsen, N.E.; Liebler, D.C.; Timmermann, B.N. Antioxidant chemistry of green tea catechins. Identification of products of the reaction of (-)-epigallocatechin gallate with peroxyl radicals. Chem. Res. Toxicol.,  1999, 12(4), 382-386.
[http://dx.doi.org/10.1021/tx990003t] [PMID:  10207128] 
[137] 
Nagle, D.G.; Ferreira, D.; Zhou, Y-D. Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives. Phytochemistry,  2006, 67(17), 1849-1855.
[http://dx.doi.org/10.1016/j.phytochem.2006.06.020] [PMID:  16876833] 
[138] 
Wolfe, K.; Wu, X.; Liu, R.H. Antioxidant activity of apple peels. J. Agric. Food Chem.,  2003, 51(3), 609-614.
[http://dx.doi.org/10.1021/jf020782a] [PMID:  12537430] 
[139] 
Mubarak, A.; Swinny, E.E.; Ching, S.Y.L.; Jacob, S.R.; Lacey, K.; Hodgson, J.M.; Croft, K.D.; Considine, M.J. Polyphenol composition of plum selections in relation to total antioxidant capacity. J. Agric. Food Chem.,  2012, 60(41), 10256-10262.
[http://dx.doi.org/10.1021/jf302903k] [PMID:  22971250] 
[140] 
Hudthagosol, C.; Haddad, E.H.; McCarthy, K.; Wang, P.; Oda, K.; Sabaté, J. Pecans acutely increase plasma postprandial antioxidant capacity and catechins and decrease LDL oxidation in humans. J. Nutr.,  2011, 141(1), 56-62.
[http://dx.doi.org/10.3945/jn.110.121269] [PMID:  21106921] 
[141] 
Jung, Y.D.; Ellis, L.M. Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea. Int. J. Exp. Pathol.,  2001, 82(6), 309-316.
[http://dx.doi.org/10.1046/j.1365-2613.2001.00205.x] [PMID:  11846837] 
[142] 
Liao, S.; Umekita, Y.; Guo, J.; Kokontis, J.M.; Hiipakka, R.A. Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Lett.,  1995, 96(2), 239-243.
[http://dx.doi.org/10.1016/0304-3835(95)03948-V] [PMID:  7585463] 
[143] 
Lu, Y.P.; Lou, Y.R.; Xie, J.G.; Peng, Q.Y.; Liao, J.; Yang, C.S.; Huang, M.T.; Conney, A.H. Topical applications of caffeine or (-)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice. Proc. Natl. Acad. Sci. USA,  2002, 99(19), 12455-12460.
[http://dx.doi.org/10.1073/pnas.182429899] [PMID:  12205293] 
[144] 
Thangapazham, R.L.; Singh, A.K.; Sharma, A.; Warren, J.; Gaddipati, J.P.; Maheshwari, R.K. Green tea polyphenols and its constituent epigallocatechin gallate inhibits proliferation of human breast cancer cells in vitro and in vivo. Cancer Lett.,  2007, 245(1-2), 232-241.
[http://dx.doi.org/10.1016/j.canlet.2006.01.027] [PMID:  16519995] 
[145] 
Peairs, A.; Dai, R.; Gan, L.; Shimp, S.; Rylander, M.N.; Li, L.; Reilly, C.M. Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells. Cell. Mol. Immunol.,  2010, 7(2), 123-132.
[http://dx.doi.org/10.1038/cmi.2010.1] [PMID:  20140007] 
[146] 
Riegsecker, S.; Wiczynski, D.; Kaplan, M.J.; Ahmed, S. Potential benefits of green tea polyphenol EGCG in the prevention and treatment of vascular inflammation in rheumatoid arthritis. Life Sci.,  2013, 93(8), 307-312.
[http://dx.doi.org/10.1016/j.lfs.2013.07.006] [PMID:  23871988] 
[147] 
Tipoe, G.L.; Leung, T.M.; Liong, E.C.; Lau, T.Y.H.; Fung, M.L.; Nanji, A.A. Epigallocatechin-3-gallate (EGCG) reduces liver inflammation, oxidative stress and fibrosis in carbon tetrachloride (CCl4)-induced liver injury in mice. Toxicology,  2010, 273(1-3), 45-52.
[http://dx.doi.org/10.1016/j.tox.2010.04.014] [PMID:  20438794] 
[148] 
Masaki, H. Role of antioxidants in the skin: anti-aging effects. J. Dermatol. Sci.,  2010, 58(2), 85-90.
[http://dx.doi.org/10.1016/j.jdermsci.2010.03.003] [PMID:  20399614] 
[149] 
Maurya, P.K.; Rizvi, S.I. Protective role of tea catechins on erythrocytes subjected to oxidative stress during human aging. Nat. Prod. Res.,  2009, 23(12), 1072-1079.
[http://dx.doi.org/10.1080/14786410802267643] [PMID:  18846469] 
[150] 
Niu, Y.; Na, L.; Feng, R.; Gong, L.; Zhao, Y.; Li, Q.; Li, Y.; Sun, C. The phytochemical, EGCG, extends lifespan by reducing liver and kidney function damage and improving age-associated inflammation and oxidative stress in healthy rats. Aging Cell,  2013, 12(6), 1041-1049.
[http://dx.doi.org/10.1111/acel.12133] [PMID:  23834676] 
[151] 
Eng, Q.Y.; Thanikachalam, P.V.; Ramamurthy, S. Molecular understanding of epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases. J. Ethnopharmacol.,  2018, 210, 296-310.
[http://dx.doi.org/10.1016/j.jep.2017.08.035] [PMID:  28864169] 
[152] 
Wolfram, S. Effects of green tea and EGCG on cardiovascular and metabolic health. J. Am. Coll. Nutr.,  2007, 26(4), 373S-388S.
[http://dx.doi.org/10.1080/07315724.2007.10719626] [PMID:  17906191] 
[153] 
Lee, J.H.; Moon, J.H.; Kim, S.W.; Jeong, J.K.; Nazim, U.M.D.; Lee, Y.J.; Seol, J.W.; Park, S.Y. EGCG-mediated autophagy flux has a neuroprotection effect via a class III histone deacetylase in primary neuron cells. Oncotarget,  2015, 6(12), 9701-9717.
[http://dx.doi.org/10.18632/oncotarget.3832] [PMID:  25991666] 
[154] 
Mandel, S.A.; Avramovich-Tirosh, Y.; Reznichenko, L.; Zheng, H.; Weinreb, O.; Amit, T.; Youdim, M.B.H. Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway. Neurosignals,  2005, 14(1-2), 46-60.
[http://dx.doi.org/10.1159/000085385] [PMID:  15956814] 
[155] 
Bae, J.H.; Mun, K.C.; Park, W.K.; Lee, S.R.; Suh, S.I.; Baek, W.K.; Yim, M.B.; Kwon, T.K.; Song, D.K. EGCG attenuates AMPA-induced intracellular calcium increase in hippocampal neurons. Biochem. Biophys. Res. Commun.,  2002, 290(5), 1506-1512.
[http://dx.doi.org/10.1006/bbrc.2002.6372] [PMID:  11820792] 
[156] 
Annabi, B.; Bouzeghrane, M.; Moumdjian, R.; Moghrabi, A.; Béliveau, R. Probing the infiltrating character of brain tumors: inhibition of RhoA/ROK-mediated CD44 cell surface shedding from glioma cells by the green tea catechin EGCg. J. Neurochem.,  2005, 94(4), 906-916.
[http://dx.doi.org/10.1111/j.1471-4159.2005.03256.x] [PMID:  15992376] 
[157] 
Zhang, W.; Jia, J. Green tea extract, epigallocatechin-3-gallate, inhibits the growth and invasive ability of human glioma cells. Mol. Med. Rep.,  2008, 1(5), 735-739.
[http://dx.doi.org/10.3892/mmr_00000021] [PMID:  21479478] 
[158] 
Li, H.; Li, Z.; Xu, Y.M.; Wu, Y.; Yu, K.K.; Zhang, C.; Ji, Y.H.; Ding, G.; Chen, F.X. Epigallocatechin-3-gallate induces apoptosis, inhibits proliferation and decreases invasion of glioma cell. Neurosci. Bull.,  2014, 30(1), 67-73.
[http://dx.doi.org/10.1007/s12264-013-1394-z] [PMID:  24338484] 
[159] 
van Baarlen, P. Legendre, L.; van Kan, J.A.L. Botrytis: Biology, pathology and control; Springer, 2007, pp. 143-161.
[http://dx.doi.org/10.1007/978-1-4020-2626-3_9] 
[160] 
Gehm, B.D.; McAndrews, J.M.; Chien, P-Y.; Jameson, J.L. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc. Natl. Acad. Sci. USA,  1997, 94(25), 14138-14143.
[http://dx.doi.org/10.1073/pnas.94.25.14138] [PMID:  9391166] 
[161] 
Roy, S.; Khanna, S.; Alessio, H.M.; Vider, J.; Bagchi, D.; Bagchi, M.; Sen, C.K. Anti-angiogenic property of edible berries. Free Radic. Res.,  2002, 36(9), 1023-1031.
[http://dx.doi.org/10.1080/1071576021000006662] [PMID:  12448828] 
[162] 
Klimova, B.; Novotny, M.; Kuca, K. Anti-aging drugs - prospect of longer life? Curr. Med. Chem.,  2018, 25(17), 1946-1953.
[http://dx.doi.org/10.2174/0929867325666171129215251] [PMID:  29189123] 
[163] 
Dadi, P.K.; Ahmad, M.; Ahmad, Z. Inhibition of ATPase activity of Escherichia coli ATP synthase by polyphenols. Int. J. Biol. Macromol.,  2009, 45(1), 72-79.
[http://dx.doi.org/10.1016/j.ijbiomac.2009.04.004] [PMID:  19375450] 
[164] 
Ahmad, Z.; Laughlin, T.F. Medicinal chemistry of ATP synthase: a potential drug target of dietary polyphenols and amphibian antimicrobial peptides. Curr. Med. Chem.,  2010, 17(25), 2822-2836.
[http://dx.doi.org/10.2174/092986710791859270] [PMID:  20586714] 
[165] 
Ahmad, Z.; Ahmad, M.; Okafor, F.; Jones, J.; Abunameh, A.; Cheniya, R.P.; Kady, I.O. Effect of structural modulation of polyphenolic compounds on the inhibition of Escherichia coli ATP synthase. Int. J. Biol. Macromol.,  2012, 50(3), 476-486.
[http://dx.doi.org/10.1016/j.ijbiomac.2012.01.019] [PMID:  22285988] 
[166] 
Yao, J.; Wang, J.Y.; Liu, L.; Li, Y.X.; Xun, A.Y.; Zeng, W.S.; Jia, C.H.; Wei, X.X.; Feng, J.L.; Zhao, L.; Wang, L.S. Anti-oxidant effects of resveratrol on mice with DSS-induced ulcerative colitis. Arch. Med. Res.,  2010, 41(4), 288-294.
[http://dx.doi.org/10.1016/j.arcmed.2010.05.002] [PMID:  20637373] 
[167] 
Lançon, A.; Frazzi, R.; Latruffe, N. Anti-oxidant, antiinflammatory and anti-angiogenic properties of resveratrol in ocular diseases. Molecules,  2016, 21(3), 304.
[http://dx.doi.org/10.3390/molecules21030304] [PMID:  26950104] 
[168] 
Marinova, E.M.; Yanishlieva, N.V.; Totseva, I.R. Anti-oxidant activity and mechanism of action of trans-resveratrol in different lipid systems. Int. J. Food Sci. Technol.,  2002, 37(2), 145-152.
[http://dx.doi.org/10.1046/j.1365-2621.2002.00551.x] 
[169] 
Bradamante, S.; Barenghi, L.; Villa, A. Cardiovascular protective effects of resveratrol. Cardiovasc. Drug Rev.,  2004, 22(3), 169-188.
[http://dx.doi.org/10.1111/j.1527-3466.2004.tb00139.x] [PMID:  15492766] 
[170] 
Das, M.; Das, D.K. Resveratrol and cardiovascular health. Mol. Aspects Med.,  2010, 31(6), 503-512.
[http://dx.doi.org/10.1016/j.mam.2010.09.001] [PMID:  20837050] 
[171] 
Petrovski, G.; Gurusamy, N.; Das, D.K. Resveratrol in cardiovascular health and disease. Ann. N. Y. Acad. Sci.,  2011, 1215(1), 22-33.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05843.x] [PMID:  21261638] 
[172] 
Zordoky, B.N.M.; Robertson, I.M.; Dyck, J.R.B. Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim. Biophys. Acta,  2015, 1852(6), 1155-1177.
[http://dx.doi.org/10.1016/j.bbadis.2014.10.016] [PMID:  25451966] 
[173] 
Sanadgol, N.; Zahedani, S.S.; Sharifzadeh, M.; Khalseh, R.; Barbari, G.R.; Abdollahi, M. Recent updates in imperative natural compounds for healthy brain and nerve function: a systematic review of implications for multiple sclerosis. Curr. Drug Targets,  2017, 18(13), 1499-1517.
[http://dx.doi.org/10.2174/1389450118666161108124414] [PMID:  27829351] 
[174] 
Gasparrini, M.; Giampieri, F.; Alvarez Suarez, J.M.; Mazzoni, L. Y Forbes Hernandez, T.; Quiles, J.L.; Bullon, P.; Battino, M. AMPK as a new attractive therapeutic target for disease prevention: the role of dietary compounds AMPK and disease prevention. Curr. Drug Targets,  2016, 17(8), 865-889.
[http://dx.doi.org/10.2174/1573399811666150615150235] [PMID:  26844571] 
[175] 
Strycharz, J.; Rygielska, Z.; Swiderska, E.; Drzewoski, J.; Szemraj, J.; Szmigiero, L.; Sliwinska, A. SIRT1 as a therapeutic target in diabetic complications. Curr. Med. Chem.,  2018, 25(9), 1002-1035.
[http://dx.doi.org/10.2174/0929867324666171107103114] [PMID:  29110598] 
[176] 
Navarro Brugal, G.; Martínez Pinilla, E.; Sánchez Melgar, A.; Ortiz, R.; Noé Mata, V.; Martín, M.; Franco Fernández, R. A genomics approach identifies selective effects of transresveratrol in cerebral cortex neuron and glia gene expression. PLoS One,  2017, 12(4), e0176067
[http://dx.doi.org/10.1371/journal.pone.0176067] 
[177] 
Ryu, J.; Yoon, N.A.; Seong, H.; Jeong, J.Y.; Kang, S.; Park, N.; Choi, J.; Lee, D.H.; Roh, G.S.; Kim, H.J.; Cho, G.J.; Choi, W.S.; Park, J.Y.; Park, J.W.; Kang, S.S. Resveratrol induces glioma cell apoptosis through activation of tristetraprolin. Mol. Cells,  2015, 38(11), 991-997.
[http://dx.doi.org/10.14348/molcells.2015.0197] [PMID:  26537190] 
[178] 
Wang, H.; Feng, H.; Zhang, Y. Resveratrol inhibits hypoxia-induced glioma cell migration and invasion by the p-STAT3/miR-34a axis. Neoplasma,  2016, 63(4), 532-539.
[http://dx.doi.org/10.4149/neo_2016_406] [PMID:  27268916] 
[179] 
Sato, A.; Okada, M.; Shibuya, K.; Watanabe, E.; Seino, S.; Suzuki, K.; Narita, Y.; Shibui, S.; Kayama, T.; Kitanaka, C. Resveratrol promotes proteasome-dependent degradation of Nanog via p53 activation and induces differentiation of glioma stem cells. Stem Cell Res. (Amst.),  2013, 11(1), 601-610.
[http://dx.doi.org/10.1016/j.scr.2013.04.004] [PMID:  23651583] 
[180] 
Ryu, J.; Ku, B.M.; Lee, Y.K.; Jeong, J.Y.; Kang, S.; Choi, J.; Yang, Y.; Lee, D.H.; Roh, G.S.; Kim, H.J.; Cho, G.J.; Choi, W.S.; Kim, N.; Kang, S.S. Resveratrol reduces TNF-α- induced U373MG human glioma cell invasion through regulating NF-κB activation and uPA/uPAR expression. Anticancer Res.,  2011, 31(12), 4223-4230.
[PMID:  22199285] 
[181] 
Wang, G.; Dai, F.; Yu, K.; Jia, Z.; Zhang, A.; Huang, Q.; Kang, C.; Jiang, H.; Pu, P. Resveratrol inhibits glioma cell growth via targeting oncogenic microRNAs and multiple signaling pathways. Int. J. Oncol.,  2015, 46(4), 1739-1747.
[http://dx.doi.org/10.3892/ijo.2015.2863] [PMID:  25646654] 
[182] 
Cilibrasi, C.; Riva, G.; Romano, G.; Cadamuro, M.; Bazzoni, R.; Butta, V.; Paoletta, L.; Dalprà, L.; Strazzabosco, M.; Lavitrano, M.; Giovannoni, R.; Bentivegna, A. Resveratrol impairs glioma stem cells proliferation and motility by modulating the wnt signaling pathway. PLoS One,  2017, 12(1), e0169854
[http://dx.doi.org/10.1371/journal.pone.0169854] [PMID:  28081224] 
[183] 
Fossen, T.; Pedersen, A.T.; Andersen, O.M. Flavonoids from red onion (Allium cepa). Phytochemistry,  1998, 47(2), 281-285.
[http://dx.doi.org/10.1016/S0031-9422(97)00423-8] 
[184] 
Bilyk, A.; Sapers, G.M. Distribution of quercetin and kaempferol in lettuce, kale, chive, garlic chive, leek, horseradish, red radish, and red cabbage tissues. J. Agric. Food Chem.,  1985, 33(2), 226-228.
[http://dx.doi.org/10.1021/jf00062a017] 
[185] 
Gupta, A.; Birhman, K.; Raheja, I.; Sharma, S.K.; Kar, H.K. Quercetin: a wonder bioflavonoid with therapeutic potential in disease management. Asian Pac. J. Trop. Dis.,  2016, 6(3), 248-252.
[http://dx.doi.org/10.1016/S2222-1808(15)61024-6] 
[186] 
Kang, Z.C.; Tsai, S-J.; Lee, H. Quercetin inhibits benzo[a]pyrene-induced DNA adducts in human Hep G2 cells by altering cytochrome P-450 1A1 gene expression. Nutr. Cancer,  1999, 35(2), 175-179.
[http://dx.doi.org/10.1207/S15327914NC352_12] [PMID:  10693172] 
[187] 
Bischoff, S.C. Quercetin: potentials in the prevention and therapy of disease. Curr. Opin. Clin. Nutr. Metab. Care,  2008, 11(6), 733-740.
[http://dx.doi.org/10.1097/MCO.0b013e32831394b8] [PMID:  18827577] 
[188] 
Jeong, J.H.; An, J.Y.; Kwon, Y.T.; Rhee, J.G.; Lee, Y.J. Effects of low dose quercetin: cancer cell-specific inhibition of cell cycle progression. J. Cell. Biochem.,  2009, 106(1), 73-82.
[http://dx.doi.org/10.1002/jcb.21977] [PMID:  19009557] 
[189] 
Kee, J.Y.; Han, Y.H.; Kim, D.S.; Mun, J.G.; Park, J.; Jeong, M.Y.; Um, J.Y.; Hong, S.H. Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis, and suppression of metastatic ability. Phytomedicine,  2016, 23(13), 1680-1690.
[http://dx.doi.org/10.1016/j.phymed.2016.09.011] [PMID:  27823633] 
[190] 
Xing, N.; Chen, Y.; Mitchell, S.H.; Young, C.Y.F. Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis,  2001, 22(3), 409-414.
[http://dx.doi.org/10.1093/carcin/22.3.409] [PMID:  11238180] 
[191] 
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] 
[192] 
Zielińska, M.; Gülden, M.; Seibert, H. Effects of quercetin and quercetin-3-O-glycosides on oxidative damage in rat C6 glioma cells. Environ. Toxicol. Pharmacol.,  2003, 13(1), 47-53.
[http://dx.doi.org/10.1016/S1382-6689(02)00129-1] [PMID:  21782648] 
[193] 
Zamin, L.L.; Filippi-Chiela, E.C.; Dillenburg-Pilla, P.; Horn, F.; Salbego, C.; Lenz, G. Resveratrol and quercetin cooperate to induce senescence-like growth arrest in C6 rat glioma cells. Cancer Sci.,  2009, 100(9), 1655-1662.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01215.x] [PMID:  19496785] 
[194] 
Siegelin, M.D.; Reuss, D.E.; Habel, A.; Rami, A.; von Deimling, A. Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells. Neuro-oncol.,  2009, 11(2), 122-131.
[http://dx.doi.org/10.1215/15228517-2008-085] [PMID:  18971417] 
[195] 
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] 
[196] 
Hu, J.; Wang, J.; Wang, G.; Yao, Z.; Dang, X. Pharmacokinetics and antitumor efficacy of DSPE-PEG2000 polymeric liposomes loaded with quercetin and temozolomide: Analysis of their effectiveness in enhancing the chemosensitization of drug-resistant glioma cells. Int. J. Mol. Med.,  2016, 37(3), 690-702.
[http://dx.doi.org/10.3892/ijmm.2016.2458] [PMID:  26782731] 
[197] 
Jones, T.; Blum, M.  Alkaloids: Chemical and biological
perspectives. Ed. SW Pelletier, Wiley (Interscience), New
York, 1983, 1, p53ff. The related google scholar page is:
                    https://scholar.google.com/scholar?hl=en&amp;as_sdt=0%2C7&amp;q=Alkaloids%3A+chemical+and+biological+perspectives%3B+%2C+1983&btnG=
[198] 
Robinson, T. Metabolism and function of alkaloids in plants. Science,  1974, 184(4135), 430-435.
[http://dx.doi.org/10.1126/science.184.4135.430] [PMID:  17736509] 
[199] 
Sugimoto, T.; Miyase, T.; Kuroyanagi, M.; Ueno, A. Limonoids and quinolone alkaloids from Evodia rutaecarpa Bentham. Chem. Pharm. Bull. (Tokyo),  1988, 36(11), 4453-4461.
[http://dx.doi.org/10.1248/cpb.36.4453] 
[200] 
Schiff, P.L. Opium and its alkaloids. Am. J. Pharm. Educ.,  2002, 66(2), 188-196.
[201] 
Kirby, G.W. Biosynthesis of the morphine alkaloids. Science,  1967, 155(3759), 170-173.
[http://dx.doi.org/10.1126/science.155.3759.170] [PMID:  5332945] 
[202] 
Svoboda, G.H.; Neuss, N.; Gorman, M. Alkaloids of Vinca rosea Linn. (Catharanthus roseus G. Don.). V. Preparation and characterization of alkaloids. J. Am. Pharm. Assoc.,  1959, 48(11), 659-666.
[http://dx.doi.org/10.1002/jps.3030481115] [PMID:  13854990] 
[203] 
Kufe, D.W.; Pollock, R.E.; Weichselbaum, R.R.; Bast,
R.C.J.; Gansler, T.S.; Holland, J.F.: Frei, El. Cancer Medicine; 6th ed. Hamilton, Canada, 2003. 
[204] 
Gigant, B.; Wang, C.; Ravelli, R.B.G.; Roussi, F.; Steinmetz, M.O.; Curmi, P.A.; Sobel, A.; Knossow, M. Structural basis for the regulation of tubulin by vinblastine. Nature,  2005, 435(7041), 519-522.
[http://dx.doi.org/10.1038/nature03566] [PMID:  15917812] 
[205] 
Martino, E.; Casamassima, G.; Castiglione, S.; Cellupica, E.; Pantalone, S.; Papagni, F.; Rui, M.; Siciliano, A.M.; Collina, S. Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering ahead. Bioorg. Med. Chem. Lett.,  2018, 28(17), 2816-2826.
[http://dx.doi.org/10.1016/j.bmcl.2018.06.044] [PMID:  30122223] 
[206] 
Bouffet, E.; Jakacki, R.; Goldman, S.; Hargrave, D.; Hawkins, C.; Shroff, M.; Hukin, J.; Bartels, U.; Foreman, N.; Kellie, S.; Hilden, J.; Etzl, M.; Wilson, B.; Stephens, D.; Tabori, U.; Baruchel, S. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J. Clin. Oncol.,  2012, 30(12), 1358-1363.
[http://dx.doi.org/10.1200/JCO.2011.34.5843] [PMID:  22393086] 
[207] 
Stagno, V.; Mallucci, C.; Avula, S.; Pizer, B. The use of neo adjuvant single-agent vinblastine for tumour shrinkage in a highly vascular paediatric low-grade glioma. Br. J. Neurosurg.,  2018, 1-3.
[http://dx.doi.org/10.1080/02688697.2018.1427212] [PMID:  29405073] 
[208] 
Kipper, F.C.; Silva, A.O.; Marc, A.L.; Confortin, G.; Junqueira, A.V.; Neto, E.P.; Lenz, G. Vinblastine and antihelmintic mebendazole potentiate temozolomide in resistant gliomas. Invest. New Drugs,  2018, 36(2), 323-331.
[http://dx.doi.org/10.1007/s10637-017-0503-7] [PMID:  28852916] 
[209] 
Wall, M.E.; Wani, M.C.; Cook, C.E.; Palmer, K.H.; McPhail, A.T.a.; Sim, G.A. Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata1, 2. J. Am. Chem. Soc.,  1966, 88(16), 3888-3890.
[http://dx.doi.org/10.1021/ja00968a057] 
[210] 
Han, J. Traditional Chinese medicine and the search for new antineoplastic drugs. J. Ethnopharmacol.,  1988, 24(1), 1-17.
[http://dx.doi.org/10.1016/0378-8741(88)90135-3] [PMID:  3059066] 
[211] 
ten Bokkel Huinink, W.; Gore, M.; Carmichael, J.; Gordon, A.; Malfetano, J.; Hudson, I.; Broom, C.; Scarabelli, C.; Davidson, N.; Spanczynski, M.; Bolis, G.; Malmström, H.; Coleman, R.; Fields, S.C.; Heron, J.F. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J. Clin. Oncol.,  1997, 15(6), 2183-2193.
[http://dx.doi.org/10.1200/JCO.1997.15.6.2183] [PMID:  9196130] 
[212] 
Creemers, G.J.; Bolis, G.; Gore, M.; Scarfone, G.; Lacave, A.J.; Guastalla, J.P.; Despax, R.; Favalli, G.; Kreinberg, R.; Van Belle, S.; Hudson, I.; Verweij, J.; Ten Bokkel Huinink, W.W. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J. Clin. Oncol.,  1996, 14(12), 3056-3061.
[http://dx.doi.org/10.1200/JCO.1996.14.12.3056] [PMID:  8955650] 
[213] 
Kurtz, J.E.; Hardy-Bessard, A.C.; Deslandres, M.; Lavau-Denes, S.; Largillier, R.; Roemer-Becuwe, C.; Weber, B.; Guillemet, C.; Paraiso, D.; Pujade-Lauraine, E. Cetuximab, topotecan and cisplatin for the treatment of advanced cervical cancer: a phase II GINECO trial. Gynecol. Oncol.,  2009, 113(1), 16-20.
[http://dx.doi.org/10.1016/j.ygyno.2008.12.040] [PMID:  19232434] 
[214] 
Bookman, M.A.; Blessing, J.A.; Hanjani, P.; Herzog, T.J.; Andersen, W.A. Topotecan in squamous cell carcinoma of the cervix: a Phase II study of the Gynecologic Oncology Group. Gynecol. Oncol.,  2000, 77(3), 446-449.
[http://dx.doi.org/10.1006/gyno.2000.5807] [PMID:  10831357] 
[215] 
von Pawel, J.; Schiller, J.H.; Shepherd, F.A.; Fields, S.Z.; Kleisbauer, J.P.; Chrysson, N.G.; Stewart, D.J.; Clark, P.I.; Palmer, M.C.; Depierre, A.; Carmichael, J.; Krebs, J.B.; Ross, G.; Lane, S.R.; Gralla, R. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J. Clin. Oncol.,  1999, 17(2), 658-667.
[http://dx.doi.org/10.1200/JCO.1999.17.2.658] [PMID:  10080612] 
[216] 
O’Brien, M.E.; Ciuleanu, T-E.; Tsekov, H.; Shparyk, Y.; Cuceviá, B.; Juhasz, G.; Thatcher, N.; Ross, G.A.; Dane, G.C.; Crofts, T. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J. Clin. Oncol.,  2006, 24(34), 5441-5447.
[http://dx.doi.org/10.1200/JCO.2006.06.5821] [PMID:  17135646] 
[217] 
Hsiang, Y.H.; Hertzberg, R.; Hecht, S.; Liu, L.F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem.,  1985, 260(27), 14873-14878.
[PMID: 2997227] 
[218] 
Hsiang, Y.H.; Lihou, M.G.; Liu, L.F. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res.,  1989, 49(18), 5077-5082.
[PMID: 2548710] 
[219] 
Matsumoto, Y.; Fujiwara, T.; Nagao, S. Determinants of drug response in camptothecin-11-resistant glioma cell lines. J. Neurooncol.,  1995, 23(1), 1-8.
[http://dx.doi.org/10.1007/BF01058453] [PMID:  7623066] 
[220] 
Weller, M.; Winter, S.; Schmidt, C.; Esser, P.; Fontana, A.; Dichgans, J.; Groscurth, P. Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin and beta-lapachone. Int. J. Cancer,  1997, 73(5), 707-714.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19971127)73:5<707:AID-IJC16>3.0.CO;2-2] [PMID:  9398050] 
[221] 
Raymond, E.; Campone, M.; Stupp, R.; Menten, J.; Chollet, P.; Lesimple, T.; Fety-Deporte, R.; Lacombe, D.; Paoletti, X.; Fumoleau, P. Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitro-camptothecin) administered orally 5 days a week in patients with glioblastoma multiforme. Eur. J. Cancer,  2002, 38(10), 1348-1350.
[http://dx.doi.org/10.1016/S0959-8049(02)00070-9] [PMID:  12091065] 
[222] 
Lee, J.H.; Lee, J.M.; Lim, K.H.; Kim, J.K.; Ahn, S.K.; Bang, Y.J.; Hong, C.I. Preclinical and phase I clinical studies with Ckd-602, a novel camptothecin derivative. Ann. N. Y. Acad. Sci.,  2000, 922(1), 324-325.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb07055.x] [PMID:  11193913] 
[223] 
Batchelor, T.T.; Gilbert, M.R.; Supko, J.G.; Carson, K.A.; Nabors, L.B.; Grossman, S.A.; Lesser, G.J.; Mikkelsen, T.; Phuphanich, S. Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11. Neuro-oncol.,  2004, 6(1), 21-27.
[http://dx.doi.org/10.1215/S1152851703000218] [PMID:  14769136] 
[224] 
Prados, M.D.; Lamborn, K.; Yung, W.K.A.; Jaeckle, K.; Robins, H.I.; Mehta, M.; Fine, H.A.; Wen, P.Y.; Cloughesy, T.; Chang, S.; Nicholas, M.K.; Schiff, D.; Greenberg, H.; Junck, L.; Fink, K.; Hess, K.; Kuhn, J. A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American brain tumor consortium study. Neuro-oncol.,  2006, 8(2), 189-193.
[http://dx.doi.org/10.1215/15228517-2005-010] [PMID:  16533878] 
[225] 
Mi, Z.; Burke, T.G. Differential interactions of camptothecin lactone and carboxylate forms with human blood components. Biochemistry,  1994, 33(34), 10325-10336.
[http://dx.doi.org/10.1021/bi00200a013] [PMID:  8068669] 
[226] 
Hsiang, Y.H.; Liu, L.F. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res.,  1988, 48(7), 1722-1726.
[PMID: 2832051] 
[227] 
Hayashi, K.; Schoonbeek, H.J.; De Waard, M.A. Bcmfs1, a novel major facilitator superfamily transporter from Botrytis cinerea, provides tolerance towards the natural toxic compounds camptothecin and cercosporin and towards fungicides. Appl. Environ. Microbiol.,  2002, 68(10), 4996-5004.
[http://dx.doi.org/10.1128/AEM.68.10.4996-5004.2002] [PMID:  12324349] 
[228] 
Chung, M.K.; Han, S.S.; Kim, J.C. Evaluation of the toxic potentials of a new camptothecin anticancer agent CKD-602 on fertility and early embryonic development in rats. Regul. Toxicol. Pharmacol.,  2006, 45(3), 273-281.
[http://dx.doi.org/10.1016/j.yrtph.2006.05.004] [PMID:  16814440] 
[229] 
Liao, H.F.; Lee, C-C.; Hsiao, P.C.; Chen, Y.F.; Tseng, C.H.; Tzeng, C.C.; Chen, Y.L.; Chen, J.C.; Chang, Y.S.; Chang, J.G. TCH1036, a indeno[1,2-c]quinoline derivative, potentially inhibited the growth of human brain malignant glioma (GBM) 8401 cells via suppression of the expression of Suv39h1 and PARP. Biomed. Pharmacother.,  2016, 82, 649-659.
[http://dx.doi.org/10.1016/j.biopha.2016.06.002] [PMID:  27470408] 
[230] 
Sampath, P.; Amundson, E.; Wall, M.E.; Tyler, B.M.; Wani, M.C.; Alderson, L.M.; Colvin, M.; Brem, H.; Weingart, J.D. Camptothecin analogs in malignant gliomas: comparative analysis and characterization. J. Neurosurg.,  2003, 98(3), 570-577.
[http://dx.doi.org/10.3171/jns.2003.98.3.0570] [PMID:  12650430] 
[231] 
Tabanor, K. Improving the Delivery of Camptothecin through the Blood-Brain Barrier via Modulation of Paracellular Pathway using E-Cadherin Peptide. Biocycle,  2014, 43.
[232] 
Breitmaier, E. Terpenes: flavors, fragrances, pharmaca, pheromones; John Wiley & Sons, 2006. 
[http://dx.doi.org/10.1002/9783527609949] 
[233] 
Goldstein, N. Getting to know the odor compounds. Biocycle,  2002, 43(7), 42-44.
[234] 
Singh, B.; Sharma, R.A. Plant terpenes: defense responses,
phylogenetic analysis, regulation and clinical applications Biotech,  2015, 5(2), 129-151.
[http://dx.doi.org/10.1007/s13205-014-0220-2] [PMID: 28324581] 
[235] 
Alghasham, A.A. Cucurbitacins - a promising target for cancer therapy. Int. J. Health Sci. (Qassim),  2013, 7(1), 77-89.
[http://dx.doi.org/10.12816/0006025] [PMID:  23559908] 
[236] 
Blaskovich, M.A.; Sun, J.; Cantor, A.; Turkson, J.; Jove, R.; Sebti, S.M. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res.,  2003, 63(6), 1270-1279.
[PMID: 12649187] 
[237] 
Chen, J.C.; Chiu, M.H.; Nie, R.L.; Cordell, G.A.; Qiu, S.X. Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat. Prod. Rep.,  2005, 22(3), 386-399.
[http://dx.doi.org/10.1039/b418841c] [PMID:  16010347] 
[238] 
Lee, D.H.; Iwanski, G.B.; Thoennissen, N.H. Cucurbitacin: ancient compound shedding new light on cancer treatment. ScientificWorldJournal,  2010, 10, 413-418.
[http://dx.doi.org/10.1100/tsw.2010.44] [PMID:  20209387] 
[239] 
Miro, M. Cucurbitacins and their pharmacological effects. Phytother. Res.,  1995, 9(3), 159-168.
[http://dx.doi.org/10.1002/ptr.2650090302] 
[240] 
Chambliss, O.L.; Jones, C.M. Cucurbitacins: specific insect attractants in Cucurbitaceae. Science,  1966, 153(3742), 1392-1393.
[http://dx.doi.org/10.1126/science.153.3742.1392] [PMID:  17814391] 
[241] 
Agrawal, A.A.; Janssen, A.; Bruin, J.; Posthumus, M.A.; Sabelis, M.W. An ecological cost of plant defence: attractiveness of bitter cucumber plants to natural enemies of herbivores. Ecol. Lett.,  2002, 5(3), 377-385.
[http://dx.doi.org/10.1046/j.1461-0248.2002.00325.x] 
[242] 
Belkin, M.; Fitzgerald, D.B. Tumor-damaging capacity of plant materials. I. Plants used as cathartics. J. Natl. Cancer Inst.,  1952, 13(1), 139-155.
[http://dx.doi.org/10.1093/jnci/13.1.139] [PMID:  14946504] 
[243] 
Recio, M.C.; Prieto, M.; Bonucelli, M.; Orsi, C.; Máñez, S.; Giner, R.M.; Cerdá-Nicolás, M.; Ríos, J-L. Anti-inflammatory activity of two cucurbitacins isolated from Cayaponia tayuya roots. Planta Med.,  2004, 70(5), 414-420.
[http://dx.doi.org/10.1055/s-2004-818968] [PMID:  15124085] 
[244] 
Escandell, J.M.; Recio, M.C.; Máñez, S.; Giner, R.M.; Cerdá-Nicolás, M.; Ríos, J.L. Cucurbitacin R reduces the inflammation and bone damage associated with adjuvant arthritis in lewis rats by suppression of tumor necrosis factor-alpha in T lymphocytes and macrophages. J. Pharmacol. Exp. Ther.,  2007, 320(2), 581-590.
[http://dx.doi.org/10.1124/jpet.106.107003] [PMID:  17065367] 
[245] 
Raman, A.; Lau, C. Anti-diabetic properties and phytochemistry of Momordica charantia L. (Cucurbitaceae). Phytomedicine,  1996, 2(4), 349-362.
[http://dx.doi.org/10.1016/S0944-7113(96)80080-8] [PMID:  23194773] 
[246] 
Su, Y.; Li, G.; Zhang, X.; Gu, J.; Zhang, C.; Tian, Z.; Zhang, J. JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment. Cancer Biol. Ther.,  2008, 7(8), 1243-1249.
[http://dx.doi.org/10.4161/cbt.7.8.6263] [PMID:  18487947] 
[247] 
Yuan, G.; Yan, S.F.; Xue, H.; Zhang, P.; Sun, J.T.; Li, G. Cucurbitacin I induces protective autophagy in glioblastoma in vitro and in vivo. J. Biol. Chem.,  2014, 289(15), 10607-10619.
[http://dx.doi.org/10.1074/jbc.M113.528760] [PMID:  24599950] 
[248] 
Hsu, Y.C.; Chen, M.J.; Huang, T.Y. Inducement of mitosis delay by cucurbitacin E, a novel tetracyclic triterpene from climbing stem of Cucumis melo L., through GADD45γ in human brain malignant glioma (GBM) 8401 cells. Cell Death Dis.,  2014, 5(2), e1087
[http://dx.doi.org/10.1038/cddis.2014.22] [PMID:  24577085] 
[249] 
Premkumar, D.R.; Jane, E.P.; Pollack, I.F. Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells. Cancer Biol. Ther.,  2015, 16(2), 233-243.
[http://dx.doi.org/10.4161/15384047.2014.987548] [PMID:  25482928] 
[250] 
Kelly, K.R.; Ecsedy, J.; Mahalingam, D.; Nawrocki, S.T.; Padmanabhan, S.; Giles, F.J.; Carew, J.S. Targeting aurora kinases in cancer treatment. Curr. Drug Targets,  2011, 12(14), 2067-2078.
[http://dx.doi.org/10.2174/138945011798829410] [PMID:  21777198] 
[251] 
Panicker, R.C.; Coyne, A.G.; Srinivasan, R. Allosteric targeting of aurora A kinase using small molecules: a step forward towards next generation medicines?, 2017.
[252] 
Canduri, F.; Perez, P.C.; Caceres, R.A.; de Azevedo, W.F., Jr Protein kinases as targets for antiparasitic chemotherapy drugs. Curr. Drug Targets,  2007, 8(3), 389-398.
[http://dx.doi.org/10.2174/138945007780058979] [PMID:  17348832] 
[253] 
Garuti, L.; Roberti, M.; Bottegoni, G.; Ferraro, M. Diaryl urea: a privileged structure in anticancer agents. Curr. Med. Chem.,  2016, 23(15), 1528-1548.
[http://dx.doi.org/10.2174/0929867323666160411142532] [PMID:  27063259] 
[254] 
Touihri-Barakati, I.; Kallech-Ziri, O.; Ayadi, W.; Kovacic, H.; Hanchi, B.; Hosni, K.; Luis, J. Cucurbitacin B purified from Ecballium elaterium (L.) A. Rich from Tunisia inhibits α5β1 integrin-mediated adhesion, migration, proliferation of human glioblastoma cell line and angiogenesis. Eur. J. Pharmacol.,  2017, 797, 153-161.
[http://dx.doi.org/10.1016/j.ejphar.2017.01.006] [PMID:  28108377] 
[255] 
Attele, A.S.; Wu, J.A.; Yuan, C.S. Ginseng pharmacology: multiple constituents and multiple actions. Biochem. Pharmacol.,  1999, 58(11), 1685-1693.
[http://dx.doi.org/10.1016/S0006-2952(99)00212-9] [PMID:  10571242] 
[256] 
Shi, W.; Wang, Y.; Li, J.; Zhang, H.; Ding, L. Investigation of ginsenosides in different parts and ages of Panax ginseng. Food Chem.,  2007, 102(3), 664-668.
[http://dx.doi.org/10.1016/j.foodchem.2006.05.053] 
[257] 
Wang, X.; Sakuma, T.; Asafu-Adjaye, E.; Shiu, G.K. Determination of ginsenosides in plant extracts from Panax ginseng and Panax quinquefolius L. by LC/MS/MS. Anal. Chem.,  1999, 71(8), 1579-1584.
[http://dx.doi.org/10.1021/ac980890p] [PMID:  10221076] 
[258] 
Park, H. The history of ginseng cultivation in the orient. Acta Hortic.,  2003, (620), 453-460.
[http://dx.doi.org/10.17660/ActaHortic.2003.620.55] 
[259] 
Chong-Zhi, W.; Anderson, S.; Wei, D.; Tong-Chuan, H.; Chun-Su, Y. Red ginseng and cancer treatment. Chin. J. Nat. Med.,  2016, 4(1), 7-16.
[http://dx.doi.org/10.3724/SP.J.1009.2016.00007] [PMID:  26850342] 
[260] 
Court, W.E. Ginseng, the genus panax, 1st ed; Harwood Academic Publishers: London, 2000. 
[261] 
Kim, J.H.; Yi, Y.S.; Kim, M.Y.; Cho, J.Y. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J. Ginseng Res.,  2017, 41(4), 435-443.
[http://dx.doi.org/10.1016/j.jgr.2016.08.004] [PMID:  29021688] 
[262] 
Shin, B.K.; Kwon, S.W.; Park, J.H. Chemical diversity of Ginseng saponins from Panax ginseng. J. Ginseng Res.,  2015, 39(4), 287-298.
[http://dx.doi.org/10.1016/j.jgr.2014.12.005] [PMID:  26869820] 
[263] 
Fu, W.; Yu, X.; Lu, Z.; Sun, F.; Wang, Y.; Zhang, Y.; Zhang, Y.; Chen, Y.; Xu, H.; Sui, D. Protective effects of ginsenoside Rb2 on myocardial ischemia in vivo and in vitro. Int. J. Clin. Exp. Med.,  2016, 9(6), 9843-9855.
[264] 
Xu, Y.F.; Zhao, Y.; Zhang, H.; Zhang, X.; Yang, F. Antihypoxia and anti-oxidant effects of ginseng protein on mice. Food Sci. Technol. (Campinas),  2012, 3.
[265] 
Li, L.C.; Piao, H.M.; Zheng, M.Y.; Lin, Z.H.; Choi, Y.H.; Yan, G.H. Ginsenoside Rh2 attenuates allergic airway inflammation by modulating nuclear factor-κB activation in a murine model of asthma. Mol. Med. Rep.,  2015, 12(5), 6946-6954.
[http://dx.doi.org/10.3892/mmr.2015.4272] [PMID:  26502836] 
[266] 
Singh, U.P.; Singh, N.P.; Busbee, B.; Guan, H.; Singh, B.; Price, R.L.; Taub, D.D.; Mishra, M.K.; Nagarkatti, M.; Nagarkatti, P.S. Alternative medicines as emerging therapies for inflammatory bowel diseases. Int. Rev. Immunol.,  2012, 31(1), 66-84.
[http://dx.doi.org/10.3109/08830185.2011.642909] [PMID:  22251008] 
[267] 
Kim, J.H. Cardiovascular diseases and Panax ginseng: a review on molecular mechanisms and medical applications. J. Ginseng Res.,  2012, 36(1), 16-26.
[http://dx.doi.org/10.5142/jgr.2012.36.1.16] [PMID:  23717100] 
[268] 
Lee, C.H.; Kim, J.H. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J. Ginseng Res.,  2014, 38(3), 161-166.
[http://dx.doi.org/10.1016/j.jgr.2014.03.001] [PMID:  25378989] 
[269] 
Bai, L.; Gao, J.; Wei, F.; Zhao, J.; Wang, D.; Wei, J. Therapeutic potential of ginsenosides as an adjuvant treatment for diabetes. Front. Pharmacol.,  2018, 9, 423.
[http://dx.doi.org/10.3389/fphar.2018.00423] [PMID:  29765322] 
[270] 
Majeed, F.; Malik, F.Z.; Ahmed, Z.; Afreen, A.; Afzal, M.N.; Khalid, N. Ginseng phytochemicals as therapeutics in oncology: recent perspectives. Biomed. Pharmacother.,  2018, 100, 52-63.
[http://dx.doi.org/10.1016/j.biopha.2018.01.155] [PMID:  29421582] 
[271] 
Guan, N.; Huo, X.; Zhang, Z.; Zhang, S.; Luo, J.; Guo, W. Ginsenoside Rh2 inhibits metastasis of glioblastoma multiforme through Akt-regulated MMP13. Tumour Biol.,  2015, 36(9), 6789-6795.
[http://dx.doi.org/10.1007/s13277-015-3387-1] [PMID:  25835975] 
[272] 
Sin, S.; Kim, S.Y.; Kim, S.S. Chronic treatment with ginsenoside Rg3 induces Akt-dependent senescence in human glioma cells. Int. J. Oncol.,  2012, 41(5), 1669-1674.
[http://dx.doi.org/10.3892/ijo.2012.1604] [PMID:  22922739] 
[273] 
Liu, G.Y.; Bu, X.; Yan, H.; Jia, W.W.G. 20S-protopanaxadiol-induced programmed cell death in glioma cells through caspase-dependent and -independent pathways. J. Nat. Prod.,  2007, 70(2), 259-264.
[http://dx.doi.org/10.1021/np060313t] [PMID:  17261067] 
[274] 
Choi, Y.J.; Lee, H.J.; Kang, D.W.; Han, I.H.; Choi, B.K.; Cho, W.H. Ginsenoside Rg3 induces apoptosis in the U87MG human glioblastoma cell line through the MEK signaling pathway and reactive oxygen species. Oncol. Rep.,  2013, 30(3), 1362-1370.
[http://dx.doi.org/10.3892/or.2013.2555] [PMID:  23783960] 
[275] 
Sun, C.; Yu, Y.; Wang, L.; Wu, B.; Xia, L.; Feng, F.; Ling, Z.; Wang, S. Additive antiangiogenesis effect of ginsenoside Rg3 with low-dose metronomic temozolomide on rat glioma cells both in vivo and in vitro. J. Exp. Clin. Cancer Res.,  2016, 35(1), 32.
[http://dx.doi.org/10.1186/s13046-015-0274-y] [PMID:  26872471] 
[276] 
Hai, J.; Lin, Q.; Lu, Y.; Zhang, H.; Yi, J. Induction of apoptosis in rat C6 glioma cells by panaxydol. Cell Biol. Int.,  2007, 31(7), 711-715.
[http://dx.doi.org/10.1016/j.cellbi.2007.01.003] [PMID:  17320424] 
[277] 
Li, S.; Gao, Y.; Ma, W.; Guo, W.; Zhou, G.; Cheng, T.; Liu, Y. EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2. Tumour Biol.,  2014, 35(6), 5593-5598.
[http://dx.doi.org/10.1007/s13277-014-1739-x] [PMID:  24557544] 
[278] 
Su, X.; Zhang, D.; Zhang, H.; Zhao, K.; Hou, W. Preparation
and characterization of angiopep-2 functionalized ginsenoside-
Rg3 loaded nanoparticles and the effect on C6
glioma cells. Pharma. Dev. Technol,  2019, 1-11.
[http://dx.doi.org/10.1080/10837450.2018.1551901] [PMID: 30601070] 
[279] 
Jia, W.M.; Yang, L.M.L.I. Jie.Han, Z.H.H.U. Synthesis of the Antitumor β-Elemene Derivatives. Youji Huaxue,  1991, 6.
[280] 
Zheng, S.; Yang, H.; Zhang, S.; Wang, X.; Yu, L.; Lu, J.; Li, J. Initial study on naturally occurring products from traditional Chinese herbs and vegetables for chemoprevention. J. Cell. Biochem. Suppl.,  1997, 27(S27), 106-112.
[http://dx.doi.org/10.1002/(SICI)1097-4644(1997)27+<106:AID-JCB17>3.0.CO;2-L] [PMID:  9591200] 
[281] 
Zhu, J.; Lower-Nedza, A.D.; Hong, M.; Jie, S.; Wang, Z.; Yingmao, D.; Tschiggerl, C.; Bucar, F.; Brantner, A.H. Chemical composition and antimicrobial activity of three essential oils from Curcuma wenyujin. Nat. Prod. Commun.,  2013, 8(4), 523-526.
[http://dx.doi.org/10.1177/1934578X1300800430] [PMID:  23738470] 
[282] 
Chen, W.; Lu, Y.; Wu, J.; Gao, M.; Wang, A.; Xu, B. β -elemene inhibits melanoma growth and metastasis via suppressing vascular endothelial growth factor-mediated angiogenesis. Cancer Chemother. Pharmacol.,  2011, 67(4), 799-808.
[http://dx.doi.org/10.1007/s00280-010-1378-x] [PMID:  20563582] 
[283] 
Liu, Y. Jiang, Z.Y.; Zhou, Y.L.; Qiu, H.H.; Wang, G.; Luo, Y.; Liu, J.B.; Liu, X.W.; Bu, W.Q.; Song, J.; Cui, L.; Jia, X.B.; Feng, L. β -elemene regulates endoplasmic reticulum stress to induce the apoptosis of NSCLC cells through PERK/IRE1α/ATF6 pathway. Biomed. Pharmacother.,  2017, 93, 490-497.
[http://dx.doi.org/10.1016/j.biopha.2017.06.073] [PMID:  28672279] 
[284] 
Yu, Z. Wang, R.; Xu, L.; Xie, S.; Dong, J.; Jing, Y. β-Elemene piperazine derivatives induce apoptosis in human leukemia cells through downregulation of c-FLIP and generation of ROS. PLoS One,  2011, 6(1), e15843
[http://dx.doi.org/10.1371/journal.pone.0015843] [PMID:  21283566] 
[285] 
Chen, H.; Shi, L.; Cheng, Z.Y.; Yao, L.; Yang, Y.Y.; Pan, L. Effects of beta-elemene on proliferation and apoptosis of human multiple myeloma cell RPMI-8226. Zhongguo Shi Yan Xue Ye Xue Za Zhi,  2010, 18(2), 368-371.
[PMID:  20416170] 
[286] 
Chen, H.; Shi, L.; Wang, S.Y.; Yang, J.C.; Pan, L. Effect of β-elemene on proliferation of human multiple myeloma cells. Chinese Traditional Patent Medicine,  2010, 32(5), 730-732.
[287] 
Yu, Z. Wang, R.; Xu, L.; Dong, J.; Jing, Y N-(β-Elemene13-yl) tryptophan methyl ester induces apoptosis in human leukemia cells and synergizes with arsenic trioxide through a hydrogen peroxide dependent pathway. Cancer Lett.,  2008, 269(1), 165-173.
[http://dx.doi.org/10.1016/j.canlet.2008.04.034] [PMID:  18538921] 
[288] 
Liu, J. Zhang, Y.; Qu, J.; Xu, L.; Hou, K.; Zhang, J.; Qu, X.; Liu, Y. β -Elemene-induced autophagy protects human gastric cancer cells from undergoing apoptosis. BMC Cancer,  2011, 11(1), 183.
[http://dx.doi.org/10.1186/1471-2407-11-183] [PMID:  21595977] 
[289] 
Li, Q.Q.; Wang, G.; Reed, E.; Huang, L.; Cuff, C.F. Evaluation of cisplatin in combination with β-elemene as a regimen for prostate cancer chemotherapy. Basic Clin. Pharmacol. Toxicol.,  2010, 107(5), 868-876.
[http://dx.doi.org/10.1111/j.1742-7843.2010.00592.x] [PMID:  22545969] 
[290] 
Li, X.; Wang, G.; Zhao, J.; Ding, H.; Cunningham, C.; Chen, F.; Flynn, D.C.; Reed, E.; Li, Q.Q. Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase. Cell. Mol. Life Sci.,  2005, 62(7-8), 894-904.
[http://dx.doi.org/10.1007/s00018-005-5027-1] [PMID:  15868412] 
[291] 
Ding, X.F.; Shen, M.; Xu, L.Y.; Dong, J.H.; Chen, G. 13,14-bis(cis-3,5-dimethyl-1-piperazinyl)-β-elemene, a novel β-elemene derivative, shows potent antitumor activities via inhibition of mTOR in human breast cancer cells. Oncol. Lett.,  2013, 5(5), 1554-1558.
[http://dx.doi.org/10.3892/ol.2013.1213] [PMID:  23761818] 
[292] 
Lu, X. Wang, Y.; Luo, H.; Qiu, W.; Han, H.; Chen, X.; Yang, L. β-elemene inhibits the proliferation of T24 bladder carcinoma cells through upregulation of the expression of Smad4. Mol. Med. Rep.,  2013, 7(2), 513-518.
[http://dx.doi.org/10.3892/mmr.2012.1206] [PMID:  23228961] 
[293] 
Yao, Y.Q.; Ding, X.; Jia, Y.C.; Huang, C.X.; Wang, Y.Z.; Xu, Y.H. Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. Cancer Lett.,  2008, 264(1), 127-134.
[http://dx.doi.org/10.1016/j.canlet.2008.01.049] [PMID:  18442668] 
[294] 
Zhu, T.; Zhao, Y.; Zhang, J.; Li, L.; Zou, L.; Yao, Y.; Xu, Y. β -Elemene inhibits proliferation of human glioblastoma cells and causes cell-cycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6. Int. J. Oncol.,  2011, 38(2), 419-426.
[http://dx.doi.org/10.3892/ijo.2010.855] [PMID:  21132268] 
[295] 
Zhang, H. Xu, F.; Xie, T.; Jin, H.; Shi, L. β-elemene induces glioma cell apoptosis by downregulating survivin and its interaction with hepatitis B X-interacting protein. Oncol. Rep.,  2012, 28(6), 2083-2090.
[http://dx.doi.org/10.3892/or.2012.2022] [PMID:  22965456] 
[296] 
Zhao, Y.S. Zhu, T.Z.; Chen, Y.W.; Yao, Y.Q.; Wu, C.M.; Wei, Z.Q.; Wang, W.; Xu, β-elemene inhibits Hsp90/Raf-1 molecular complex inducing apoptosis of glioblastoma cells. J. Neurooncol.,  2012, 107(2), 307-314.
[http://dx.doi.org/10.1007/s11060-011-0770-7] [PMID:  22160627] 
[297] 
Zhu, Y.; Hu, J.; Shen, F.; Shen, H.; Liu, W.; Zhang, J. The cytotoxic effect of β-elemene against malignant glioma is enhanced by base-excision repair inhibitor methoxyamine. J. Neurooncol.,  2013, 113(3), 375-384.
[http://dx.doi.org/10.1007/s11060-013-1136-0] [PMID:  23700323] 
[298] 
Zhu, T.; Li, X.; Luo, L.; Wang, X.; Li, Z.; Xie, P.; Gao, X.; Song, Z.; Su, J.; Liang, G. Reversion of malignant phenotypes of human glioblastoma cells by β-elemene through β-catenin-mediated regulation of stemness-, differentiation- and epithelial-to-mesenchymal transition-related molecules. J. Transl. Med.,  2015, 13(1), 356.
[http://dx.doi.org/10.1186/s12967-015-0727-2] [PMID:  26563263] 
[299] 
Zhu, T.; Xu, Y.; Dong, B.; Zhang, J.; Wei, Z.; Xu, Y.; Yao, Y. β-elemene inhibits proliferation of human glioblastoma cells through the activation of glia maturation factor β and induces sensitization to cisplatin. Oncol. Rep.,  2014, 26(2), 405-413.
[http://dx.doi.org/10.3892/or.2011.1276] [PMID:  21519795] 
[300] 
Zhu, T.Z.; Li, X.M.; Luo, L.H.; Song, Z.Q.; Gao, X.; Li, Z.Q.; Su, J.Y.; Liang, G.B. β-elemene inhibits stemness, promotes differentiation and impairs chemoresistance to temozolomide in glioblastoma stem-like cells. Int. J. Oncol.,  2014, 45(2), 699-709.
[http://dx.doi.org/10.3892/ijo.2014.2448] [PMID:  24841897] 
[301] 
Mu, L. Wang, T.; Chen, Y.; Tang, X.; Yuan, Y.; Zhao, Y. β-Elemene enhances the efficacy of gefitinib on glioblastoma multiforme cells through the inhibition of the EGFR signaling pathway. Int. J. Oncol.,  2016, 49(4), 1427-1436.
[http://dx.doi.org/10.3892/ijo.2016.3626] [PMID:  27498706] 
[302] 
Fahey, J.W.; Zalcmann, A.T.; Talalay, P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry,  2001, 56(1), 5-51.
[http://dx.doi.org/10.1016/S0031-9422(00)00316-2] [PMID:  11198818] 
[303] 
Hecht, S.S. Inhibition of carcinogenesis by isothiocyanates. Drug Metab. Rev.,  2000, 32(3-4), 395-411.
[http://dx.doi.org/10.1081/DMR-100102342] [PMID:  11139137] 
[304] 
Zhang, Y.; Talalay, P. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res.,  1994, 54(7)(Suppl.), 1976s-1981s.
[PMID:  8137323] 
[305] 
Zhang, Y.; Yao, S.; Li, J. Vegetable-derived isothiocyanates: anti-proliferative activity and mechanism of action. Proc. Nutr. Soc.,  2006, 65(1), 68-75.
[http://dx.doi.org/10.1079/PNS2005475] [PMID:  16441946] 
[306] 
Chen, C.; Kong, A.N.T. Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects. Trends Pharmacol. Sci.,  2005, 26(6), 318-326.
[http://dx.doi.org/10.1016/j.tips.2005.04.004] [PMID:  15925707] 
[307] 
Yang, M.D.; Lai, K.C.; Lai, T.Y.; Hsu, S.C.; Kuo, C.L.; Yu, C.S.; Lin, M.L.; Yang, J.S.; Kuo, H.M.; Wu, S.H.; Chung, J.G. Phenethyl isothiocyanate inhibits migration and invasion of human gastric cancer AGS cells through suppressing MAPK and NF-kappaB signal pathways. Anticancer Res.,  2010, 30(6), 2135-2143.
[PMID:  20651362] 
[308] 
Wolf, M.A.; Claudio, P.P. Benzyl isothiocyanate inhibits HNSCC cell migration and invasion, and sensitizes HNSCC cells to cisplatin. Nutr. Cancer,  2014, 66(2), 285-294.
[http://dx.doi.org/10.1080/01635581.2014.868912] [PMID:  24447182] 
[309] 
Martin, S.L.; Royston, K.J.; Tollefsbol, T.O. The role of non-coding RNAs and isothiocyanates in cancer. Mol. Nutr. Food Res.,  2018, 62(18), e1700913
[http://dx.doi.org/10.1002/mnfr.201700913] [PMID:  29532604] 
[310] 
Zhu, Y.; Zhang, L.; Zhang, G.D.; Wang, H.O.; Liu, M.Y.; Jiang, Y.; Qi, L.S.; Li, Q.; Yang, P. Potential mechanisms of benzyl isothiocyanate suppression of invasion and angiogenesis by the U87MG human glioma cell line. Asian Pac. J. Cancer Prev.,  2014, 15(19), 8225-8228.
[http://dx.doi.org/10.7314/APJCP.2014.15.19.8225] [PMID:  25339010] 
[311] 
Gupta, B.; Chiang, L.; Chae, K.; Lee, D.H. Phenethyl isothiocyanate inhibits hypoxia-induced accumulation of HIF-1α and VEGF expression in human glioma cells. Food Chem.,  2013, 141(3), 1841-1846.
[http://dx.doi.org/10.1016/j.foodchem.2013.05.006] [PMID:  23870899] 
[312] 
Lee, C.S.; Cho, H.J.; Jeong, Y.J.; Shin, J.M.; Park, K.K.; Park, Y.Y.; Bae, Y.S.; Chung, I.K.; Kim, M.; Kim, C.H.; Jin, F.; Chang, H.W.; Chang, Y.C. Isothiocyanates inhibit the invasion and migration of C6 glioma cells by blocking FAK/JNK-mediated MMP-9 expression. Oncol. Rep.,  2015, 34(6), 2901-2908.
[http://dx.doi.org/10.3892/or.2015.4292] [PMID:  26397194] 
[313] 
Sankawa, U.; Ebizuka, Y.; Miyazaki, T.; Isomura, Y.; Otsuka, H.; Shibata, S.; Inomata, M.; Fukuoka, F. Antitumor activity of shikonin and its derivatives. Chem. Pharm. Bull. (Tokyo),  1977, 25(9), 2392-2395.
[http://dx.doi.org/10.1248/cpb.25.2392] [PMID:  589729] 
[314] 
Cheng, H.W.; Chen, F.A.; Hsu, H.C.; Chen, C.Y. Photochemical decomposition of alkannin/shikonin enantiomers. Int. J. Pharm.,  1995, 120(2), 137-144.
[http://dx.doi.org/10.1016/0378-5173(94)00367-E] 
[315] 
Tanaka, S.; Tajima, M.; Tsukada, M.; Tabata, M. A comparative study on anti-inflammatory activities of the enantiomers, shikonin and alkannin. J. Nat. Prod.,  1986, 49(3), 466-469.
[http://dx.doi.org/10.1021/np50045a014] [PMID:  3760886] 
[316] 
Fu, Z.; Deng, B.; Liao, Y.; Shan, L.; Yin, F.; Wang, Z.; Zeng, H.; Zuo, D.; Hua, Y.; Cai, Z. The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis. BMC Cancer,  2013, 13(1), 580.
[http://dx.doi.org/10.1186/1471-2407-13-580] [PMID:  24314238] 
[317] 
Shahsavari, Z.; Karami-Tehrani, F.; Salami, S.; Ghasemzadeh, M. RIP1K and RIP3K provoked by shikonin induce cell cycle arrest in the triple negative breast cancer cell line, MDA-MB-468: necroptosis as a desperate programmed suicide pathway. Tumour Biol.,  2016, 37(4), 4479-4491.
[http://dx.doi.org/10.1007/s13277-015-4258-5] [PMID:  26496737] 
[318] 
Wada, N.; Kawano, Y.; Fujiwara, S.; Kikukawa, Y.; Okuno, Y.; Tasaki, M.; Ueda, M.; Ando, Y.; Yoshinaga, K.; Ri, M.; Iida, S.; Nakashima, T.; Shiotsu, Y.; Mitsuya, H.; Hata, H. Shikonin, dually functions as a proteasome inhibitor and a necroptosis inducer in multiple myeloma cells. Int. J. Oncol.,  2015, 46(3), 963-972.
[http://dx.doi.org/10.3892/ijo.2014.2804] [PMID:  25530098] 
[319] 
Huang, C.; Luo, Y.; Zhao, J.; Yang, F.; Zhao, H.; Fan, W.; Ge, P. Shikonin kills glioma cells through necroptosis mediated by RIP-1. PLoS One,  2013, 8(6), e66326
[http://dx.doi.org/10.1371/journal.pone.0066326] [PMID:  23840441] 
[320] 
Zhou, Z.; Lu, B.; Wang, C.; Wang, Z.; Luo, T.; Piao, M.; Meng, F.; Chi, G.; Luo, Y.; Ge, P. RIP1 and RIP3 contribute to shikonin-induced DNA double-strand breaks in glioma cells via increase of intracellular reactive oxygen species. Cancer Lett.,  2017, 390, 77-90.
[http://dx.doi.org/10.1016/j.canlet.2017.01.004] [PMID:  28108311] 
[321] 
Liu, J.; Wang, P.; Xue, Y.X.; Li, Z.; Qu, C.B.; Liu, Y.H. Enhanced antitumor effect of shikonin by inhibiting endoplasmic reticulum stress via JNK/c-Jun pathway in human glioblastoma stem cells. Biochem. Biophys. Res. Commun.,  2015, 466(1), 103-110.
[http://dx.doi.org/10.1016/j.bbrc.2015.08.115] [PMID:  26321663] 
[322] 
Zhang, F.Y.; Hu, Y.; Que, Z.Y.; Wang, P.; Liu, Y.H.; Wang, Z.H.; Xue, Y.X. Shikonin inhibits the migration and invasion of human glioblastoma cells by targeting phosphorylated β-catenin and phosphorylated PI3K/Akt: a potential mechanism for the anti-glioma efficacy of a traditional Chinese herbal medicine. Int. J. Mol. Sci.,  2015, 16(10), 23823-23848.
[http://dx.doi.org/10.3390/ijms161023823] [PMID:  26473829] 
[323] 
Liu, J.; Qu, C.B.; Xue, Y.X.; Li, Z.; Wang, P.; Liu, Y.H. MiR-143 enhances the antitumor activity of shikonin by targeting BAG3 expression in human glioblastoma stem cells. Biochem. Biophys. Res. Commun.,  2015, 468(1-2), 105-112.
[http://dx.doi.org/10.1016/j.bbrc.2015.10.153] [PMID:  26541455] 
[324] 
Yang, J.T.; Li, Z.L.; Wu, J.Y.; Lu, F.J.; Chen, C.H. An oxidative stress mechanism of shikonin in human glioma cells. PLoS One,  2014, 9(4), e94180
[http://dx.doi.org/10.1371/journal.pone.0094180] [PMID:  24714453] 
[325] 
van den Bent, M.J.; Baumert, B.; Erridge, S.C.; Vogelbaum, M.A.; Nowak, A.K.; Sanson, M.; Brandes, A.A.; Clement, P.M.; Baurain, J.F.; Mason, W.P.; Wheeler, H.; Chinot, O.L.; Gill, S.; Griffin, M.; Brachman, D.G.; Taal, W.; Rudà, R.; Weller, M.; McBain, C.; Reijneveld, J.; Enting, R.H.; Weber, D.C.; Lesimple, T.; Clenton, S.; Gijtenbeek, A.; Pascoe, S.; Herrlinger, U.; Hau, P.; Dhermain, F.; van Heuvel, I.; Stupp, R.; Aldape, K.; Jenkins, R.B.; Dubbink, H.J.; Dinjens, W.N.M.; Wesseling, P.; Nuyens, S.; Golfinopoulos, V.; Gorlia, T.; Wick, W.; Kros, J.M. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet,  2017, 390(10103), 1645-1653.
[http://dx.doi.org/10.1016/S0140-6736(17)31442-3] [PMID:  28801186] 
[326] 
Nghiemphu, P.L.; Bahng, H.H.; Lai, A.; Faiq, N.; Yong, W.H.; Green, R.M.; Polikoff, J.; Spier, C.E.; Iwamoto, F.M.; Lassman, A.B. American Society of Clinical Oncology; , 2017. 
[327] 
Cheng, W.; Zhang, C.; Ren, X.; Wang, Z.; Liu, X.; Han, S.; Wu, A. Treatment strategy and IDH status improve nomogram validity in newly diagnosed GBM patients. Neuro-oncol.,  2017, 19(5), 736-738.
[http://dx.doi.org/10.1093/neuonc/nox012] [PMID:  28339964] 
[328] 
Hirst, T.C.; Vesterinen, H.M.; Sena, E.S.; Egan, K.J.; Macleod, M.R.; Whittle, I.R. Systematic review and meta-analysis of temozolomide in animal models of glioma: was clinical efficacy predicted? Br. J. Cancer,  2013, 108(1), 64-71.
[http://dx.doi.org/10.1038/bjc.2012.504] [PMID:  23321511] 
[329] 
Yin, A.A.; Zhang, L.H.; Cheng, J.X.; Dong, Y.; Liu, B.L.; Han, N.; Zhang, X. Radiotherapy plus concurrent or sequential temozolomide for glioblastoma in the elderly: a meta-analysis. PLoS One,  2013, 8(9), e74242
[http://dx.doi.org/10.1371/journal.pone.0074242] [PMID:  24086323] 
[330] 
Mirimanoff, R.O.; Gorlia, T.; Mason, W.; Van den Bent, M.J.; Kortmann, R.D.; Fisher, B.; Reni, M.; Brandes, A.A.; Curschmann, J.; Villa, S.; Cairncross, G.; Allgeier, A.; Lacombe, D.; Stupp, R. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J. Clin. Oncol.,  2006, 24(16), 2563-2569.
[http://dx.doi.org/10.1200/JCO.2005.04.5963] [PMID:  16735709] 
[331] 
Yan, Y.R.; Xie, Q.; Li, F.; Zhang, Y.; Ma, J.W.; Xie, S.M.; Li, H.Y.; Zhong, X.Y. Epithelial-to-mesenchymal transition is involved in BCNU resistance in human glioma cells. Neuropathology,  2014, 34(2), 128-134.
[http://dx.doi.org/10.1111/neup.12062] [PMID:  24112388] 
[332] 
Yi, D.Y.; Su, Q.; Zhang, F.C.; Fu, P.; Zhang, Q.; Cen, Y.C.; Zhao, H.Y.; Xiang, W. Effect of microRNA-128 on cisplatin resistance of glioma SHG-44 cells by targeting JAG1. J. Cell. Biochem.,  2018, 119(4), 3162-3173.
[http://dx.doi.org/10.1002/jcb.26469] [PMID:  29091297] 
[333] 
Cui, L.; Fu, J.; Pang, J.C.S.; Qiu, Z.K.; Liu, X.M.; Chen, F.R.; Shi, H.L.; Ng, H.K.; Chen, Z.P. Overexpression of IL-7 enhances cisplatin resistance in glioma. Cancer Biol. Ther.,  2012, 13(7), 496-503.
[http://dx.doi.org/10.4161/cbt.19592] [PMID:  22415136] 
[334] 
Dai, Z.; Li, S.R.; Zhu, P.F.; Liu, L.; Wang, B.; Liu, Y.P.; Luo, X.D.; Zhao, X.D. Isocostunolide inhibited glioma stem cell by suppression proliferation and inducing caspase dependent apoptosis. Bioorg. Med. Chem. Lett.,  2017, 27(13), 2863-2867.
[http://dx.doi.org/10.1016/j.bmcl.2017.04.075] [PMID:  28487072] 
[335] 
Shervington, A.; Pawar, V.; Menon, S.; Thakkar, D.; Patel, R. The sensitization of glioma cells to cisplatin and tamoxifen by the use of catechin. Mol. Biol. Rep.,  2009, 36(5), 1181-1186.
[http://dx.doi.org/10.1007/s11033-008-9295-3] [PMID:  18581255] 
[336] 
Yin, H.; Zhou, Y.; Wen, C.; Zhou, C.; Zhang, W.; Hu, X.; Wang, L.; You, C.; Shao, J. Curcumin sensitizes glioblastoma to temozolomide by simultaneously generating ROS and disrupting AKT/mTOR signaling. Oncol. Rep.,  2014, 32(4), 1610-1616.
[http://dx.doi.org/10.3892/or.2014.3342] [PMID:  25050915] 
[337] 
Wu, H.; Liu, Q.; Cai, T.; Chen, Y.D.; Wang, Z.F. Induction of microRNA-146a is involved in curcumin-mediated enhancement of temozolomide cytotoxicity against human glioblastoma. Mol. Med. Rep.,  2015, 12(4), 5461-5466.
[http://dx.doi.org/10.3892/mmr.2015.4087] [PMID:  26239619] 
[338] 
Lan, F.; Yang, Y.; Han, J.; Wu, Q.; Yu, H.; Yue, X. Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression. Int. J. Oncol.,  2016, 48(2), 559-568.
[http://dx.doi.org/10.3892/ijo.2015.3271] [PMID:  26648123] 
[339] 
Filippi-Chiela, E.C.; Thomé, M.P.; Bueno e Silva, M.M.; Pelegrini, A.L.; Ledur, P.F.; Garicochea, B.; Zamin, L.L.; Lenz, G. Resveratrol abrogates the temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the temozolomide-induced senescence in glioma cells. BMC Cancer,  2013, 13(1), 147.
[http://dx.doi.org/10.1186/1471-2407-13-147] [PMID:  23522185] 
[340] 
Schneider, C.; Gordon, O.N.; Edwards, R.L.; Luis, P.B. Degradation of curcumin: from mechanism to biological implications. J. Agric. Food Chem.,  2015, 63(35), 7606-7614.
[http://dx.doi.org/10.1021/acs.jafc.5b00244] [PMID:  25817068] 
[341] 
Gordon, O.N.; Luis, P.B.; Sintim, H.O.; Schneider, C. Unraveling curcumin degradation: autoxidation proceeds through spiroepoxide and vinylether intermediates en route to the main bicyclopentadione. J. Biol. Chem.,  2015, 290(8), 4817-4828.
[http://dx.doi.org/10.1074/jbc.M114.618785] [PMID:  25564617] 
[342] 
Mohanty, C.; Sahoo, S.K. The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. Biomaterials,  2010, 31(25), 6597-6611.
[http://dx.doi.org/10.1016/j.biomaterials.2010.04.062] [PMID:  20553984] 
[343] 
Pardridge, W.M. The blood-brain barrier: bottleneck in brain drug development. NeuroRx,  2005, 2(1), 3-14.
[http://dx.doi.org/10.1602/neurorx.2.1.3] [PMID:  15717053] 
[344] 
Sun, M.; Gao, Y.; Guo, C.; Cao, F.; Song, Z.; Xi, Y.; Yu, A.; Li, A.; Zhai, G. Enhancement of transport of curcumin to brain in mice by poly (n-butylcyanoacrylate) nanoparticle. J. Nanopart. Res.,  2010, 12(8), 3111-3122.
[http://dx.doi.org/10.1007/s11051-010-9907-4] 
[345] 
Tsai, Y.M.; Chien, C.F.; Lin, L.C.; Tsai, T.H. Curcumin and its nano-formulation: the kinetics of tissue distribution and blood-brain barrier penetration. Int. J. Pharm.,  2011, 416(1), 331-338.
[http://dx.doi.org/10.1016/j.ijpharm.2011.06.030] [PMID:  21729743] 
[346] 
Zhang, P.; Hu, L.; Yin, Q.; Feng, L.; Li, Y. Transferrin-modified c[RGDfK]-paclitaxel loaded hybrid micelle for sequential blood-brain barrier penetration and glioma targeting therapy. Mol. Pharm.,  2012, 9(6), 1590-1598.
[http://dx.doi.org/10.1021/mp200600t] [PMID:  22497485] 
[347] 
Miura, Y.; Takenaka, T.; Toh, K.; Wu, S.; Nishihara, H.; Kano, M.R.; Ino, Y.; Nomoto, T.; Matsumoto, Y.; Koyama, H.; Cabral, H.; Nishiyama, N.; Kataoka, K. Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier. ACS Nano,  2013, 7(10), 8583-8592.
[http://dx.doi.org/10.1021/nn402662d] [PMID:  24028526] 
[348] 
Ying, X.; Wang, Y.; Xu, H.; Li, X.; Yan, H.; Tang, H.; Wen, C.; Li, Y. The construction of the multifunctional targeting ursolic acids liposomes and its apoptosis effects to C6 glioma stem cells. Oncotarget,  2017, 8(38), 64129-64142.
[http://dx.doi.org/10.18632/oncotarget.19784] [PMID:  28969057] 
[349] 
Li, X.T.; Ju, R.J.; Li, X.Y.; Zeng, F.; Shi, J.F.; Liu, L.; Zhang, C.X.; Sun, M.G.; Lou, J.N.; Lu, W.L. Multifunctional targeting daunorubicin plus quinacrine liposomes, modified by wheat germ agglutinin and tamoxifen, for treating brain glioma and glioma stem cells. Oncotarget,  2014, 5(15), 6497-6511.
[http://dx.doi.org/10.18632/oncotarget.2267] [PMID:  25153726] 
[350] 
Wolinsky, J.B.; Colson, Y.L.; Grinstaff, M.W. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J. Control. Release,  2012, 159(1), 14-26.
[http://dx.doi.org/10.1016/j.jconrel.2011.11.031] [PMID:  22154931] 
[351] 
Brem, H.; Gabikian, P. Biodegradable polymer implants to treat brain tumors. J. Control. Release,  2001, 74(1-3), 63-67.
[http://dx.doi.org/10.1016/S0168-3659(01)00311-X] [PMID:  11489483] 
[352] 
Brem, H.; Mahaley, M.S., Jr; Vick, N.A.; Black, K.L.; Schold, S.C., Jr; Burger, P.C.; Friedman, A.H.; Ciric, I.S.; Eller, T.W.; Cozzens, J.W. Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J. Neurosurg.,  1991, 74(3), 441-446.
[http://dx.doi.org/10.3171/jns.1991.74.3.0441] [PMID:  1993909] 
[353] 
Westphal, M.; Hilt, D.C.; Bortey, E.; Delavault, P.; Olivares, R.; Warnke, P.C.; Whittle, I.R.; Jääskeläinen, J.; Ram, Z. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncol.,  2003, 5(2), 79-88.
[http://dx.doi.org/10.1093/neuonc/5.2.79] [PMID:  12672279] 
[354] 
Westphal, M.; Ram, Z.; Riddle, V.; Hilt, D.; Bortey, E. Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir. (Wien),  2006, 148(3), 269-275.
[http://dx.doi.org/10.1007/s00701-005-0707-z] [PMID:  16482400] 
[355] 
McGirt, M.J.; Than, K.D.; Weingart, J.D.; Chaichana, K.L.; Attenello, F.J.; Olivi, A.; Laterra, J.; Kleinberg, L.R.; Grossman, S.A.; Brem, H.; Quiñones-Hinojosa, A. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J. Neurosurg.,  2009, 110(3), 583-588.
[http://dx.doi.org/10.3171/2008.5.17557] [PMID:  19046047] 
[356] 
Bourdillon, P.; Boissenot, T.; Goldwirt, L.; Nicolas, J.; Apra, C.; Carpentier, A. Incomplete copolymer degradation of in situ chemotherapy. J. Mater. Sci. Mater. Med.,  2018, 29(3), 25.
[http://dx.doi.org/10.1007/s10856-018-6032-x] [PMID:  29455370] 
Rights & Permissions Print Cite
Article Metrics
68
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867326666190809221332	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Phytochemical-Mediated Glioma Targeted Treatment: Drug Resistance and Novel Delivery Systems

Abstract

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the Treatment of Chronic Inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

Current Medicinal Chemistry

Phytochemical-Mediated Glioma Targeted Treatment: Drug Resistance and Novel Delivery Systems

Abstract

Call for Papers in Thematic Issues

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the Treatment of Chronic Inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

Related Journals

Related Books

Related Articles
