Beneficial action of Citrus flavonoids on multiple cancer-related biological pathways

Current Cancer Drug Targets

Volumn 7, Issue 8, 2007, Pages 795-809

  Benavente Garcia O ^a   Castillo, J ^a   Alcaraz, M ^b   Vicente, V ^b   Del Rio J A ^c   Ortuno A ^c  

^a 80320 Alcantarilla   (Spain)

^b UNIVERSITY OF MURCIA   (Spain)

^c UNIVERSITY OF MURCIA   (Spain)

Author keywords

Apigenin; Cancer; Citrus; Diosmin; Flavonoid; Rutin; Tangeretin

Indexed keywords

ANTHOCYANIN; APIGENIN; AURANTIIN; BAICALEIN; BIOFLAVONOID; CHRISIN; DIOSMIN; ERIODICTYOL; FLAVANONE DERIVATIVE; FLAVONE DERIVATIVE; FLAVONOL DERIVATIVE; GALLIC ACID; HESPERETIN; ISOFELURIC ACID; KAEMPFEROL; LUTEOLIN; MYRICETIN; PROCYANIDIN; QUERCETIN; RUTOSIDE; SINAPIC ACID; TANGERETIN; TRIMETHOXIBENZOIC ACID; UNCLASSIFIED DRUG;

ARTICLE; CANCER CELL; CITRUS FRUIT; HUMAN; LUNG METASTASIS; METASTASIS INHIBITION; NEOPLASM; NONHUMAN;

ANIMALS; ANTINEOPLASTIC AGENTS, PHYTOGENIC; CITRUS; FLAVONOIDS; HUMANS; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 37449002090     PISSN: 15680096     EISSN: None     Source Type: Journal    
DOI: 10.2174/156800907783220435     Document Type: Article

References (158)

1. Benavente-García, O.; Castillo, J.; Marín, F. R.; Ortuño, A.; Del Rio, J. A. Uses and Properties of Citrus Flavonoids. J. Agr. Food Chem. 1997, 45, 4505-4515.
2. Hodek, P.; Trefil, P.; Stiborova, M. Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem.-Biol. Interact. 2002, 139, 1-21.
3. Castillo, J.; Benavente-García, O.; Del Río, J. A. Naringin and Neohesperidin levels during development of leaves, flowers and fruits of Citrus aurantium. Plant Physiol. 1992, 99, 67-73.
4. Benavente-García, O.; Castillo, J.; Del Río, J. A. Changes in neodiosmin levels during the development of Citrus aurantium leaves and fruits. Postulation of a neodiosmin biosynthetic pathway. J. Agr. Food Chem. 1993, 41, 1916-1919.
5. Del Río, J. A.; Ortuño, A.; Marín, F. R.; García Puig, D.; Sabater, F. Bioproduction of neohesperidin and naringin in callus cultures of Citrus aurantium. Plant Cell Rep. 1992, 11, 592-596.
6. Del Río, J. A.; Ortuño, A. In Biotechnology in Agriculture and Forestry. Vol. 28. Medicinal and Aromatic Plants VIII: Citrus paradisi Macf. (Grapefruit): in vitro culture and the bioproduction of sesquiterpenes nootkatone, valencene and other secondary metabolites; Bajaj, Y. P. S., Ed.; Springer-Verlag: New York, 1994, pp.123-138, ISBN. 3-540-57446-8 S.
7. Del Río, J. A.; Fuster, M. D.; Sabater, F.; Porras, I.; García-Lidón, A.; Ortuño, A. Effect of benzylaminopurine on the flavanones hesperidin, hesperetin 7-O-glucoside, and prunin in tangelo Nova fruits. J. Agr. Food Chem. 1995, 43, 2030-2034.
8. Del Río, J. A.; Fuster, M. D.; Sabater, F.; Porras, I.; García-Lidón, A.; Ortuño, A. Selection of Citrus varieties highly productive for the neohesperidin dihydrochalcone precursor. Food Chem. 1997, 59, 433-437.
9. Del Río, J. A.; Arcas, M. C.; Benavente-García, O.; Sabater, F.; Ortuño, A. Changes of polymethoxylated flavones levels during development of Citrus aurantium (cv. Sevillano) fruits. Planta Med. 1998, 64, 575-576.
10. Ooghe, W. C.; Ooghe, S. J.; Detavernier, C. M.; Huyghebaert, A. Characterization of orange juice (Citrus sinensis) by polymethoxyflavones. J. Agr. Food Chem. 1994, 42, 2191-2195.
11. Ortuño, A.; García-Puig, D.; Fuster, M. D.; Pérez, M. L.; Sabater, F.; Porras, I.; García-Lidón, A.; Del Río, J. A. Flavanone and Nootkatone levels in different varieties of grapefruits and pummelo. J. Agr. Food Chem. 1995, 43, 1-5.
12. Ortuño, A.; Reynaldo, I.; Fuster, M. D.; Botía, J.; García Puig, D.; Sabater, F.; García-Lidón, A.; Porras, I.; Del Río, J. A. Citrus cultivars with high flavonoid contents in the fruits. Sci. Hortic. 1997, 68, 231-236.
13. Ortuño, A.; Arcas, M. C.; Benavente-García, O.; Del Río, J. A. Evolution of polymethoxy flavones during development of tangelo Nova fruits. Food Chem. 1999, 66, 217-220.
14. Bär, A.; Borrego, F.; Benavente, O.; Castillo, J.; Del Río, J. A. Neohesperidin dihydrochalcone: properties and applications. Food Sci. Technol. 1990, 23, 371-376.
15. Del Río, J. A.; Arcas, M. C.; Benavente-García, O.; Ortuño, A. Citrus polymethoxylated flavones can confer resistance against Phytophthora citrophthora, Penicillium digitatum and Geotrichum species. J. Agr. Food Chem. 1998, 46, 4423-4428.
16. Del Río, J. A.; Ortuño, A. In Crop Management and Postharvest Handling of Horticultural Products. Vol. IV: Diseases and Disorders of Fruits and Vegetables: Biosynthesis of Flavonoids in Citrus and its involvement in the antifungal defense mechanisms; Dris, R.; Niskanen, R., Jain, S. M., Eds.; World Food RD Ltd. Publishers, 2003, pp. 189-223, ISBN. 1-57808-279-X.
17. Del Río, J. A.; Gómez, P.; Báidez, G. A.; Arcas, M. C.; Botía, J. M.; Ortuño, A. Changes in the level of polymethoxyflavones and flavones as part of the defence mechanism of Citrus sinensis (cv. Valencia late) fruits against Phytophthora citrophthora. J. Agr. Food Chem. 2004, 52, 1913-1917.
18. Arcas, M. C.; Botía, J. M.; Ortuño, A.; Del Río, J. A. UV irradiation alters the levels of flavonoids involved in the defence mechanism of Citrus aurantium fruits against Penicillium digitatum. Eur. J. Plant Pathol. 2000, 106, 617-622.
19. Ortuño, A.; Botía, J. M.; Fuster, M. D.; Porras, I.; García-Lidón, A.; Del Río, J. A. Effect of Scoparone (6,7-dimethoxycoumarin) biosynthesis on the resistance of Tangelo Nova, Citrus paradisi, and Citrus aurantium fruits against Phytophthora parasitica. J. Agr. Food Chem. 1997, 45, 2740-2743.
20. Ortuño, A.; Arcas, M. C.; Botía, J. M.; Fuster, M. D.; Del Río, J. A. Increasing resistance against Phytophthora citrophthora in tangelo Nova fruits by modylating polymethoxyflavones levels. J. Agr. Food Chem. 2002, 50, 2836-2839.
21. Ortuño, A.; Báidez, A.; Gómez, P.; Arcas, M. C.; Porras, I.; García-Lidón, A.; Del Río, J. A. Citrus paradisi and Citrus sinensis flavonoids: Their influence in the defence mechanism against Penicillium digitatum. Food Chem. 2006, 98, 351-358.
22. Del Río, J. A; Fuster, M. D.; Gómez, P.; Porras, I.; García-Lidón, A.; Ortuño, A. Citrus limon: A source of flavonoids of pharmaceutical interest. Food Chem. 2004, 84, 457-461.
23. Manthey, J. A.; Guthrie, N; Grhmann, K. Biological properties of citrus flavonoids pertaining to cancer and Inflammation. Curr. Med. Chem. 2001, 8, 135-153.
24. Depeint, F.; Gee, J. M.; Williamson, G.; Johnson, I. T. Evidence for consistent patterns between flavonoid structures and cellular activities. P. Nutr. Soc. 2002, 61, 97-103.
25. Le Marchend, L. Cancer preventive effects of flavonoids-a review. Biomed. Pharmacother. 2002, 56, 296-301.
26. Bravo, L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr. Rev. 1998, 56, 317-333.
27. Rodriguez, J.; Yañez, J.; Vicente, V.; Alcaraz, M.; Benavente-Garcia, O.; Castillo, J.; Lorente, J.; Lozano, J. A. Effects of several flavonoids on the growth of B16F10 and SK-MEL-1 melanoma cell lines: relationship between structure and activity. Melanoma Res. 2002, 12, 99-107.
28. Martínez, C.; Yañez, J.; Alcaraz, M.; Bernavente-Garcia, O.; Castillo, J.; Lorente, J.; Vicente, V. Effects of several polyhydroxylated flavonoids on the growth of B16F10 melanoma and Melan-a cell lines. Influence of sequential oxidation state on the flavonoid skeleton. Melanoma Res. 2003, 13, 3-9.
29. Kawaii, S.; Tomono, Y.; Katase, E.; Ogawa, K.; Yano, M. Antiproliferative activity of flavonoids on several cancer cell lines. Biosci. Biotech. Biochem. 1999, 63, 896-899.
30. Casagrande, F.; Darbon, J. Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependet kinases CDK2 and CDK1. Biochem. Pharmacol. 2001, 61, 1205-1215.
31. Manthey, J. A.; Guthrie, N. Antiproliferative activities of citrus flavonoids against six human cancer cell lines. J. Agr. Food Chem. 2002, 50, 5837-5843.
32. Mayr, G. W.; Windhorst, S.; Hillemeier, K. Antiproliferative plant and synthetic polyphenolics are specific inhibitors of vertebrate inositol-1,4,5-triphosphate 3-kinases and inositol polyphosphate multikinase. J. Biol. Chem. 2005, 280, 13229-13240.
33. Bagli, E.; Stefaniotou, M.; Morbidelli, L.; Ziche, M.; Psillas, K.; Murphy, C.; Fotsis, T. Luteolin inghibits vascular endothelial growth factor-induced angiogenesis; Inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3′-kinase activity. Cancer Res. 2004, 64, 7936-7946.
34. Yañez, J.; Martínez, C.; Rodríguez, J.; Canteras M.; Alcaraz, M.; Vicente V. Efecto de seis flavonoides sobre el crecimiento de la línea de melanoma humano SK.Mel-1. Oncología 2002, 25, 210-216.
35. Martínez, C.; Yañez, J.; Rodríguez, J.; Canteras, M.; Alcaraz, M.; Vicente, V. Inhibición del crecimiento de la línea de melanoma B16-F10 por diferentes compuestos polifenólicos. Rev. Esp. Patol. 2001, 34, 317-324.
36. Benavente-García, O.; Castillo, J.; Lorente, J.; Alcaraz, M.; Yañez, J.; Martinez, C.; Vicente, V.; Lozano, J. A. Antiproliferative activity of several phenolic compounds against melanoma cell lines: relationship between structure and activity. Agrofood Industry High-Tech 2005, 4, 30-34.
37. Kandaswami, C.; Perkins, E.; Soloniuk, D. S.; Drzewiecki, G.; Middleton, E., Jr. Antiproliferative effects of citrus flavonoids on a human squamous cell carcinoma in vitro. Cancer Lett. 1991, 56, 147-152.
38. Piantelli, M.; Rinelli, A.; Macri, E.; Maggiano, N.; Larocca, L. M.; Scerrati, A.; Roselli, R.; Iacoangeli, M.; Scambia, G.; Capella, A.; Ranelletti, F. O. Type II estrogen binding sites and antiproliferative activity of quercetin in human meningiomas. Cancer 1993, 63, 193-198.
39. Kuo, S. M. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett. 1996, 110, 41-48.
40. Kuntz, S.; Wenzel, U.; Daniel, H. Comparative analysis of the effects of flavonoids on proliferation, Cytotoxicity, and apoptosis in human colon cancer cell lines. Eur. J. Nutr. 1999, 38, 133-142.
41. Hirano, T.; Gotoh, M.; Oka, K. Natural flavonoids and lignans are potent cytostatic agents against human leukaemic HL-60 cells. Life Sci. 1994, 55, 1061-1069.
42. Fotsis, T.; Pepper, M. S.; Aktas, E.; Breit, S.; Rasku, S.; Adlercreutz, H.; Wahala, K.; Montesano, R.; Schweigerer, L. Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res. 1997, 57, 2916-2921.
43. Sanchez, I.; Calderon, J.; Ruiz, B.; Tellez, J.; Calzada, L.; Taboada, J. in vitro Cytotoxicity of flavonoids against MK2 and C6 tomour cells. Phytother. Res. 2001, 290-293.
44. Hirano, T.; Abe, K.; Gotoh, M.; Oka, K. Citrus flavone tangeretin inhibit leukaemic HL-60 cells growth partially through induction of apoptosis with less cytotoxicity on normal lymphocytes. Br. J. Cancer 1995, 72, 1380-1388.
45. Kawaii, S.; Tomono, Y.; Katase, E.; Ogawa, K.; Yano, M. Effect of citrus flavonoids on HL-60 cell differentiation. Anticancer Res. 1999, 19, 1261-1269.
46. Chiang, L. C.; Ng, L. T.; Lin, I. C.; Kuo, P. L.; Lin, C. C. Antiproliferative effect of apigenin and its apoptotic induction in human Hep G2 cells. Cancer Lett. 2006, 237, 207-214.
47. Agullo, G.; Gamet-Payrastre, L.; Fernandez, Y.; Anciaux, N.; Demigné, C.; Rémésy, C. Comparative effects of flavonoids on the growth, viability and metabolism of a colonia adenocarcinoma cell line (HT29 cells). Cancer Lett. 1996, 105, 61-70.
48. Kandaswami, C.; Lee, L. T.; Lee, P. P.; Hwang, J. J.; Ke, F. C.; Huang, Y. T.; Lee, M. T. The antitumor activities of flavonoids. In vivo 2005, 19, 895-909.
49. Agullo, G.; Gamet-Payrastre, L.; Manenti, S.; Viala, C.; Rémésy, C.; Chap, H.; Payrastre, B. Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem. Pharmacol. 1997, 53, 1649-1657.
50. Huang, H. C.; Wang, H. R.; Hsieh, L. M. Antiproliferative effect of baicalein, a flavonoid from Chinese herb, on vascular smooth muscle cell. Eur. J. Pharmacol. 1994, 251, 91-93.
51. Sugiyama, S.; Umehara, K.; Kuroyanagi, M.; Ueno, A.; Taki, T. Studies on the differentiation inducers of myeloid leukemic cells from Citrus species. Chem. Pharm. Bull. 1993, 41, 714-719.
52. Ohno, T.; Inoue, M.; Ogihara, Y. Cytotoxic activity of gallic acid against liver metastasis of mastocytoma cells P-815. Anticancer Res. 2001, 21, 3875-3880.
53. Qiu, X.; Takemura, G.; Koshiji, M.; Hayakawa, Y.; Kanoh, M.; Maruyama, R.; Ohno, Y.; Minatoguchi, S.; Akao, S.; Fukuda, K.; Fujiwara, T.; Fujiwara, H. Gallic acid induces vascular smooth muscle cell death via hydroxyl radical production. Heart Vessels 2000, 15, 90-99.
54. Le Bail, J. C.; Varnat, F.; Nicolas, J. C.; Habrioux, G. Estrogenic and antiproliferative activities on MCF-7 human breast cancer cells by flavonoids. Cancer Lett. 1998, 130, 209-216.
55. Brownson, D. M.; Azios, N. G.; Fuqua, B. K.; Dharmawardhane, S. F.; Mabry T. J. Flavonoids effects relevant to cancer. J. Nutr. 2002, 132, 3482S-3489S.
56. Pan, M. H.; Chen, W. J.; Lin-Shiau, S. Y.; Ho, C. T.; Lin, J. K. Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis 2002, 23, 1677-1684.
57. Sherr, C. J. Cancer cell cycles. Science 1996, 274, 1672-1677.
58. Lepley, D. M.; Li, B.; Birt, D. F.; Pelling, J. C. The chemopreventive flavonoid apigenin induces G2/M arrest in keratinocytes. Carcinogenesis 1996, 17, 2367-2375.
59. Sato, F.; Matsukawa, Y.; Matsumoto, K.; Nishino, H.; Sakai, T. Apigenin induces morphological differentiation and G2-M arrest in rat neuronal cells. Biochem. Biophs. Res. Commun. 1994, 204, 578-584.
60. Liu, H; Radisky, D. C.; Nelson, C. M.; Zhang, H.; Fata, J. E.; Roth, R. A.; Bissell, M. Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. Proc. Natl. Acad. Sci. USA 2006, 103, 4134-4139.
61. Caltagirone, S.; Rossi, C.; Poggi, A.; Ranelletti, F. O.; Natali, P. G.; Brunetti, M.; Aiello, F. B.; Piantelli, M. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. J. Cancer 2000, 87, 595-600.
62. Rooprai, H. K.; Kandanearatchi, A.; Maidment, S. L.; Christidou, M.; Trillo-Pazos, G.; Dexter, D. T.; Rucklidge, G. J.; Widmer, W.; Pilkington, G. J. Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro. Neuropath. Appl. Neuro. 2001, 27, 29-39.
63. Minagawa, A.; Otani, Y.; Kubota, T.; Wada, N.; Furukawa, T.; Kumai, K.; Kameyame, K.; Okada, Y.; Fujii, M.; Yano, M.; Sato, T.; Ito, A.; Kitajima, M. The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice. Jpn. J. Cancer Res. 2001, 92, 1322-1328.
64. Vijayababu, M. R.; Arunkumar, A.; Kanagaraj, P.; Venkataraman, P.; Krishnamoorthy, G.; Arunakaran, J. Quercetin downregulates matrix metalloproteinases 2 and 9 proteins expression in prostate cancer cells (PC-3). Mol. Cell. Biochem. 2006, 287, 109-116.
65. Bracke, M. E.; Vyncke, B. M.; Van Larebeke, N. A.; Bruyneel, E. A.; De Bruyne, G. K.; De Pestel, G. H.; De Coster, W. J.; Espeel, M. F.; Mareel, M. M. The flavonoid tangeretin inhibits invasion of MO4 mouse cells into embryonic chick heart in vitro. Clin. Exp. Metastas. 1989, 7, 283-300.
66. Czyz, J.; Madeja, Z.; Irmer, U.; Korohoda, W.; Hulser, D. F. Flavonoid apigenin inhibits motility and invasiveness of carcinoma cells in vitro. Cancer Cell Biol. 2004, 114, 12-18.
67. Lee, W. J.; Wu, L. F.; Chen, W. K.; Wang, C. J.; Tseng, T. H. Inhibitory effect of luteolin on hepatocyte growth factor/scatter factor-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K-Akt pathways. Chem.-Biol. Interact. 2006, 160, 123-133.
68. Gath, L.; Nicolson, G. L.; Dulski, K. Organ specificty of metastatic tumor colonization is related to organ-selective growth properties of malignant cells. Int. J. Cancer 1986, 38, 289-294.
69. Horn-Ross, P. L. Melanoma in the Greater San Francisco Bay Area 1988-2000. Northern California Cancer Center (serial online) 2003. In: URL: http://www.nccc.org/pdf/poc/melanoma_factsheet_88- 2000.pdf.
70. Lentini, A.; Kleinman, H. K.; Mattioli, V.; Autuori-Pezzoli, V.; Nicolini, L.; Pietrini, A.; Abbruzzese, A.; Cardinali, M.; Beninati, S. Inhibition of melanoma pulmonary metastasis by methylxanthines due to decreased invasión and proliferation. Melanoma Res. 1998, 8, 131-137.
71. Menon, L. G.; Kuttan, R.; Kuttan, G. Anti-metastatic activity of curcumin and catequina. Cancer Lett. 1999, 141, 159-165.
72. Tanaka, T.; Kohno, H.; Murakami, M.; Kagami, S.; El-Bayoumy, K. Suppressing effects of dietary supplementation on organoselenium 1,4-Phenylenbis (methylene) selenocyanate and citrus antioxidant auraptene on lung metastasis of melanoma cells in mice. Cancer Res. 2000, 60, 3713-3716.
73. Yoshikawa, N.; Nakamura, K.; Yamaguchi, Y.; Kagota, S.; Shinozuka, K.; Kunitomo, M. Suitable indices for evaluating the intensity of tumor metastasis in a mouse experimental metastatic model. In vivo 2001, 15, 485-488.
74. Fuzii, H. T.; Travassos, L. R. Transiente resistance to B16F10 melanoma growth and metastasis in CD43 -/-mice. Melanoma Res. 2002, 12, 9-16.
75. Ikeda, K.; Yoshimichi, S.; Nagase, H. Inhibitory effect of Magnolol on tumor metastasis in mice. Phytother. Res. 2003, 17, 933-937.
76. Lentini, A.; Autuoria, F.; Mattiolia, P.; Caragliab, M.; Abbruzzeseb, A.; Beninati, S. Evaluation of the efficacy of potential antineoplastic drugs on tumour metastasis by a computer-assisted image analysis. Eur. J. Cancer 2000, 36, 1572-1577.
77. Spitzer, J. H.; Nunez, N. P.; Meadwos, S. A.; Galluci, R. M.; Meadows, G. G. The modulation of B16BL6 melanoma metastasis is not directly mediated by cytolytic activity of natural killer cells in alcohol-consuming mice. Alcohol. Clin. Exp. Res. 2000, 24, 837-844.
78. Blank, S. E.; Meandows, G. G. Ethanol modules metastatic potential of B16Bl6 melanoma and host responses. Alcohol. Clin. Exp. Res. 1996, 20, 624-628.
79. Silberman, S.; McGarvey, T. W.; Comrie, E.; Perky, B. The influence of ethanol on cell membrane fluidity, migration, and invasion of murine membrane cells. Exp. Cell Res. 1990, 189, 64-68.
80. Zhu, Y.; Lin, H.; Wanz, M.; Li, Z.; Wiggins, R.; Luo, Y. Up-regulation of trascription of smooth muscle myosin alkali light chain by ethanol in human breast cancer cells. Int. J. Oncol. 2001, 18, 1299-1305.
81. Tanbengwa, E. M.; Grenett, H. E.; Benza, R. L.; Abou-Agag, L. H.; Trenak, J. K.; Wheeler, C. G.; Booyse, F. M. Ethanol induced up regulation of the urokinase receptor in cultured human endothelial cells. Alcohol. Clin. Exp. Res. 2001, 25, 163-170.
82. Visioli, F.; Borsani, L.; Galli, C. Diet and prevention of coronary heart disease. The potential role of phytochemicals. Cardiovasc. Res. 2000, 47, 419-425.
83. Nogata, Y.; Ohta, H.; Sumida, T.; Sekiya, K. Effect of extraction method on the concentrations of selected bioactive compounds in mandarin juice. J. Agr. Food Chem. 2003, 51, 7346-7351.
84. Haenen, G. R.; Paquay, J. B.; Korthouwere, R. E.; Bast, A. Peroxynitrile scavenging by flavonoids. Biochem. Biophs. Res. Commun. 1997, 236, 591-593.
85. Huang, Y. T.; Hwang, J. J.; Lee, P. P.; Ke, F. C.; Huang, J. H.; Huang, C. J.; Kandaswami, C.; Middleton, E., Jr.; Lee, M. T. Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br. J. Pharmacol. 1999, 128, 999-1010.
86. Yang, K.; Lamprecht, S. A.; Liu, Y.; Shinozaki, H.; Fan, K.; Leung, D.; Newmark, H.; Steele, V. E.; Kelloff, G. J.; Lipkin, M. Chemoprevention studies of the flavonoids quercetin and rutin in normal and azoxymethane-treated mouse colon. Carcinogenesis 2000, 21, 1655-1660.
87. Menon, L. G.; Kuttan, R.; Kuttan, G. Inhibition of lung metastasis in mice induced by B16F10 melanoma cells by polyphenolic compounds. Cancer Lett. 1995, 95, 221-225.
88. Zheng, Q.; Hirose, Y.; Yoshimi, N.; Murakami, A.; Koshimizu, K.; Ohigashi, H.; Sakata, K.; Matsumoto, Y.; Sayama, Y.; Mori, H. Further investigation of the modifying effect of various chemopreventive agents on apoptosis and cell proliferation in human colon cancer cells. J. Cancer Res. Clin. Oncol. 2002, 128, 539-546.
89. Tanaka, T.; Makita, H.; Kawabata, K.; Mori, H.; Kakumoto, M.; Satoh, K.; Hara, A.; Sumida, T.; Tanaka, T.; Ogawa, H. Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring flavonoids, diosmin and hesperidin. Carcinogenesis 1997, 18, 957-965.
90. Tanaka, T.; Makita, H.; Ohnishi, M.; Mori, H.; Satoh, K.; Hara, A.; Sumida, T.; Fukutani, K.; Tanaka, T.; Ogawa, H. Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rats by flavonoids diosmin and hesperidin, each alone and in combination. Cancer Res. 1997, 57, 246-252.
91. Yang, M.; Tanaka, T.; Hirose, Y.; Deguchi, T.; Mori, H.; Kawada, Y. Chemopreventive effects of diosmin and hesperidin on N-butyl-N-(4- hydroxybutyl) nitrosamine-induced urinary-bladder carcinogenesis in male ICR mice. Int. J. Cancer 1997, 73, 719-724.
92. Lyseng-Williamson, K. A.; Perry, C. M. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs 2003, 63, 71-100.
93. Pickelmann, S.; Nolte, D.; Leiderer, R.; Mollmann, M.; Schutze, E.; Messmer, K. Effects of the phlebotropic drug Daflon 500 mg on postischemic reperfusion injury in striated skin muscle: a histomorphologic study in the hamster. J. Lab. Clin. Med. 1999, 134, 536-545.
94. Korthui, R. J.; Gute, D. C. Anti-inflammatory actions of a micronized, purified flavonoid fraction in ischemia/reperfusion. Adv. Exp. Med. Biol. 2002, 505, 181-190.
95. Coleridge-Smith, P. D. From skin disorders to venous leg ulcers: pathophysiology and efficacy of Daflon 500 mg in ulcer healing. Angiology 2003, 54, S45-S50.
96. Kroon, P. A.; Clifford, M. N.; Crozier, A.; Day, A. J.; Donovan, J. L.; Manach, C.; Williamson, G. How should we assess the effects of exposure to dietary polyphenols in vitro? Am. J. Clin. Nutr. 2004, 80, 15-21.
97. Perego, R.; Beccaglia, P.; Angelini, M.; Villa, P.; Cova, D. Pharmacokinetic studies of diosmin and diosmetin in perfused rat liver. Xenobiotica 1993, 23, 1345-1352.
98. Cova, D.; De Angelis, L.; Giavarini, F.; Palladini, G.; Perego, R. Pharmacokinetics and metabolism of oral diosmin in healthy volunteers. Int. J. Clin. Pharmacol. Ther. Toxicol. 1992, 30, 29-33.
99. Nielsen, S. E.; Breinholt, V.; Justesen, U.; Cornett, C.; Dragsted, L. O. in vitro biotransformation of flavonoids by rat liver microsomes. Xenobiotica 1998, 28, 389-401.
100. Nielsen, S. E.; Breinholt, V.; Cornett, C.; Dragsted, L. O. Biotransformation of the citrus flavone tangeretin in rats. Identification of metabolites with intact flavone nucleus. Food Chem. Toxicol. 2000, 38, 739-746.
101. Manach, C.; Texier, O.; Morand, C.; Crespy, V.; Regerat, F.; Demigne, C.; Remesy, C. Comparison of the bioavailability of quercetin and catechin in rats. Free Radic. Biol. Med. 1999, 27, 1259-1266.
102. Guerrero, J. A.; Lozano, M. A.; Castillo, J.; Benavente-García, O.; Vicente, V.; Rivera, J. Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor. J. Thromb. Haemostas. 2005, 2, 1-8.
103. Huag, Y. T.; Hwang, J. J.; Lee, P. P.; Ke, F. C.; Huang, J. H.; Huang, C. J.; Kandaswami, C.; Middleton, E.; Lee, M. T. Effects of luteolin and quercetin, inhibitors of tyrosine kinase on cell growth and metastasis- associated properties in A431 cells overexpressing epidermal growth factor receptor. Br. J. Pharmacol. 1999, 128, 999-1010. *Nueva Indexar.
104. Carmeliet, P.; Jain, R. K. Angiogenesis in cancer and other diseases. Nature 2000, 407(6801), 249-257.
105. Dulak, J.; Jozkowicz, A. Anti-angiogenic and anti-inflammatory effects of statins: relevance to anti-cancer therapy. Curr. Cancer Drug Targets 2005, 5, 579-594.
106. Carmeliet, P. Angiogenesis in health and disease. Nat. Med. 2003, 9, 653-660.
107. Singh, R. P.; Agarwal, R. Tumor angiogenesis: a potential target in cancer control by phytochemicals. Curr. Cancer Drug Targets 2003, 3, 205-217.
108. Folkman, J.; Merler, E.; Abernathy, C.; Williams, G. Isolation of a tumor factor responsible of angiogenesis. J. Exp. Med. 1971, 133, 275-288.
109. Woodhouse, E. C.; Chuaqui, R. F.; Liotta, L. A. General mechanisms of metastasis. Cancer 1997, 80, 1529-1537.
110. Ferrara, N.; Alitalo, K. Clinical applications of angiogenic growth factors and their inhibitors. Nat. Med. 1999, 5, 1359-1364.
111. Tosseti, F.; Ferrari, N.; De Flora, S.; Albini, A. " Angioprevention": angiogenesis is a common and key target for cancer chemoprotective agents. FASEB J. 2002, 16, 2-14.
112. Ferrara, N. VEGF: an update on biological and therapeutic aspects. Curr. Opin. Biotechnol. 2000, 11, 617-624.
113. Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorogenesis. Cell 1996, 86, 353-364.
114. Folkman, J. Incipient angiogenesis. J. Natl. Cancer Inst. 2000, 92, 94-95.
115. Szatrowsky, T. P.; Nathan, C. F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991, 51, 794-798.
116. Shono, T.; Ono, M.; Izumi, H.; JImi, S.; Matsushima, K.; Okamoto, T.; Cono, K.; Kuwano, M. Involvement of the transcription factor NFκB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress. Mol. Cell Biol.1996, 16, 4231-4239.
117. Liu, X. H.; Kirschenbaum, A.; Yao, S.; Lee, R.; Holland, J. F.; Levine, A. C. Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo. J. Urology 2000, 164, 820-825.
118. Masferrer, J. L.; Leahy, K. M.; Koki, A. T.; Zweifel, B. S.; Settle, S. L.; Woernet, B. M.; Edwards, D. A.; Flickinger, A. G.; Moore, R. J.; Seibert, K. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000, 60, 1306-1331.
119. Oshima, M.; Dinchuck, J. E.; Kargman, S. L.; Oshima, H.; Hancock, B.; Kwong, E.; Trzaskos, J. M.; Evans, J. F.; Taketo, M. M. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase-2 (COX-2). Cell 1996, 87, 803-809.
120. Ryter, S. W.; Tyrrell, R. M. Synglet molecular oxygen ((1)O2): a possible effector of eukaryotic gene expression. Free Radic. Biol. Med. 1998, 24, 1520-1534.
121. Burdon, R. H. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic. Biol. Med. 1994, 18, 775-794.
122. Nie, D.; Krishnamoorthy, S.; Jin, R.; Tang, K.; Chen, Y.; Qiao, Y.; Zacharek, A.; Guo, Y.; Milanini, J.; Pages, G.; Honn, K. V. Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells. J. Biol. Chem. 2006, 281, 18601-18609.
123. Pages, G.; Milanini, J.; Richard, D. E.; Berra, E.; Gothie, E.; Vinals, F.; Pouyssegur, J. Signaling angiogenesis via p42/p44 MAP kinase cascade. Ann. N.Y. Acad. Sci. 2000, 902, 187-200.
124. Pipili-Synetos, E.; Sakkoula, E.; Haralabopoulos, G.; Andriopoulou, P.; Peristeris, P.; Maragoudakis, M. E. Evidence that nitric oxide is an endogenous antiangiogenic mediator. Br. J. Pharmacol. 1994, 111, 894-902.
125. Gallo, O.; Massini, E.; Morbidelli, L.; Franchi, A.; Fini-Storchi, I.; Vergari, W. A.; Ziche, M. Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J. Natl. Cancer Inst. 1998, 90, 587-596.
126. Fukumura, D.; Gohongi, T.; Kadambi, A.; Izumi, Y.; Ang, J.; Yun, C. O.; Buerk, D. G.; Huang, P. L.; Jain, R. K. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc. Natl. Acad. Sci. USA 2001, 98, 2604-2609.
127. Stetler-Stevenson, W. G.; Yu, A. E. Proteases in invasion: matrix metalloproteinases. Semin. Cancer Biol. 2001, 11, 143-153.
128. Cai, T.; Fassina, G. F.; Giunciuglio, D.; Moroni, M.; Aluigi, M. G.; Masiello, L.; Fontanini, S.; D'Agostini, F.; De Flora, S.; Noonan, D. M.; Albini, A. N-acetylcysteine inhibits endothelial cell invasion and angiogenesis while protecting from apoptosis. Lab. Investig. 1999, 79, 1151-1159.
129. Kleinman, H. K.; Koblinsky, J.; Lee, S.; Engbring, J. Role of basement membrane in tumor growth and metastasis. Surg. Oncol. Clin. N. Am. 2001, 10, 329-338.
130. Lippman, S. L.; Matrisian, L. M. Protease inhibitors in oral carcinogenesis and chemoprevention. Clin. Cancer Res. 2000, 6, 4599-4603.
131. Shweiki, D.; Itin, A.; Soffer, D.; Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992, 359, 853-845.
132. Zhu, Z.; Bohlen, P.; Witte, L. Clinical development of angiogenesis inhibitors to vascular endothelial growth factor and its receptors as cancer therapeutics. Curr. Cancer Drug Targets 2002, 2, 135-156.
133. Forsythe, J. A.; Jiang, B. H.; Iyer, N. V.; Agani, F.; Leung, S. W.; Koos, R. D.; Semenza, G. L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell Biol. 1996, 4605-4613.
134. Semenza, G. L. HIF-1 and mechanisms of hypoxia sensing. Curr. Opin. Cell Biol. 2001, 13, 167-171.
135. Tosseti, F.; Noonan, D. M.; Albini, A. Choking hypoxia-inducible factor 1α: a novel mechanism for connective tissue growth factor inhibition of angiogenesis. J. Natl. Cancer Inst. 2006, 14, 946-948.
136. Wang, G. L.; Semenza, G. L. Purification and characterization of hypoxiainducible factor 1. J. Biol. Chem. 1995, 270, 1230-1237.
137. Semenza, G. L. HIF-1 and human disease: one highly involved factor. Genes Dev. 2000, 14, 1983-1991.
138. Hajitou, A.; Sounni, N. E.; Devy, L.; Grignet-Debrus, C.; Lewalle, J. M.; Li, H.; Deroanner, C. F.; Lu, H.; Colige, A.; Nusgens, B. V.; Frankenne, F.; Maron A.; Yeh, P.; Perricaudet, M.; Chang, Y.; Soria, C.; Calberg-Becq, C.M.; Foidart, J. M.; Noel, A. Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis. Cancer Res. 2001, 61, 3450-3457.
139. Hajitou, A.; Grignet-Debrus, C.; Devy, L.; Bernd, S.; Blancher, S.; Deroanner, C. F.; Bajou, K.; Fong, T.; Chiang, Y.; Foidart, J. M.; Noel, A. MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J. 2002, 16, 1802-1804.
140. Lu, D.; Jimenez, X.; Zhang, H.; Wu, Y.; Bohlen, P.; Witte, L.; Zhu, Z. Complete inhibition of vascular endothelial growth factor (VEGF) activities with a bifunctional diabody directed against both VEGF kinase receptors, fms-like tyrosine kinase receptor and kinase insert domain-containing receptor. Cancer Res. 2001, 61, 7002-7008.
141. Shaleen, R. M.; Tseng, W. W.; Davis, D. W.; Liu, W.; Reinmuth, N.; Vellagas, R.; Wieczorek, A. A.; Ogura, Y.; McConkey, D. J.; Drazan, K. E.; Bucana, C. D.; McMahon, G.; Ellis, L. M. Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res. 2001, 61, 1464-1468.
142. Lin, B.; Podar, K.; Gupta, D.; Tai, Y. T.; Li, S.; Weller, E.; Hideshima, T.; Lentzsch, S.; Davies, F.; Li, C.; Weisberg, E.; Schlossman, R. L.; Richardson, P. G.; Griffin, J. D.; Wood, J.; Munshi, N. C.; Anderson, K. C.; The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2002, 62, 5019-5026.
143. Albini, A.; Tosetti, F.; Benelli, R.; Noonan, D. M. Tumor inflammatory angiogenesis and its chemoprevention. Cancer Res. 2005, 65, 10637-10641.
144. Schindler, R.; Mentlein, R. Flavonoids and vitamin E reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells. J. Nutr. 2006, 136, 1477-1482.
145. Pepper, M. S.; Hazel, S. J.; Humpel, M.; Schleuning, W. D. 8-prenylnaringenin, a novel phytoestrogen, inhibits angiogenesis in vitro and vivo. J. Cell Physiol. 2004, 199, 98-107.
146. Tan, W. F.; Lin, L. P.; Li, M. H.; Zhang, Y. X.; Tong, Y. G.; Xiao, D.; Ding, J. Quercetin, a dietary-derived flavonoid, possesses antiangiogenic potential. Eur. J. Pharmacol. 2003, 459, 255-262.
147. Hasebe, Y.; Egawa, K.; Yamazaki, Y.; Kunimoto, S.; Hirai, Y.; Ida, Y.; Nose, K. Specific inhibition of hypoxia-inducible factor (HIF)-1α activation and of vascular endothelial growth factor (VEGF) production by flavonoids. Biol. Pharmacol. Bull. 2003, 26, 1379-1383.
148. Kim, J. D.; Liu, L.; Guo, W.; Meydani, M. Chemical structure of flavonoids in relation to modulation of angiogenesis and immune-endothelial cell adhesion. J. Nutr. Biochem. 2006, 17, 165-176.
149. Fotsis, T.; Pepper, M. S.; Montesano, R.; Aktas, E.; Breit, S.; Schweigerer, L.; Rasku, S.; Wahala, K.; Adlercreutz, H. Phytoestrogens and inhibition of angiogenesis. Baillieres Clin. Endocrinol. Metab. 1998, 12, 649-666.
150. Fotsis, T.; Pepper, M. S.; Aktas, E.; Breit, S.; Rasku, S.; Adlercreutz, H.; Wahala, K.; Montesano, R.; Schweigerer, L.; Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res. 1997, 57, 2916-2921.
151. Trochon, V.; Blot, E.; Cymbalista, F.; Engelmann, C.; Tang, R. P.; Thomaidis, A.; Vasse, M.; Soria, J.; Lu, H.; Soria, C. Apigenin inhibits endothelial-cell proliferation in G(2)/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression. Int. J. Cancer 2000, 85, 691-696.
152. Kim M. H. Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases. J. Cell Biochem. 2003, 89, 529-538.
153. Osada, M.; Imaoka, S.; Funae, Y. Apigenin supresses the expresión of VEGF, an important factor for angiogenesis, in endotelial cells via degradation of HIF-1alpha protein. FEBS Lett. 2004, 575, 59-63.
154. Fang, J.; Xia, Ch., Cao, Z.; Zheng. J. Z.; Reed, E.; Jiang, B. H. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 2005, 19, 342-353.
155. Liu, L. Z.; Fang, J.; Zhou, Q.; Hu, X.; Shi, X.; Jiang, B. H. Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: implication of chemoprevention of lung cancer. Mol. Pharmacol. 2005, 68, 635-643.
156. Fang, J.; Zhou, Q.; Liu, L. Z.; Xia, C.; Hu, X.; Shi, X.; Jiang, B. H. Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. Carcinogenesis 2006, [Epub ahead of print]PMID: 17071632.
157. Engelmann, C.; Blot, E.; Panis, Y.; Bauer, S.; Trochon, V.; Nagy, H. J.; Lu, H.; Soria, C. apigenin-strong cytostatic and anti-angiogenic action in vitro contrasted by lack of efficacy in vivo. Phytomedicine 2002, 9, 489-495.
158. Donnini, S.; Finetti, F.; Lusini, L.; Morbidelli, L.; Cheynier, V.; Barron, D.; Williamson, G.; Waltenberger J.; Ziche, M. Divergent effects of quercetin conjugates on angiogenesis. Br. J. Nutr. 2006, 95, 1016-1023.