Silibinin inhibits VEGF secretion and age-related macular degeneration in a hypoxia-dependent manner through the PI-3 kinase/Akt/mTOR pathway

British Journal of Pharmacology

Volumn 168, Issue 4, 2013, Pages 920-931

  Lin, C H ^a   Li, C H ^a,b   Liao, P L ^c   Tse, L S ^a   Huang, W K ^a   Cheng, H W ^a   Cheng, Y W ^a  

^a TAIPEI MEDICAL UNIVERSITY   (Taiwan)

^b TAIPEI MEDICAL UNIVERSITY   (Taiwan)

^c NATIONAL TAIWAN UNIVERSITY   (Taiwan)

Author keywords

age related macular degeneration; HIF 1 ; hypoxia; neovascularization; silibinin

Indexed keywords

HYPOXIA INDUCIBLE FACTOR 1ALPHA; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROCOLLAGEN PROLINE 2 OXOGLUTARATE 4 DIOXYGENASE; PROLINE HYDROXYLASE 2; PROTEIN KINASE B; SILIBININ; UNCLASSIFIED DRUG; VASCULOTROPIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BIOACCUMULATION; BROWN NORWAY RAT; CELL HYPOXIA; CONTROLLED STUDY; DOWN REGULATION; DRUG EFFECT; FLUORESCENCE ANGIOGRAPHY; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; PIGMENT EPITHELIUM; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN SYNTHESIS INHIBITION; RAT; RETINA EDEMA; RETINA MACULA AGE RELATED DEGENERATION; SUBRETINAL NEOVASCULARIZATION; TREATMENT RESPONSE; WESTERN BLOTTING;

ANGIOGENESIS INHIBITORS; ANIMALS; ANOXIA; AUTOPHAGY; BLOTTING, WESTERN; CELL HYPOXIA; CELLS, CULTURED; DISEASE MODELS, ANIMAL; EPITHELIAL CELLS; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; MACULAR DEGENERATION; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; RATS; RATS, INBRED BN; RETINAL PIGMENT EPITHELIUM; SIGNAL TRANSDUCTION; SILYMARIN; TOR SERINE-THREONINE KINASES; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84872957049     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2012.02227.x     Document Type: Article

References (52)

1. Abdel-Rahman MH, Yang Y, Salem MM, Meadows S, Massengill JB, Li PK, et al. (2010). Investigation of the potential utility of a linomide analogue for treatment of choroidal neovascularization. Exp Eye Res 91: 837-843.
2. Abu El-Asrar AM, Nawaz MI, Kangave D, Siddiquei MM, Ola MS, Opdenakker G, (2011). Angiogenesis regulatory factors in the vitreous from patients with proliferative diabetic retinopathy. Acta Diabetol (in press).
3. Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW, (1999). Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 274: 23463-23467.
4. Arjamaa O, Nikinmaa M, Salminen A, Kaarniranta K, (2009). Regulatory role of HIF-1alpha in the pathogenesis of age-related macular degeneration (AMD). Ageing Res Rev 8: 349-358.
5. Befani CD, Vlachostergios PJ, Hatzidaki E, Patrikidou A, Bonanou S, Simos G, et al. (2012). Bortezomib represses HIF-1alpha protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells. J Mol Med (Berl) 90: 45-54.
6. Beinhardt S, Rasoul-Rockenschaub S, Scherzer TM, Ferenci P, (2011). Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C. J Hepatol 54: 591-592; author reply 592-593.
7. Bird AC, (2010). Therapeutic targets in age-related macular disease. J Clin Invest 120: 3033-3041.
8. Caldwell RB, Bartoli M, Behzadian MA, El-Remessy AE, Al-Shabrawey M, Platt DH, et al. (2005). Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress. Curr Drug Targets 6: 511-524.
9. Canales RD, Luo Y, Willey JC, Austermiller B, Barbacioru CC, Boysen C, et al. (2006). Evaluation of DNA microarray results with quantitative gene expression platforms. Nat Biotechnol 24: 1115-1122.
10. Cao R, Jensen LD, Soll I, Hauptmann G, Cao Y, (2008). Hypoxia-induced retinal angiogenesis in zebrafish as a model to study retinopathy. PLoS ONE 3: e2748.
11. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB, (1987). Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47: 936-942.
12. Chen L, Endler A, Shibasaki F, (2009). Hypoxia and angiogenesis: regulation of hypoxia-inducible factors via novel binding factors. Exp Mol Med 41: 849-857.
13. Cheung CW, Gibbons N, Johnson DW, Nicol DL, (2010). Silibinin-A promising new treatment for cancer. Anticancer Agents Med Chem 10: 186-195.
14. Chung EK, Stadler WM, (2008). Vascular endothelial growth factor pathway-targeted therapy as initial systemic treatment of patients with renal cancer. Clin Genitourin Cancer 6 (Suppl. 1): S22-S28.
15. DeClerck K, Elble RC, (2010). The role of hypoxia and acidosis in promoting metastasis and resistance to chemotherapy. Front Biosci 15: 213-225.
16. Edelman JL, Castro MR, (2000). Quantitative image analysis of laser-induced choroidal neovascularization in rat. Exp Eye Res 71: 523-533.
17. Fan S, Li L, Chen S, Yu Y, Qi M, Tashiro S, et al. (2011). Silibinin induced-Autophagic and apoptotic death is associated with an increase in reactive oxygen and nitrogen species in HeLa cells. Free Radic Res 45: 1307-1324.
18. Fenton TR, Gout IT, (2011). Functions and regulation of the 70kDa ribosomal S6 kinases. Int J Biochem Cell Biol 43: 47-59.
19. Garcia-Maceira P, Mateo J, (2009). Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy. Oncogene 28: 313-324.
20. Gonzalez Viejo I, Ferrer Novella C, Pueyo Royo V, (2011). [Use of anti-VEGF (anti-vascular endothelial growth factor) in retinopathy of prematurity (ROP)]. Arch Soc Esp Oftalmol 86: 207-208.
21. Gu M, Singh RP, Dhanalakshmi S, Agarwal C, Agarwal R, (2007). Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice. Cancer Res 67: 3483-3491.
22. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. (2002). Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8: 128-135.
23. Halper J, (2010). Growth factors as active participants in carcinogenesis: a perspective. Vet Pathol 47: 77-97.
24. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, et al. (2002). Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22: 7004-7014.
25. Jiang H, Zhu YS, Xu H, Sun Y, Li QF, (2010). Inflammatory stimulation and hypoxia cooperatively activate HIF-1α in bronchial epithelial cells: involvement of PI3K and NF-κB. Am J Physiol Lung Cell Mol Physiol 298: L660-L669.
26. Jing Y, Liu LZ, Jiang Y, Zhu Y, Guo NL, Barnett J, et al. (2012). Cadmium increases HIF-1 and VEGF expression through ROS, ERK, and AKT signaling pathways and induces malignant transformation of human bronchial epithelial cells. Toxicol Sci 125: 10-19.
27. Kaur M, Agarwal R, (2007). Silymarin and epithelial cancer chemoprevention: how close we are to bedside? Toxicol Appl Pharmacol 224: 350-359.
28. Kernt M, Neubauer AS, Liegl RG, Hirneiss C, Alge CS, Wolf A, et al. (2010). Sorafenib prevents human retinal pigment epithelium cells from light-induced overexpression of VEGF, PDGF and PlGF. Br J Ophthalmol 94: 1533-1539.
29. Klein R, Klein BE, Knudtson MD, Meuer SM, Swift M, Gangnon RE, (2007). Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology 114: 253-262.
30. Klein R, Chou CF, Klein BE, Zhang X, Meuer SM, Saaddine JB, (2011). Prevalence of age-related macular degeneration in the US population. Arch Ophthalmol 129: 75-80.
31. Kolar P, Gaber T, Perka C, Duda GN, Buttgereit F, (2011). Human early fracture hematoma is characterized by inflammation and hypoxia. Clin Orthop Relat Res 469: 3118-3126.
32. Li H, Ge C, Zhao F, Yan M, Hu C, Jia D, et al. (2011). Hypoxia-inducible factor 1 alpha-Activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin beta1 signaling in human hepatocellular carcinoma. Hepatology 54: 910-919.
33. Luangdilok S, Box C, Harrington K, Rhys-Evans P, Eccles S, (2011). MAPK and PI3K signalling differentially regulate angiogenic and lymphangiogenic cytokine secretion in squamous cell carcinoma of the head and neck. Eur J Cancer 47: 520-529.
34. Manalo KB, Choong PF, Becerra SP, Dass CR, (2011). Pigment epithelium-derived factor as an anticancer drug and new treatment methods following the discovery of its receptors: a patent perspective. Expert Opin Ther Pat 21: 121-130.
35. Mayer KE, Myers RP, Lee SS, (2005). Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat 12: 559-567.
36. Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, et al. (2009). Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 284: 16767-16775.
37. Mozaffarieh M, Schotzau A, Josifova T, Flammer J, (2009). The effect of ranibizumab versus photodynamic therapy on DNA damage in patients with exudative macular degeneration. Mol Vis 15: 1194-1199.
38. Noh EM, Yi MS, Youn HJ, Lee BK, Lee YR, Han JH, et al. (2011). Silibinin enhances ultraviolet B-induced apoptosis in mcf-7 human breast cancer cells. J Breast Cancer 14: 8-13.
39. Oh EJ, Park K, Choi JS, Joo CK, Hahn SK, (2009). Synthesis, characterization, and preliminary assessment of anti-Flt1 peptide-hyaluronate conjugate for the treatment of corneal neovascularization. Biomaterials 30: 6026-6034.
40. Salminen A, Kauppinen A, Hyttinen JM, Toropainen E, Kaarniranta K, (2010). Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization. Mol Med 16: 535-542.
41. Sawada O, Miyake T, Kakinoki M, Sawada T, Kawamura H, Ohji M, (2010). Aqueous vascular endothelial growth factor after intravitreal injection of pegaptanib or ranibizumab in patients with age-related macular degeneration. Retina 30: 1034-1038.
42. Schnell CR, Stauffer F, Allegrini PR, OReilly T, McSheehy PM, Dartois C, et al. (2008). Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 68: 6598-6607.
43. Shenoy SK, Han S, Zhao YL, Hara MR, Oliver T, Cao Y, et al. (2012). beta-Arrestin1 mediates metastatic growth of breast cancer cells by facilitating HIF-1-dependent VEGF expression. Oncogene 31: 282-292.
44. Singh RP, Gu M, Agarwal R, (2008). Silibinin inhibits colorectal cancer growth by inhibiting tumor cell proliferation and angiogenesis. Cancer Res 68: 2043-2050.
45. Skondra D, Noda K, Almulki L, Tayyari F, Frimmel S, Nakazawa T, et al. (2008). Characterization of azurocidin as a permeability factor in the retina: involvement in VEGF-induced and early diabetic blood-retinal barrier breakdown. Invest Ophthalmol Vis Sci 49: 726-731.
46. Sudhagar S, Sathya S, Lakshmi BS, (2011). Rapid non-genomic signalling by 17beta-oestradiol through c-Src involves mTOR-dependent expression of HIF-1alpha in breast cancer cells. Br J Cancer 105: 953-960.
47. Taylor AC, Seltz LM, Yates PA, Peirce SM, (2010). Chronic whole-body hypoxia induces intussusceptive angiogenesis and microvascular remodeling in the mouse retina. Microvasc Res 79: 93-101.
48. Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, et al. (2006). Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12: 122-127.
49. Tobe T, Okamoto N, Vinores MA, Derevjanik NL, Vinores SA, Zack DJ, et al. (1998). Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci 39: 180-188.
50. Varghese L, Agarwal C, Tyagi A, Singh RP, Agarwal R, (2005). Silibinin efficacy against human hepatocellular carcinoma. Clin Cancer Res 11: 8441-8448.
51. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. (2000). Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60: 1541-1545.
52. Zi X, Agarwal R, (1999). Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 96: 7490-7495.