The paradoxical pro- and antiangiogenic actions of resveratrol: therapeutic applications in cancer and diabetes

Annals of the New York Academy of Sciences

Volumn 1386, Issue 1, 2016, Pages 3-15

  Kamaleddin, Mohammad Amin ^a  

^a UNIVERSITY OF TEHRAN   (Iran)

Author keywords

angiogenesis; cancer; diabetes; red wine; resveratrol

Indexed keywords

GLYCOGEN SYNTHASE KINASE 3BETA; HEME OXYGENASE 1; HYPOXIA INDUCIBLE FACTOR 1ALPHA; NITRIC OXIDE; REACTIVE OXYGEN METABOLITE; RESVERATROL; THIOREDOXIN; ANGIOGENESIS INHIBITOR; ANGIOGENIC FACTOR; STILBENE DERIVATIVE;

ANGIOGENESIS; ANTIANGIOGENIC ACTIVITY; ARTICLE; BLOOD VESSEL; BREAST CANCER; CHELATION; CONCENTRATION RESPONSE; DIABETES MELLITUS; DIGESTIVE SYSTEM CANCER; DRUG EFFECT; ENZYME ACTIVITY; HUMAN; HYPOXIA; LUNG CANCER; NEOPLASM; NONHUMAN; OXIDATIVE STRESS; OXYGEN CONCENTRATION; PROSTATE CANCER; SKIN CANCER; ANIMAL; DOSE RESPONSE; METABOLISM; NEOPLASMS; PATHOLOGY; VASCULARIZATION;

ANGIOGENESIS INDUCING AGENTS; ANGIOGENESIS INHIBITORS; ANIMALS; DIABETES MELLITUS; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; NEOPLASMS; STILBENES;

EID: 85006790153     PISSN: 00778923     EISSN: 17496632     Source Type: Journal    
DOI: 10.1111/nyas.13283     Document Type: Article

References (131)

1. Ushio-Fukai, M. & Y. Nakamura. 2008. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 266: 37–52.
2. Chung, A.S. & N. Ferrara. 2011. Developmental and pathological angiogenesis. Annu. Rev. Cell Dev. Biol. 27: 563–584.
3. Zhao, Q. & Z. Li. 2015. Angiogenesis. BioMed Res. Int. 2015: 135861
4. Saharinen, P., L. Eklund, K. Pulkki, et al. 2011. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol. Med. 17: 347–362.
5. Weis, S.M. & D.A. Cheresh. 2011. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med. 17: 1359–1370.
6. Patel-Hett, S. & P.A. D'Amore. 2011. Signal transduction in vasculogenesis and developmental angiogenesis. Int. J. Dev. Biol. 55: 353–363.
7. Koch, S., S. Tugues, X. Li, et al. 2011. Signal transduction by vascular endothelial growth factor receptors. Biochem. J. 437: 169–183.
8. Li, H., Z. Yan, J. Zhu, et al. 2011. Neuroprotective effects of resveratrol on ischemic injury mediated by improving brain energy metabolism and alleviating oxidative stress in rats. Neuropharmacology 60: 252–258.
9. Mokni, M., F. Limam, S. Elkahoui, et al. 2007. Strong cardioprotective effect of resveratrol, a red wine polyphenol, on isolated rat hearts after ischemia/reperfusion injury. Arch. Biochem. Biophys. 457: 1–6.
10. Kang, O.H., H.J. Jang, H.S. Chae, et al. 2009. Anti-inflammatory mechanisms of resveratrol in activated HMC-1 cells: pivotal roles of NF-kappaB and MAPK. Pharmacol. Res. 59: 330–337.
11. Yao, J., J.Y. Wang, L. Liu, et al. 2010. Anti-oxidant effects of resveratrol on mice with DSS-induced ulcerative colitis. Arch. Med. Res. 41: 288–294.
12. Kaga, S., L. Zhan, M. Matsumoto, et al. 2005. Resveratrol enhances neovascularization in the infarcted rat myocardium through the induction of thioredoxin-1, heme oxygenase-1 and vascular endothelial growth factor. J. Mol. Cell. Cardiol. 39: 813–822.
13. Wang, H., H. Zhou, Y. Zou, et al. 2010. Resveratrol modulates angiogenesis through the GSK3β/β-catenin/TCF-dependent pathway in human endothelial cells. Biochem. Pharmacol. 80: 1386–1395.
14. Thirunavukkarasu, M., S.V. Penumathsa, S. Koneru, et al. 2007. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic. Biol. Med. 43: 720–729.
15. Simao, F., A.S. Pagnussat, J.H. Seo, et al. 2012. Pro-angiogenic effects of resveratrol in brain endothelial cells: nitric oxide-mediated regulation of vascular endothelial growth factor and metalloproteinases. J. Cereb. Blood Flow Metab. 32: 884–895.
16. Wang, N., S.H. Ko, W. Chai, et al. 2011. Resveratrol recruits rat muscle microvasculature via a nitric oxide-dependent mechanism that is blocked by TNFalpha. Am. J. Physiol. Endocrinol. Metab. 300: E195–E201.
17. Takahashi, S. & Y. Nakashima. 2012. Repeated and long-term treatment with physiological concentrations of resveratrol promotes NO production in vascular endothelial cells. Br. J. Nutr. 107: 774–780.
18. Hung, L.M., M.J. Su & J.K. Chen. 2004. Resveratrol protects myocardial ischemia–reperfusion injury through both NO-dependent and NO-independent mechanisms. Free Radic. Biol. Med. 36: 774–781.
19. Takahashi, S., T. Uchiyama & K.-I. Toda. 2009. Differential effect of resveratrol on nitric oxide production in endothelial f-2 cells. Biol. Pharm. Bull. 32: 1840–1843.
20. Juan, S.H., T.H. Cheng, H.C. Lin, et al. 2005. Mechanism of concentration-dependent induction of heme oxygenase-1 by resveratrol in human aortic smooth muscle cells. Biochem. Pharmacol. 69: 41–48.
21. Yu, H.-P., T.-L. Hwang, P.-W. Hsieh, et al. 2011. Role of estrogen receptor-dependent upregulation of P38 MAPK/heme oxygenase 1 in resveratrol-mediated attenuation of intestinal injury after trauma-hemorrhage. Shock 35: 517–523.
22. Shih, A., F.B. Davis, H.Y. Lin, et al. 2002. Resveratrol induces apoptosis in thyroid cancer cell lines via a MAPK- and p53-dependent mechanism. J. Clin. Endocrinol. Metab. 87: 1223–1232.
23. De Amicis, F., F. Giordano, A. Vivacqua, et al. 2011. Resveratrol, through NF-Y/p53/Sin3/HDAC1 complex phosphorylation, inhibits estrogen receptor alpha gene expression via p38MAPK/CK2 signaling in human breast cancer cells. FASEB J. 25: 3695–3707.
24. Pozo-Guisado, E., M.J. Lorenzo-Benayas & P.M. Fernandez-Salguero. 2004. Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation. Int. J. Cancer 109: 167–173.
25. Dudley, J., S. Das, S. Mukherjee, et al. 2009. Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. J. Nutr. Biochem. 20: 443–452.
26. Wang, H., H. Zhou, Y. Zou, et al. 2010. Resveratrol modulates angiogenesis through the GSK3beta/beta-catenin/TCF-dependent pathway in human endothelial cells. Biochem. Pharmacol. 80: 1386–1395.
27. Thirunavukkarasu, M., S.V. Penumathsa, S. Koneru, et al. 2007. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic. Biol. Med. 43: 720–729.
28. Das, S., C.G. Fraga & D.K. Das. 2006. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB. Free Radic. Res. 40: 1066–1075.
29. Shakibaei, M., A. Mobasheri & C. Buhrmann. 2011. Curcumin synergizes with resveratrol to stimulate the MAPK signaling pathway in human articular chondrocytes in vitro. Genes Nutr. 6: 171–179.
30. Klinge, C.M., N.S. Wickramasinghe, M.M. Ivanova, et al. 2008. Resveratrol stimulates nitric oxide production by increasing estrogen receptor alpha-Src–caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells. FASEB J. 22: 2185–2197.
31. Takahashi, S. & Y. Nakashima. 2012. Repeated and long-term treatment with physiological concentrations of resveratrol promotes NO production in vascular endothelial cells. Br. J. Nutr. 107: 774–780.
32. Hattori, R., H. Otani, N. Maulik, et al. 2002. Pharmacological preconditioning with resveratrol: role of nitric oxide. Am. J. Physiol. Heart Circ. Physiol. 282: H1988–H1995.
33. Chang, H.-C., T.-G. Chen, Y.-T. Tai, et al. 2011. Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells. J. Cereb. Blood Flow Metab. 31: 842–854.
34. Lyons, J.M., 3rd, J.E. Schwimer, C.T. Anthony, et al. 2010. The role of VEGF pathways in human physiologic and pathologic angiogenesis. J. Surg. Res. 159: 517–527.
35. Cisowski, J., A. Loboda, A. Jozkowicz, et al. 2005. Role of heme oxygenase-1 in hydrogen peroxide-induced VEGF synthesis: effect of HO-1 knockout. Biochem. Biophys. Res. Commun. 326: 670–676.
36. Huang, H.M., Y.C. Liang, T.H. Cheng, et al. 2005. Potential mechanism of blood vessel protection by resveratrol, a component of red wine. Ann. N.Y. Acad. Sci. 1042: 349–356.
37. Liu, P.L., J.R. Tsai, A.L. Charles, et al. 2010. Resveratrol inhibits human lung adenocarcinoma cell metastasis by suppressing heme oxygenase 1-mediated nuclear factor-kappaB pathway and subsequently downregulating expression of matrix metalloproteinases. Mol. Nutr. Food Res. 54(Suppl. 2): S196–S204.
38. Yang, R., H. Zhang & L. Zhu. 2011. Inhibitory effect of resveratrol on the expression of the VEGF gene and proliferation in renal cancer cells. Mol. Med. Rep. 4: 981–983.
39. Chen, H.J., L.S. Hsu, Y.T. Shia, et al. 2012. The beta-catenin/TCF complex as a novel target of resveratrol in the Wnt/beta-catenin signaling pathway. Biochem. Pharmacol. 84: 1143–1153.
40. Chen, L., K. Huang, L. Han, et al. 2011. β-Catenin/Tcf-4 complex transcriptionally regulates AKT1 in glioma. Int. J. Oncol. 39: 883–890.
41. Kaga, S., L. Zhan, E. Altaf, et al. 2006. Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. J. Mol. Cell. Cardiol. 40: 138–147.
42. Vergara, D., P. Simeone, D. Toraldo, et al. 2012. Resveratrol downregulates Akt/GSK and ERK signalling pathways in OVCAR-3 ovarian cancer cells. Mol. Biosyst. 8: 1078–1087.
43. Kundu, J.K., K.S. Chun, S.O. Kim, et al. 2004. Resveratrol inhibits phorbol ester-induced cyclooxygenase-2 expression in mouse skin: MAPKs and AP-1 as potential molecular targets. Biofactors 21: 33–39.
44. Klinge, C.M., K.A. Blankenship, K.E. Risinger, et al. 2005. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J. Biol. Chem. 280: 7460–7468.
45. Patel, J., K. Landers, R.H. Mortimer, et al. 2010. Regulation of hypoxia inducible factors (HIF) in hypoxia and normoxia during placental development. Placenta 31: 951–957.
46. Zhang, Q., X. Tang, Q.Y. Lu, et al. 2005. Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells. Mol. Cancer Ther. 4: 1465–1474.
47. Park, S.Y., K.J. Jeong, J. Lee, et al. 2007. Hypoxia enhances LPA-induced HIF-1alpha and VEGF expression: their inhibition by resveratrol. Cancer Lett. 258: 63–69.
48. Wu, H., X. Liang, Y. Fang, et al. 2008. Resveratrol inhibits hypoxia-induced metastasis potential enhancement by restricting hypoxia-induced factor-1 alpha expression in colon carcinoma cells. Biomed. Pharmacother. 62: 613–621.
49. Bian, C.X., Z. Shi, Q. Meng, et al. 2010. P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression. Biochem. Biophys. Res. Commun. 398: 395–399.
50. Callapina, M., J. Zhou, T. Schmid, et al. 2005. NO restores HIF-1alpha hydroxylation during hypoxia: role of reactive oxygen species. Free Radic. Biol. Med. 39: 925–936.
51. Ziche, M. & L. Morbidelli. 2000. Nitric oxide and angiogenesis. J. Neurooncol. 50: 139–148.
52. Gresele, P., P. Pignatelli, G. Guglielmini, et al. 2008. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J. Nutr. 138: 1602–1608.
53. Cho, D.I., N.Y. Koo, W.J. Chung, et al. 2002. Effects of resveratrol-related hydroxystilbenes on the nitric oxide production in macrophage cells: structural requirements and mechanism of action. Life Sci. 71: 2071–2082.
54. Fan, J., H. Cai, S. Yang, et al. 2008. Comparison between the effects of normoxia and hypoxia on antioxidant enzymes and glutathione redox state in ex vivo culture of CD34(+) cells. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 151: 153–158.
55. Jozkowicz, A., A. Nigisch, J. Wegrzyn, et al. 2004. Opposite effects of prostaglandin-J2 on VEGF in normoxia and hypoxia: role of HIF-1. Biochem. Biophys. Res. Commun. 314: 31–38.
56. Messmer-Blust, A., X. An & J. Li. 2009. Hypoxia-regulated angiogenic inhibitors. Trends Cardiovasc. Med. 19: 252–256.
57. Lin, S., K.G. Shyu, C.C. Lee, et al. 2002. Hyperbaric oxygen selectively induces angiopoietin-2 in human umbilical vein endothelial cells. Biochem. Biophys. Res. Commun. 296: 710–715.
58. Peng, Z., P. Ren, Z. Kang, et al. 2008. Up-regulated HIF-1alpha is involved in the hypoxic tolerance induced by hyperbaric oxygen preconditioning. Brain Res. 1212: 71–78.
59. Ren, P., Z. Kang, G. Gu, et al. 2008. Hyperbaric oxygen preconditioning promotes angiogenesis in rat liver after partial hepatectomy. Life Sci. 83: 236–241.
60. Li, Y., C. Zhou, J.W. Calvert, et al. 2005. Multiple effects of hyperbaric oxygen on the expression of HIF-1 alpha and apoptotic genes in a global ischemia–hypotension rat model. Exp. Neurol. 191: 198–210.
61. Frombaum, M., S. Le Clanche, D. Bonnefont-Rousselot, et al. 2012. Antioxidant effects of resveratrol and other stilbene derivatives on oxidative stress and *NO bioavailability: potential benefits to cardiovascular diseases. Biochimie 94: 269–276.
62. Scoditti, E., N. Calabriso, M. Massaro, et al. 2012. Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer. Arch. Biochem. Biophys. 527: 81–89.
63. Chen, J., B. Liu, J. Yuan, et al. 2012. Atorvastatin reduces vascular endothelial growth factor (VEGF) expression in human non-small cell lung carcinomas (NSCLCs) via inhibition of reactive oxygen species (ROS) production. Mol. Oncol. 6: 62–72.
64. Sasabe, E., Z. Yang, S. Ohno, et al. 2010. Reactive oxygen species produced by the knockdown of manganese-superoxide dismutase up-regulate hypoxia-inducible factor-1alpha expression in oral squamous cell carcinoma cells. Free Radic. Biol. Med. 48: 1321–1329.
65. Liu, L.Z., X.W. Hu, C. Xia, et al. 2006. Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic. Biol. Med. 41: 1521–1533.
66. Maulik, N. & D.K. Das. 2002. Redox signaling in vascular angiogenesis. Free Radic. Biol. Med. 33: 1047–1060.
67. Yoshida, T., H. Nakamura, H. Masutani, et al. 2005. The involvement of thioredoxin and thioredoxin binding protein-2 on cellular proliferation and aging process. Ann. N.Y. Acad. Sci. 1055: 1–12.
68. Haendeler, J., V. Tischler, J. Hoffmann, et al. 2004. Low doses of reactive oxygen species protect endothelial cells from apoptosis by increasing thioredoxin-1 expression. FEBS Lett. 577: 427–433.
69. Sartelet, H., A.L. Rougemont, M. Fabre, et al. 2011. Activation of the phosphatidylinositol 3′-kinase/AKT pathway in neuroblastoma and its regulation by thioredoxin 1. Hum. Pathol. 42: 1727–1739.
70. Adluri, R.S., M. Thirunavukkarasu, L. Zhan, et al. 2011. Thioredoxin 1 enhances neovascularization and reduces ventricular remodeling during chronic myocardial infarction: a study using thioredoxin 1 transgenic mice. J. Mol. Cell. Cardiol. 50: 239–247.
71. Nivet-Antoine, V., C.H. Cottart, H. Lemarechal, et al. 2010. trans-Resveratrol downregulates Txnip overexpression occurring during liver ischemia–reperfusion. Biochimie 92: 1766–1771.
72. Chai, T.F., Y.C. Leck, H. He, et al. 2011. Hypoxia-inducible factor independent down-regulation of thioredoxin-interacting protein in hypoxia. FEBS Lett. 585: 492–498.
73. Zhou, J., C. Eleni, G. Spyrou, et al. 2008. The mitochondrial thioredoxin system regulates nitric oxide-induced HIF-1alpha protein. Free Radic. Biol. Med. 44: 91–98.
74. Li, X., Y. Rong, M. Zhang, et al. 2009. Up-regulation of thioredoxin interacting protein (Txnip) by p38 MAPK and FOXO1 contributes to the impaired thioredoxin activity and increased ROS in glucose-treated endothelial cells. Biochem. Biophys. Res. Commun. 381: 660–665.
75. D'Andrea, L.D., A. Romanelli, R. Di Stasi, et al. 2010. Bioinorganic aspects of angiogenesis. Dalton Trans. 39: 7625–7636.
76. Saghiri, M., J. Orangi, A. Asatourian, et al. 2015. Functional role of inorganic trace elements in angiogenesis Part II: (Cr, Si, Zn, Cu, and S). Crit. Rev. Oncol. Hematol. 96: 143–155
77. Garber, K. 2015. Cancer's copper connections. Science 349: 129.
78. Urso, E. & M. Maffia. 2015. Behind the link between copper and angiogenesis: established mechanisms and an overview on the role of vascular copper transport systems. J. Vasc. Res. 52: 172–196.
79. Zheng, L., P. Han, J. Liu, et al. 2015. Role of copper in regression of cardiac hypertrophy. Pharmacol. Ther. 148: 66–84.
80. Santini, C., M. Pellei, V. Gandin, et al. 2013. Advances in copper complexes as anticancer agents. Chem. Rev. 114: 815–862.
81. Sagar, S.M., D. Yance & R. Wong. 2006. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1. Curr. Oncol. 13: 14.
82. Mroczek-Sosnowska, N., E. Sawosz, K.P. Vadalasetty, et al. 2015. Nanoparticles of copper stimulate angiogenesis at systemic and molecular level. Int. J. Mol. Sci. 16: 4838–4849.
83. Denoyer, D., S. Masaldan, S. La Fontaine, et al. 2015. Targeting copper in cancer therapy: ‘Copper That Cancer’. Metallomics 7: 1459–1476.
84. Gupte, A. & R.J. Mumper. 2009. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treat. Rev. 35: 32–46.
85. Tamboli, V.F., N. Re, C. Coletti, et al. 2012. A joint experimental and theoretical investigation on the oxidative coupling of resveratrol induced by copper and iron ions. Int. J. Mass Spectrom. 319: 55–63.
86. Granzotto, A. & P. Zatta. 2014. Resveratrol and Alzheimer's disease: message in a bottle on red wine and cognition. Front. Aging Neurosci. 6: 95.
87. Muqbil, I., F. WJ Beck, B. Bao, et al. 2012. Old wine in a new bottle: the Warburg effect and anticancer mechanisms of resveratrol. Curr. Pharm. Des. 18: 1645–1654.
88. Frankel, E., A. Waterhouse & J.E. Kinsella. 1993. Inhibition of human LDL oxidation by resveratrol. Lancet 341: 1103–1104.
89. Belguendouz, L., L. Fremont & A. Linard. 1997. Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins. Biochem. Pharmacol. 53: 1347–1355.
90. Camaré, C., M. Trayssac, B. Garmy-Susini, et al. 2015. Oxidized LDL-induced angiogenesis involves sphingosine 1-phosphate: prevention by anti-S1P antibody. Br. J. Pharmacol. 172: 106–118.
91. Dandapat, A., C. Hu, L. Sun, et al. 2007. Small concentrations of oxLDL induce capillary tube formation from endothelial cells via LOX-1–dependent redox-sensitive pathway. Arterioscler. Thromb. Vasc. Biol. 27: 2435–2442.
92. Kalra, N., P. Roy, S. Prasad, et al. 2008. Resveratrol induces apoptosis involving mitochondrial pathways in mouse skin tumorigenesis. Life Sci. 82: 348–358.
93. Caltagirone, S., C. Rossi, A. Poggi, et al. 2000. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int. J. Cancer 87: 595–600.
94. Aziz, M.H., F. Afaq & N. Ahmad. 2005. Prevention of ultraviolet-B radiation damage by resveratrol in mouse skin is mediated via modulation in survivin. Photochem. Photobiol. 81: 25–31.
95. Asensi, M., I. Medina, A. Ortega, et al. 2002. Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic. Biol. Med. 33: 387–398.
96. Banerjee, S., C. Bueso-Ramos & B.B. Aggarwal. 2002. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 62: 4945–4954.
97. Tang, H.Y., A. Shih, H.J. Cao, et al. 2006. Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells. Mol. Cancer Ther. 5: 2034–2042.
98. Whitsett, T., M. Carpenter & C.A. Lamartiniere. 2006. Resveratrol, but not EGCG, in the diet suppresses DMBA-induced mammary cancer in rats. J. Carcinog. 5: 15.
99. Garvin, S., K. Ollinger & C. Dabrosin. 2006. Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett. 231: 113–122.
100. Su, J.L., C.Y. Yang, M. Zhao, et al. 2007. Forkhead proteins are critical for bone morphogenetic protein-2 regulation and anti-tumor activity of resveratrol. J. Biol. Chem. 282: 19385–19398.
101. Medina-Aguilar, R., L.A. Marchat, E. Arechaga Ocampo, et al. 2016. Resveratrol inhibits cell cycle progression by targeting Aurora kinase A and Polo-like kinase 1 in breast cancer cells. Oncol. Rep. 35: 3696–3704.
102. Wang, L., H. Guo, L. Yang, et al. 2013. Morusin inhibits human cervical cancer stem cell growth and migration through attenuation of NF-kappaB activity and apoptosis induction. Mol. Cell. Biochem. 379: 7–18.
103. Harper, C.E., B.B. Patel, J. Wang, et al. 2007. Resveratrol suppresses prostate cancer progression in transgenic mice. Carcinogenesis 28: 1946–1953.
104. Seeni, A., S. Takahashi, K. Takeshita, et al. 2008. Suppression of prostate cancer growth by resveratrol in the transgenic rat for adenocarcinoma of prostate (TRAP) model. Asian Pac. J. Cancer Prev. 9: 7–14.
105. Zhou, H.B., J.J. Chen, W.X. Wang, et al. 2005. Anticancer activity of resveratrol on implanted human primary gastric carcinoma cells in nude mice. World J. Gastroenterol. 11: 280–284.
106. Trincheri, N.F., G. Nicotra, C. Follo, et al. 2007. Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D. Carcinogenesis 28: 922–931.
107. Hwang, J.T., D.W. Kwak, S.K. Lin, et al. 2007. Resveratrol induces apoptosis in chemoresistant cancer cells via modulation of AMPK signaling pathway. Ann. N.Y. Acad. Sci. 1095: 441–448.
108. Bishayee, A. & N. Dhir. 2009. Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis. Chem. Biol. Interact. 179: 131–144.
109. Lee, E.O., H.J. Lee, H.S. Hwang, et al. 2006. Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. Carcinogenesis 27: 2059–2069.
110. van Ginkel, P.R., D. Sareen, L. Subramanian, et al. 2007. Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria. Clin. Cancer Res. 13: 5162–5169.
111. Chen, Y., S.H. Tseng, H.S. Lai, et al. 2004. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery 136: 57–66.
112. Tseng, S.H., S.M. Lin, J.C. Chen, et al. 2004. Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin. Cancer Res. 10: 2190–2202.
113. Niedzwiecki, A., M.W. Roomi, T. Kalinovsky, et al. 2016. Anticancer efficacy of polyphenols and their combinations. Nutrients 8. doi: 10.3390/nu8090552.
114. Udenigwe, C.C., V.R. Ramprasath, R.E. Aluko, et al. 2008. Potential of resveratrol in anticancer and anti-inflammatory therapy. Nutr. Rev. 66: 445–454.
115. Sun, C., F. Zhang, X. Ge, et al. 2007. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell. Metab. 6: 307–319.
116. Kumar, A., R.K. Kaundal, S. Iyer, et al. 2007. Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life Sci. 80: 1236–1244.
117. Ates, O., S.R. Cayli, N. Yucel, et al. 2007. Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats. J. Clin. Neurosci. 14: 256–260.
118. Sharma, S., S.K. Kulkarni & K. Chopra. 2007. Effect of resveratrol, a polyphenolic phytoalexin, on thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Fundam. Clin. Pharmacol. 21: 89–94.
119. Shibata, M.A., Y. Akao, E. Shibata, et al. 2007. Vaticanol C, a novel resveratrol tetramer, reduces lymph node and lung metastases of mouse mammary carcinoma carrying p53 mutation. Cancer Chemother. Pharmacol. 60: 681–691.
120. Yao, L., J. Wan, H. Li, et al. 2015. Resveratrol relieves gestational diabetes mellitus in mice through activating AMPK. Reprod. Biol. Endocrinol. 13: 118.
121. Wong, R.H., D. Raederstorff & P.R. Howe. 2016. Acute resveratrol consumption improves neurovascular coupling capacity in adults with type 2 diabetes mellitus. Nutrients 8. doi: 10.3390/nu8070425.
122. Wong, R.H., R.S. Nealon, A. Scholey, et al. 2016. Low dose resveratrol improves cerebrovascular function in type 2 diabetes mellitus. Nutr. Metab. Cardiovasc. Dis. 26: 393–399.
123. Pound, L.D., S.M. Comstock & K.L. Grove. 2014. Consumption of a Western-style diet during pregnancy impairs offspring islet vascularization in a Japanese macaque model. Am. J. Physiol. Endocrinol. Metab. 307: E115–E123.
124. Faid, I., H. Al-Hussaini & N. Kilarkaje. 2015. Resveratrol alleviates diabetes-induced testicular dysfunction by inhibiting oxidative stress and c-Jun N-terminal kinase signaling in rats. Toxicol. Appl. Pharmacol. 289: 482–494.
125. Mozafari, M., A.A. Nekooeian, E. Mashghoolozekr, et al. 2015. The cardioprotective effects of resveratrol in rats with simultaneous type 2 diabetes and renal hypertension. Nat. Prod. Commun. 10: 335–338.
126. Bagul, P.K., N. Deepthi, R. Sultana, et al. 2015. Resveratrol ameliorates cardiac oxidative stress in diabetes through deacetylation of NFkB-p65 and histone 3. J. Nutr. Biochem. 26: 1298–1307.
127. Gao, Y., L. Kang, C. Li, et al. 2016. Resveratrol ameliorates diabetes-induced cardiac dysfunction through AT1R-ERK/p38 MAPK signaling pathway. Cardiovasc. Toxicol. 16: 130–137.
128. Alcaraz, M.J., P. Fernandez & M.I. Guillen. 2003. Anti-inflammatory actions of the heme oxygenase-1 pathway. Curr. Pharm. Des. 9: 2541–2551.
129. Kim, H.S., C. Skurk, S.R. Thomas, et al. 2002. Regulation of angiogenesis by glycogen synthase kinase-3beta. J. Biol. Chem. 277: 41888–41896.
130. Hoang, M.V., J.A. Nagy & D.R. Senger. 2011. Cdc42-mediated inhibition of GSK-3beta improves angio-architecture and lumen formation during VEGF-driven pathological angiogenesis. Microvasc. Res. 81: 34–43.
131. Zhou, H., L. Shang, X. Li, et al. 2009. Resveratrol augments the canonical Wnt signaling pathway in promoting osteoblastic differentiation of multipotent mesenchymal cells. Exp. Cell Res. 315: 2953–2962.