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Posted on October 22, 2016 by ymccooper2013 Tagged AKT-mTOR pathwayapoptosisCurcuminEGCGepigallocatechinuterine leiomyosarcoma	CommentsNo Comments on Epigallocatechin-3-gallate potentiates curcumin’s ability to suppress uterine leiomyosarcoma cell growth and induce apoptosis.
Epigallocatechin-3-gallate potentiates curcumin‘s ability to suppress uterine leiomyosarcoma cell growth and induce apoptosis.
1Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Seiryomachi 1-1, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Uterine leiomyosarcoma (LMS) has an unfavorable response to standard chemotherapeutic regimens. Two natural occurring compounds, curcumin and epigallocatechin gallate (EGCG), are reported to have anti-cancer activity. We previously reported that curcumin reduced uterine LMS cell proliferation by targeting the AKT-mTOR pathway. However, challenges remain in overcoming curcumin‘s low bioavailability.
The human LMS cell line SKN was used. The effect of EGCG, curcumin or their combination on cell growth was detected by MTS assay. Their effect on AKT, mTOR, and S6 was detected by Western blotting. The induction of apoptosis was determined by Western blotting using cleaved-PARP specific antibody, caspase-3 activity and TUNEL assay. Intracellular curcumin level was determined by a spectrophotometric method. Antibody against EGCG cell surface receptor, 67-kDa laminin receptor (67LR), was used to investigate the role of the receptor in curcumin‘s increased potency by EGCG.
J Pineal Res. 2016 Mar;60(2):167-77. doi: 10.1111/jpi.12298. Epub 2015 Dec 23.
Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma.
1Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
2Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.
3Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
4Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA.
Leiomyosarcoma (LMS) represents a highly malignant, rare soft tissue sarcoma with high rates of morbidity and mortality. Previously, we demonstrated that tissue-isolated human LMS xenografts perfused in situ are highly sensitive to the direct anticancer effects of physiological nocturnal blood levels of melatonin which inhibited tumour cell proliferative activity, linoleic acid (LA) uptake and metabolism to 13-hydroxyoctadecadienoic acid (13-HODE). Here, we show the effects of low pharmacological blood concentrations of melatonin following oral ingestion of a melatonin supplement by healthy adult human female subjects on tumour proliferative activity, aerobic glycolysis (Warburg effect) and LA metabolic signalling in tissue-isolated LMS xenografts perfused in situ with this blood. Melatonin markedly suppressed aerobic glycolysis and induced a complete inhibition of tumour LA uptake, 13-HODE release, as well as significant reductions in tumour cAMP levels, DNA content and [(3) H]-thymidine incorporation into DNA. Furthermore, melatonin completely suppressed the phospho-activation of ERK 1/2, AKT, GSK3β and NF-kB (p65). The addition of S20928, a nonselective melatonin antagonist, reversed these melatonin inhibitory effects. Moreover, in in vitro cell culture studies, physiological concentrations of melatonin repressed cell proliferation and cell invasion. These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA uptake and other related signalling mechanisms. An understanding of these novel signalling pathway(s) and their association with aerobic glycolysis and LA metabolism in human LMS may lead to new circadian-based therapies for the prevention and treatment of LMS and potentially other mesenchymally derived solid tumours.
new blood vessels when tumour cell foci are in an indolent state. Many efficacious chemopreventive drugs function by preventing angiogenesis in the tumour microenvironment. Blocking the vascularization of incipient tumours should maintain a dormancy state such that neoplasia or cancer exist without disease. The current limitations of antiangiogenic cancer therapy may well be related to the use of antiangiogenic agents too late in the disease course. In this Review, we suggest mechanisms and strategies for using antiangiogenesis agents in a safe, preventive clinical angioprevention setting, proposing different levels of clinical angioprevention according to risk, and indicate potential drugs to be employed at these levels. Finally, angioprevention may go well beyond cancer in the prevention of a range of chronic disorders where angiogenesis is crucial, including different forms of inflammatory or autoimmune diseases, ocular disorders, and neurodegeneration.
Cancer has been identified by the United Nations as a non-communicable disease posing a global health threat with considerable economic consequences.1,2 The cost of cancer care in the USA alone is projected to rise from US$125 billion in 2010 to US$207 billion by 2020.2 Although great strides have been made in reducing mortality from cardiovascular disease and other non- communicable diseases through preventive efforts, cancer is still usually treated at advanced, often metastatic, disease stages.3 Screening methods have improved prognosis for some cancers;4 however, early detection is not yet possi- ble for most malignancies, and the value of screening has been challenged for some tumours.5 Targeted therapies are emerging as useful therapies, but treating all patients with these costly agents is not economically sustainable.6,7 As the world population exceeds 7 billion, cancer prevention clearly becomes an urgent goal to pursue.
Many cancers can be prevented by lifestyle changes, such as avoiding tobacco use, excessive UV exposure, infectious agents, poor dietary habits and obesity.8 Behavioural studies suggest that promotion of healthy dietary habits and exercise is only moderately success- ful.9 Thus, cancer prevention remains a difficult task. Preclinical evidence suggests that cancer prevention is feasible, but for the population at large the question is how.
Angiogenesis and inflammation are two host-dependent and interdependent hallmarks of cancer13 that have an early permissive role in tumorigenesis (Figure 1). Angio- prevention is the term that we used 10 years ago when we proposed that angiogenesis inhibition was a common target of most cancer chemopreventive drugs.14 Although epithelial cells that harbour mutations retain distinct, organ-specific phenotypes, endothelial cells are gener- ally untransformed and a common target across many cancers. Increasing evidence supports the angioprevention approach in preclinical models as well as in epidemiological and clinical intervention studies in humans.
biological escape mechanisms by tumours.18 All these data raise the question: ‘are angiogenesis inhibitors being used in an optimal scenario?’Angioprevention applies angiogenesis inhibition to predisposing conditions,14 such as chronic inflammation, hyperplastic or preneoplastic lesions, and occult tumours. Angiopreventive drugs are chemopreventive compounds that counteract angiogenesis and/or the underlying inflammation. The goal is to influence the tumour micro- environment so that host defence systems are fortified to more durably suppress the development of clinically detectable tumours. Microscopic foci of transformed cells are very common in healthy individuals. Autopsy studies have shown that approximately 40% of women between 40 and 49 years old have occult breast cancers.19 Similarly, in situ prostate cancer has been detected post- mortem in 24% of men aged 60–70 years.20 Microscopic thyroid cancers are estimated to be present in 98% of individuals by the age of 70.21,22 Yet, these cancers are diagnosed in only 2%, 8%, and <0.5%, respectively, in these age groups. The body’s intrinsic ability to prevent tumour angiogenesis is one mechanism by which cancers are maintained in a prolonged dormant state.23 Although it is not known which individuals with occult cancers will go on to develop clinical disease, angioprevention has the potential to avert this fate.
proangiogenic polarization have been demonstrated for most tumour microenvironment immune cells including dendritic, mast, T and B cells.25,26,28,29,31 Blocking chronic inflammation can prevent protumour polarization and contribute to angioprevention.
Redox stress is another key component of oncogenic- induced chronic inflammation.13,25–27 Oxygen radicals can activate endothelial cells and influence cytokine release and vascular permeability.82 Antioxidants are widely pro- posed for cancer prevention,83 and in endothelial cells an antioxidant response may restore redox homeostasis.84 Many angiopreventive agents exert pleiotropic effects by inhibiting angiogenesis and inflammation mediated by redox-sensitive targets, such as NF-κB, Akt, mTOR (Figure 3).85,86 Because energy restriction and metabolic regulation have anti-inflammatory and angiosuppressive consequences,84,87,88 another benefit of angioprevention could be weight control (Box 1).
promoting stimuli. We propose four distinct levels of angioprevention (Figure 4).
This level is aimed at cancer prevention in the general healthy population at ‘lowest’ risk of developing cancer. In these low-risk individuals, intervention must be safe with few, if any, adverse effects. Possible interventions include dietary factors and scientifically supported dietary sup- plements, caloric restriction, and aspirin, which is already used to prevent heart attack or stroke. Combinations of drugs or foods and nutritional supplements might have synergistic angiopreventive activity.89 For level I angio- prevention, regulatory approval might be unnecessary as long as the interventions are safe and suitable for general application.
(including diabetes). The higher cancer risk of indivi- duals in this group justifies a higher risk tolerance for the angioprevention agents used than in level I.
Whether regulatory approval is required for clinical application of angioprevention remains an open ques- tion. Dietary and over-the-counter drug angioprevention may not even require physician involvement at level I, while interventions from level II to level IV will need to be prescribed by a clinician.
Clinical trials that assess antiangiogenesis and angiopre- vention as an end point are underway (Table 1), increasing the urgency for identifying biomarkers for angiogenesis.17 However, a number of chemopreventive angiogenesis inhibitory agents have shown clinical efficacy. Here, we describe selected compounds that demonstrate angiopreventive benefits.
30 days) exerts caloric-restriction-like effects, improves lipid profiles and decreases inflammatory markers.142 Considering that metabolic disorders are associated with pathological angiogenesis and chronic inflammation143 and can be predisposing conditions for some cancers,70 these results constitute an important premise for further clinical studies.
and inflammation boosts anticancer defence mecha- nisms and provides protection against a broad spectrum of neoplasms.
backbone to be more antiangiogenic and more suitable as angiopreventives. Synthetic chemistry and molecular tailoring may be used to design angiopreventive diet derivatives or pharmaceuticals.
Clinical trials are now underway to test the efficacy of angiopreventive molecules such as curcumin, artemi- sinin, resveratrol, genistein, synthetic triterpenoids, and isothiocyanates in neurological, cardiovascular degener- ative diseases, and cancer at levels III and IV as defined in this article. Given the global health priorities facing socie- ties today, and with the cancer pandemic in our sights, angioprevention and its clinical development is a concept whose time has arrived.
(V. W. Li, W. W. Li). Department of Biotechnologies and Life Sicences, University of Insubria, Viale Ottorino Rossi 9, Varese 21100, Italy (D. M. Noonan).
Bloom, D. E. et al. The Global Economic Burden of Non-communicable Diseases [online], http:// www3.weforum.org/docs/WEF_Harvard_HE_ GlobalEconomicBurdenNonCommunicable Diseases_2011.pdf (2011).
Feuer, E. J. & Brown, M. L. Projections of the cost of cancer care in the United States: 2010–2020. J. Natl Cancer Inst. 103, 117–128 (2011).
Albini, A. & Sporn, M. B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 7, 139–147 (2007).
Qaseem, A. et al. Screening for colorectal cancer: a guidance statement from the American College of Physicians. Ann. Intern. Med. 156, 378–386 (2012).
Nishizawa, S. et al. Prospective evaluation of whole-body cancer screening with multiple modalities including [18F]fluorodeoxyglucose positron emission tomography in a healthy population: a preliminary report. J. Clin. Oncol. 27, 1767–1773 (2009).
Shih,Y.C.etal.Economicburdenofrenalcell carcinoma: part I–an updated review. Pharmacoeconomics 29, 315–329 (2011).
Whyte, S., Pandor, A., Stevenson, M. & Rees, A. Bevacizumab in combination with fluoropyrimidine-based chemotherapy for the first-line treatment of metastatic colorectal cancer. Health Technol. Assess. 14, 47–53 (2010).
Willyard, C. Lifestyle: Breaking the cancer habit. Nature 471, S16–S17 (2011).
10. [No authors listed] Stat bite: Lifetime risk of being diagnosed with cancer. J. Natl Cancer Inst. 95, 1745 (2003).
11. Sporn, M. B. & Newton, D. L. Chemoprevention of cancer with retinoids. Fed. Proc. 38, 2528–2534 (1979).
cancer progression. Nat. Med. 17, 320–329 (2011).
13. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
14. Tosetti, F., Ferrari, N., De Flora, S. & Albini, A. Angioprevention’: angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J. 16, 2–14 (2002).
15. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
16. Ebos, J. M. & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011).
17. Jayson, G. C., Hicklin, D. J. & Ellis, L. M. Antiangiogenic therapy—evolving view based on clinical trial results. Nat. Rev. Clin. Oncol. 9, 297–303 (2012).
18. Ferrara, N. Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis. Curr. Opin. Hematol. 17, 219–224 (2010).
19. Nielsen, M., Thomsen, J. L., Primdahl, S., Dyreborg, U. & Andersen, J. A. Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br. J. Cancer 56, 814–819 (1987).
20. Sanchez-Chapado, M., Olmedilla, G., Cabeza, M., Donat, E. & Ruiz, A. Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study. Prostate 54, 238–247 (2003).
21. Black, W. C. & Welch, H. G. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N. Engl. J. Med. 328, 1237–1243 (1993).
22. Harach, H. R., Franssila, K. O. & Wasenius, V. M. Occult papillary carcinoma of the thyroid.
A “normal” finding in Finland. A systematic autopsy study. Cancer 56, 531–538 (1985).
23. Folkman, J. & Kalluri, R. Cancer without disease. Nature 427, 787 (2004).
24. Albini, A., Tosetti, F., Benelli, R. & Noonan, D. M. Tumor inflammatory angiogenesis and its chemoprevention. Cancer Res. 65, 10637–10641 (2005).
25. de Visser, K. E., Eichten, A. & Coussens, L. M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 6, 24–37 (2006).
26. Noonan, D. M., De Lerma Barbaro, A., Vannini, N., Mortara, L. & Albini, A. Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev. 27, 31–40 (2008).
27. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).
28. Mantovani, A. & Sica, A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231–237 (2010).
29. Coffelt, S. B. et al. Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. Am. J. Pathol. 176, 1564–1576 (2010).
Fridlender, Z. G. & Albelda, S. M. Tumor-associated neutrophils: friend or foe? Carcinogenesis 33, 949–955 (2012).
DeNardo, D. G., Andreu, P. & Coussens, L. M. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 29, 309–316 (2010).
Mason, S. D. & Joyce, J. A. Proteolytic networks in cancer. Trends Cell Biol. 21, 228–237 (2011).
Cao, Y. & Cao, R. Angiogenesis inhibited by drinking tea. Nature 398, 381 (1999).
Albini, A., Indraccolo, S., Noonan, D. M. &Pfeffer, U. Functional genomics of endothelial cells treated with anti-angiogenic or angiopreventive drugs. Clin. Exp. Metastasis 27, 419–439 (2010).
Araldi, E. M. et al. Natural and synthetic agents targeting inflammation and angiogenesis for chemoprevention of prostate cancer.
Curr. Cancer Drug Targets 8, 146–155 (2008).
Tahanian, E., Sanchez, L. A., Shiao, T. C., Roy, R. & Annabi, B. Flavonoids targeting of IκB phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells. Drug Des. Devel. Ther. 5, 299–309 (2011).
Yang, M. D. et al. Phenethyl isothiocyanate inhibits migration and invasion of human gastric cancer AGS cells through suppressing MAPK and NF-kappaB signal pathways. Anticancer Res. 30, 2135–2143 (2010).
Priyadarsini, R. V., Vinothini, G. & Nagini, S. Eugenol induces apoptosis and inhibits invasion and angiogenesis in a rat model of gastric carcinogenesis induced by MNNG. Life Sci. 86, 936–941 (2010).
Cao, Y., Cao, R. & Brakenhielm, E. Antiangiogenic mechanisms of diet-derived polyphenols. J. Nutr. Biochem. 13, 380–390 (2002).
Ferrari, N. et al. Diet-derived phytochemicals: from cancer chemoprevention to cardio- oncological prevention. Curr. Drug Targets 12, 1909–1924 (2011).
Li, W. W., Li, V. W., Hutnik, M. & Chiou, A. S. Tumor angiogenesis as a target for dietary cancer prevention. J. Oncol. 2012, 879623 (2012).
Sidky, Y. A. & Borden, E. C. Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses. Cancer Res. 47, 5155–5161 (1987).
Li, V. W. & Li, W. W. Antiangiogenesis in the treatment of skin cancer. J. Drugs Dermatol. 7 (Suppl. 1), s17–s24 (2008).
Li, V. W., Li, W. W., Talcott, K. E. & Zhai, A. W. Imiquimod as an antiangiogenic agent. J. Drugs Dermatol. 4, 708–717 (2005).
Sidbury, R. et al. Topically applied imiquimod inhibits vascular tumor growth in vivo. J. Invest. Dermatol. 121, 1205–1209 (2003).
Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371–1388 (1998).
Bendrik, C., Karlsson, L. & Dabrosin, C. Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer. Cancer Lett. 292, 32–40 (2010).
50. Aberg, U. W. et al. Tamoxifen and flaxseed alter angiogenesis regulators in normal human breast tissue in vivo. PLoS ONE 6, e25720 (2011).
51. Blackwell, K. L. et al. Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models. Clin. Cancer Res. 6, 4359–4364 (2000).
52. Lindahl, G., Saarinen, N., Abrahamsson, A. & Dabrosin, C. Tamoxifen, flaxseed, and the lignan enterolactone increase stroma- and cancer cell- derived IL-1Ra and decrease tumor angiogenesis in estrogen-dependent breast cancer.
Cancer Res. 71, 51–60 (2011).
correlation reveals estrogen-like trancriptional activity of Curcumin. Cell. Physiol. Biochem. 26, 471–482 (2010).
54. William, W. N. Jr, Heymach, J. V., Kim, E. S. & Lippman, S. M. Molecular targets for cancer chemoprevention. Nat. Rev. Drug Discov. 8, 213–225 (2009).
55. Rothwell,P.M.etal.Effectofdailyaspirinon long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377, 31–41 (2011).
56. Harris, R. E. Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology 17, 55–67 (2009).
57. Cui, X. et al. Resveratrol suppresses colitis and colon cancer associated with colitis.
Cancer Prev. Res. (Phila.) 3, 549–559 (2010).
58. Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).
59. Lamy, S., Akla, N., Ouanouki, A., Lord-Dufour, S. & Beliveau, R. Diet-derived polyphenols inhibit angiogenesis by modulating the interleukin-6/ STAT3 pathway. Exp. Cell Res. 318, 1586–1596 (2012).
60. Aggarwal, B. B., Vijayalekshmi, R. V. & Sung, B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long- term foe. Clin. Cancer Res. 15, 425–430 (2009).
Aggarwal, B. B. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 29, 405–434 (2010).
62. Gately, S. & Li, W. W. Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin. Oncol. 31, 2–11 (2004).
63. Fosslien, E. Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann. Clin. Lab. Sci. 31, 325–348 (2001).
64. Greenberger, S. & Bischoff, J. Infantile Hemangioma-Mechanism(s) of Drug Action on a Vascular Tumor. Cold Spring Harb. Perspect. Med. 1, a006460 (2011).
Noonan, D. M. & Albini, A. Endothelial cell aging and apoptosis in prevention and disease: E-selectin expression and modulation as a model. Curr. Pharm. Des. 14, 221–225 (2008).
66. Nishikawa, T. et al. The inhibition of autophagy potentiates anti-angiogenic effects of sulforaphane by inducing apoptosis. Angiogenesis 13, 227–238 (2010).
67. Delmas, D., Solary, E. & Latruffe, N. Resveratrol, a phytochemical inducer of multiple cell death pathways: apoptosis, autophagy and mitotic catastrophe. Curr. Med. Chem. 18, 1100–1121 (2011).
stem cells and the tumor microenvironment: soloists or choral singers. Curr. Pharm. Biotechnol. 12, 171–181 (2011).
70. Hursting, S. D., Smith, S. M., Lashinger, L. M., Harvey, A. E. & Perkins, S. N. Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis 31, 83–89 (2010).
71. Aljada, A., O’Connor, L., Fu, Y. Y. & Mousa, S. A. PPAR gamma ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. Angiogenesis 11, 361–367 (2008).
72. Merchan, J. R. et al. Antiangiogenic activity of 2-deoxy-D-glucose. PLoS ONE 5, e13699 (2010). 73. Fraisl, P., Mazzone, M., Schmidt, T. & Carmeliet, P.
77. US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/ results?term=cancer+AND+angiogenesis+AND+ %28rapamycin+OR+sirolimus+OR+ temsirolimus+OR+everolimus%29+ (2012).
78. Phoenix, K. N., Vumbaca, F. & Claffey, K. P. Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res. Treat. 113, 101–111 (2009).
79. Xavier, D. O. et al. Metformin inhibits inflammatory angiogenesis in a murine sponge model.
Biomed. Pharmacother. 64, 220–225 (2010).
80. Esfahanian, N. et al. Effect of metformin on the proliferation, migration, and MMP-2 and -9 expression of human umbilical vein endothelial cells. Mol. Med. Report 5, 1068–1074 (2012).
81. Akin, S. et al. Pigment epithelium-derived factor (PEDF) increases in type 2 diabetes after treatment with metformin. Clin. Endocrinol. (Oxf.) http:dx.doi.org/10.1111/ j.1365-2265.2012.04341.x.
82. Alom-Ruiz, S. P., Anilkumar, N. & Shah, A. M. Reactive oxygen species and endothelial activation. Antioxid. Redox Signal. 10, 1089–1100 (2008).
83. De Flora, S. et al. Multiple points of intervention in the prevention of cancer and other mutation- related diseases. Mutat. Res. 480–481, 9–22 (2001).
84. Tosetti, F., Noonan, D. M. & Albini, A. Metabolic regulation and redox activity as mechanisms for angioprevention by dietary phytochemicals. Int. J. Cancer 125, 1997–2003 (2009).
85. Aggarwal, B. B. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu. Rev. Nutr. 30, 173–199 (2010).
86. Yadav, V. R. & Aggarwal, B. B. Curcumin: a component of the golden spice, targets multiple angiogenic pathways. Cancer Biol. Ther. 11, 236–241 (2011).
87. Tan, B. K. et al. Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovasc. Res. 83, 566–574 (2009).
De Lorenzo, M. S. et al. Caloric restriction reduces growth of mammary tumors and metastases. Carcinogenesis 32, 1381–1387 (2011).
Zhou, J. R., Li, L. & Pan, W. Dietary soy and tea combinations for prevention of breast and prostate cancers by targeting metabolic syndrome elements in mice. Am. J. Clin. Nutr. 86, s882–s888 (2007).
Cazzaniga, M., Bonanni, B., Guerrieri-Gonzaga, A. & Decensi, A. Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol. Biomarkers Prev. 18, 701–705 (2009).
Cuzick, J. et al. Preventive therapy for breast cancer: a consensus statement. Lancet Oncol. 12, 496–503 (2011).
Mallery, S. R. et al. Topical application of a bioadhesive black raspberry gel modulates gene expression and reduces cyclooxygenase 2 protein in human premalignant oral lesions. Cancer Res. 68, 4945–4957 (2008).
Vannini, N. et al. The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol. Cancer Ther. 6, 3139–3146 (2007).
Kim, E. H. et al. CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice. Cancer Prev. Res. (Phila.) 5, 89–97 (2012).
Sporn, M. B. Perspective: The big C – for Chemoprevention. Nature 471, S10–S11 (2011).
(eds Maragoudakis, M. & Papadimitriou, E.) 377–417 (Research Signpost, Trivandrum, India, 2008).
Albini, A. et al. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio- oncological prevention. J. Natl Cancer Inst. 102, 14–25 (2010).
Comen, E., Norton, L. & Massague, J. Clinical implications of cancer self-seeding. Nat. Rev. Clin. Oncol. 8, 369–377 (2011).
Albini, A. & Noonan, D. M. Angiopoietin2 and tie2: tied to lymphangiogenesis and lung metastasis. New perspectives in antimetastatic antiangiogenic therapy. J. Natl Cancer Inst. 104, 429–431 (2012).
Albini, A. & Noonan, D. M. The ‘chemoinvasion’ assay, 25 years and still going strong: the use of reconstituted basement membranes to study cell invasion and angiogenesis. Curr. Opin.Cell. Biol. 22, 677–689 (2010).
Pasquier, E., Kavallaris, M. & Andre, N.Metronomic chemotherapy: new rationale for new directions. Nat. Rev. Clin. Oncol. 7, 455–465 (2010).
Spigel, D. R. et al. Phase II study of bevacizumab and chemoradiation in the preoperative or adjuvant treatment of patients with stage II/III rectal cancer. Clin. Colorectal Cancer 11, 45–52 (2012).
Allegra, C. J. et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J. Clin. Oncol. 29, 11–16 (2011).
Jonietz, E. Designing smarter cancer prevention trials. Nature 471, S20–S21 (2011).
Sogno, I., Conti, M., Consonni, P., Noonan, D. M. & Albini, A. Surface-activated chemical ionization-electrospray ionization source improves biomarker discovery with mass spectrometry. Rapid Commun. Mass Spectrom. 26, 1213–1218 (2012).
Cervi, D. et al. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 111, 1201–1207 (2008).
new vein in angiogenesis research. Sci. Signal.
Aggarwal, B. B. Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr. 6, 93–108 (2011).
111. Noratto, G. D., Angel-Morales, G., Talcott, S. T. & Mertens-Talcott, S. U. Polyphenolics from açai (Euterpe oleracea Mart.) and red muscadine grape (Vitis rotundifolia) protect human umbilical vascular endothelial cells (HUVEC) from glucose- and lipopolysaccharide (LPS)-induced inflammation and target microRNA-126. J. Agric. Food Chem. 59, 7999–8012 (2011).
112. White, N. M. et al. Metastamirs: a stepping stone towards improved cancer management. Nat. Rev. Clin. Oncol. 8, 75–84 (2011).
113. Sogno, I. et al. Angioprevention with fenretinide: targeting angiogenesis in prevention and therapeutic strategies. Crit. Rev. Oncol. Hematol. 75, 2–14 (2010).
114. Veronesi, U. et al. Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann. Oncol. 17, 1065–1071 (2006).
115. US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/ show/NCT01479192 (2011).
116. [No authors listed] Standards of medical care in diabetes—2009. Diabetes Care 32 (Suppl. 1), S13–S61 (2009).
117. Currie, C. J., Poole, C. D. & Gale, E. A.
The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 1766–1777 (2009).
118. Goodwin, P. J. et al. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti- cancer agents. Breast Cancer Res. Treat. 126, 215–220 (2011).
119. Li, D., Yeung, S. C., Hassan, M. M., Konopleva, M. & Abbruzzese, J. L. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137, 482–488 (2009).
120. Cole, B. F. et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J. Natl Cancer Inst. 101, 256–266 (2009).
121. Rothwell, P. M. et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376, 1741–1750 (2010).
122. Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378, 2081–2087 (2011).
123. Battinelli, E. M., Markens, B. A. & Italiano, J. E. Jr. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood 118, 1359–1369 (2011).
124. Borthwick, G. M. et al. Therapeutic levels of aspirin and salicylate directly inhibit a model of angiogenesis through a Cox-independent mechanism. FASEB J. 20, 2009–2016 (2006).
125. Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).
safety analysis of the Adenoma Prevention with Celecoxib Trial. Cancer Prev. Res. (Phila.) 2, 310–321 (2009).
128. Chan, A. T. et al. C-reactive protein and risk of colorectal adenoma according to celecoxib treatment. Cancer Prev. Res. (Phila.) 4, 1172–1180 (2011).
129. Elmets, C. A. et al. Chemoprevention of nonmelanoma skin cancer with celecoxib: a randomized, double-blind, placebo-controlled trial. J. Natl Cancer Inst. 102, 1835–1844 (2010).
130. Bettuzzi, S. et al. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res. 66, 1234–1240 (2006).
131. Brausi, M., Rizzi, F. & Bettuzzi, S. Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur. Urol. 54, 472–473 (2008).
132. Shimizu, M. et al. Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol. Biomarkers Prev. 17, 3020–3025 (2008).
133. Li, N., Sun, Z., Han, C. & Chen, J.
The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc. Soc. Exp. Biol. Med. 220, 218–224 (1999).
134. Ahn, W. S. et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur. J. Cancer Prev. 12, 383–390 (2003).
135. US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/ results?term=polyphenon+E+cancer (2012).
136. Cheng, A. L. et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 21, 2895–2900 (2001).
137. Dhillon, N. et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 14, 4491–4499 (2008).
138. Carroll, R. E. et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev. Res. (Phila.) 4, 354–364 (2011).
139. Cruz-Correa, M. et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 4, 1035–1038 (2006).
140. Brown, V. A. et al. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 70, 9003–9011 (2010).
141. Howells, L. M. et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev. Res. (Phila.) 4, 1419–1425 (2011).
142. Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell. Metab. 14, 612–622 (2011).
143. Siervo, M. et al. Body mass index is directly associated with biomarkers of angiogenesis and inflammation in children and adolescents. Nutrition 28, 262–266 (2012).
144. Bhattacharjee, Y. Exoplanetary research.
A distant glimpse of alien life? Science 333, 930–932 (2011).
Lally, D. R., Gerstenblith, A. T. & Regillo, C. D. Preferred therapies for neovascular age-related macular degeneration. Curr. Opin. Ophthalmol. 23, 182–188 (2012).
Breitner, J. C. et al. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement. 7, 402–411 (2011).
Desai, B. S., Schneider, J. A., Li, J. L., Carvey, P. M. & Hendey, B. Evidence of angiogenic vessels in Alzheimer’s disease. J. Neural. Transm. 116, 587–597 (2009).
Zeng, S., Hernandez, J. & Mullins, R. F. Effects of antioxidant components of AREDS vitamins and zinc ions on endothelial cell activation: implications for macular degeneration. Invest. Ophthalmol. Vis. Sci. 53, 1041–1047 (2012).
Konisti, S., Kiriakidis, S. & Paleolog, E. M. Hypoxia–a key regulator of angiogenesis and inflammation in rheumatoid arthritis. Nat. Rev. Rheumatol. 8, 153–162 (2012).
Lainer-Carr, D. & Brahn, E. Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis. Nat. Clin.
Pract. Rheumatol. 3, 434–442 (2007).
151. Cao, Y. Angiogenesis modulates adipogenesis and obesity. J. Clin. Invest. 117, 2362–2368 (2007).
152. Cao, Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat. Rev. Drug Discov. 9, 107–115 (2010).
153. Daquinag, A. C., Zhang, Y. & Kolonin, M. G. Vascular targeting of adipose tissue as an anti-obesity approach. Trends Pharmacol. Sci. 32, 300–307 (2011).
childhood obesity. DNA Cell Biol. 30, 709–714 (2011).
155. Zhang, Y. et al. Effects of catechin-enriched green tea beverage on visceral fat loss in adults with a high proportion of visceral fat: a double-blind, placebo-controlled, randomized trial.
J. Functional Foods 4, 315–322 (2012).
fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur. J. Pharmacol. 620, 138–144 (2009).
The authors would like to thank Diana Saville (Angiogenesis Foundation) for rendering medical graphics. We thank Paola Corradino (MultiMedica IRCCS) for data management, and Alessandra Panvini Rosati (MultiMedica Onlus) and Giuseppe Bertani (IRCCS–Arcispedale Santa Maria Nuova) for administrative assistance. The authors were supported by grants from the AIRC (Associazione Italiana per la Ricerca sul Cancro; IG5968 to D. M. Noolan, IG10228 to A. Albini), the Cariplo Foundation, Progetto Finalizzato of the Ministero della Sanità and by funds from the University of Insubria (fondi di Ateneo) and MultiMedica Onlus. A. Albini is currently Director of Research and Statistics Infrastructure, IRCCS– Arcispedale Santa Maria Nuova (Reggio Emilia-Italy).
All authors made a substantial contribution to researching and discussing data for this Review, and to writing the manuscript. All authors reviewed and edited the manuscript prior to submission.
D. M. Noonan and W. W. Li contributed equally to this article.

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