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Implications of flavonoids as potential modulators of cancer neovascularity

  • Review – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

The formation of new blood vessels from previous ones, angiogenesis, is critical in tissue repair, expansion or remodeling in physiological processes and in various pathologies including cancer. Despite that, the development of anti-angiogenic drugs has great potential as the treatment of cancer faces many problems such as development of the resistance to treatment or an improperly selected therapy approach. An evaluation of predictive markers in personalized medicine could significantly improve treatment outcomes in many patients.

Methods

This comprehensive review emphasizes the anticancer potential of flavonoids mediated by their anti-angiogenic efficacy evaluated in current preclinical and clinical cancer research.

Results and conclusion

Flavonoids are important groups of phytochemicals present in common diet. Flavonoids show significant anticancer effects. The anti-angiogenic effects of flavonoids are currently a widely discussed topic of preclinical cancer research. Flavonoids are able to regulate the process of tumor angiogenesis through modulation of signaling molecules such as VEGF, MMPs, ILs, HIF or others. However, the evaluation of the anti-angiogenic potential of flavonoids within the clinical studies is not frequently discussed and is still of significant scientific interest.

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References

  • Abdollahi A, Folkman J (2010) Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Update 13:16–28

    CAS  Google Scholar 

  • Abotaleb M, Samuel SM, Varghese E, Varghese S, Kubatka P, Liskova A, Büsselberg D (2019) Flavonoids in cancer and apoptosis. Cancers 11:28

    CAS  Google Scholar 

  • Adair TH, Montani JP (2010) Angiogenesis. Morgan & Claypool Life Sciences, San Rafael

    Google Scholar 

  • Aiello P, Consalvi S, Poce G, Raguzzini A, Toti E, Palmery M, Biava M, Bernardi M, Kamal MA, Perry G, Peluso I (2019) Dietary flavonoids: nano delivery and nanoparticles for cancer therapy. Semin Cancer Biol 2019:1044-579X(19)30217-2.

  • Amiri-Kordestani L, Tan AR, Swain SM (2012) Pazopanib for the treatment of breast cancer. Expert Opin Investig Drugs 21:217–225

    CAS  PubMed  Google Scholar 

  • Avram S, Ghiulai R, Pavel IZ et al (2017) Phytocompounds targeting cancer angiogenesis using the chorioallantoic membrane assay. Nat Prod Cancer Drug Discov 2017:75

    Google Scholar 

  • Barron GA, Goua M, Wahle KWJ, Bermano G (2017) Circulating levels of angiogenesis-related growth factors in breast cancer: a study to profile proteins responsible for tubule formation. Oncol Rep 38:1886–1894

    CAS  PubMed  Google Scholar 

  • Bhat TA, Singh RP (2008) Tumor angiogenesis—a potential target in cancer chemoprevention. Food Chem Toxicol 46:1334–1345

    CAS  PubMed  Google Scholar 

  • Birt DF, Jeffery E (2013) Flavonoids. Adv Nutr 4:576–577

    PubMed  PubMed Central  Google Scholar 

  • Brezani V, Smejkal K, Hosek J, Tomasova V (2018) Anti-inflammatory natural prenylated phenolic compounds—potential lead substances. Curr Med Chem 25:1094–1159

    CAS  PubMed  Google Scholar 

  • Bronte G, Andreis D, Bravaccini S, Maltoni R, Cecconetto L, Schirone A, Farolfi A, Fedeli A, Serra P, Donati C, Amadori D, Rocca A (2017) Sorafenib for the treatment of breast cancer. Expert Opin Pharmacother 18:621–630

    CAS  PubMed  Google Scholar 

  • Bueno MJ, Mouron S, Quintela-Fandino M (2017) Personalising and targeting antiangiogenic resistance: a complex and multifactorial approach. Br J Cancer 116:1119–1125

    PubMed  PubMed Central  Google Scholar 

  • Bunkar N, Shandilya R, Bhargava A, Samarth RM, Tiwari R, Mishra DK, Srivastava RK, Sharma RS, Lohiya NK, Mishra PK (2019) Nano-engineered flavonoids for cancer protection. Front Biosci 24:1097–1157

    CAS  Google Scholar 

  • Chaemsawang W, Prasongchean W, Papadopoulos KI, Ritthidej G, Sukrong S, Wattanaarsakit P (2019) The effect of okra (Abelmoschus esculentus (L.) Moench) seed extract on human cancer cell lines delivered in its native form and loaded in polymeric micelles. Int J Biomater 2019:9404383

    PubMed  PubMed Central  Google Scholar 

  • Chen JK, Peng SF, Lai KC, Liu HC, Huang YP, Lin CC, Huang AC, Chueh FS, Chung JG (2019) Fistein suppresses human osteosarcoma U-2 OS cell migration and invasion via affecting FAK, uPA and NF-ĸB signaling pathway in vitro. Vivo 33:801–810

    CAS  Google Scholar 

  • Cheng T, Zhan X (2017) Pattern recognition for predictive, preventive, and personalized medicine in cancer. EPMA J 8:51–60

    PubMed  PubMed Central  Google Scholar 

  • Chiang CH, Yeh CY, Chung JG, Chiang IT, Hsu FT (2019) Amentoflavone induces apoptosis and reduces expression of anti-apoptotic and metastasis-associated proteins in bladder cancer. Anticancer Res 39:3641–3649

    CAS  PubMed  Google Scholar 

  • Chin HK, Horng CT, Liu YS, Lu CC, Su CY, Chen PS, Chiu HY, Tsai FJ, Shieh PC, Yang JS (2018) Kaempferol inhibits angiogenic ability by targeting VEGF receptor-2 and downregulating the PI3K/AKT, MEK and ERK pathways in VEGF-stimulated human umbilical vein endothelial cells. Oncol Rep 39:2351–2357

    CAS  PubMed  Google Scholar 

  • Choi HJ, Choi HJ, Chung TW, Ha KT (2016) Luteolin inhibits recruitment of monocytes and migration of Lewis lung carcinoma cells by suppressing chemokine (C–C motif) ligand 2 expression in tumor-associated macrophage. Biochem Biophys Res Commun 470:101–106

    CAS  PubMed  Google Scholar 

  • Ci Y, Zhang Y, Liu Y, Lu S, Cao J, Li H, Zhang J, Huang Z, Zhu X, Gao J, Han M (2018) Myricetin suppresses breast cancer metastasis through down-regulating the activity of matrix metalloproteinase (MMP)-2/9. Phytother Res 32:1373–1381

    CAS  PubMed  Google Scholar 

  • Da J, Xu M, Wang Y, Li W, Lu M, Wang Z (2019) Kaempferol promotes apoptosis while inhibiting cell proliferation via androgen-dependent pathway and suppressing vasculogenic mimicry and invasion in prostate cancer. Anal Cell Pathol 2019:1907698

    Google Scholar 

  • Darweesh RS, Ayoub NM, Nazzal S (2019) Gold nanoparticles and angiogenesis: molecular mechanisms and biomedical applications. Int J Nanomed 14:7643–7663

    CAS  Google Scholar 

  • Duan L, Ding W, Liu X, Cheng X, Cai J, Hua E, Jiang H (2017) Biosynthesis and engineering of kaempferol in Saccharomyces cerevisiae. Microb Cell Fact 16:165

    PubMed  PubMed Central  Google Scholar 

  • Farsad-Naeimi A, Alizadeh M, Esfahani A, Darvish Aminabad E (2018) Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. Food Funct 9:2025–2031

    CAS  PubMed  Google Scholar 

  • Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400

    CAS  PubMed  Google Scholar 

  • Fu JD, Yao JJ, Wang H, Cui WG, Leng J, Ding LY, Fan KY (2019) Effects of EGCG on proliferation and apoptosis of gastric cancer SGC7901 cells via down-regulation of HIF-1α and VEGF under a hypoxic state. Eur Rev Med Pharmacol Sci 23:155–161

    PubMed  Google Scholar 

  • Garcia A, Kandel JJ (2012) Notch: a key regulator of tumor angiogenesis and metastasis. Histol Histopathol 27:151–156

    PubMed  PubMed Central  Google Scholar 

  • Gee JR, Saltzstein DR, Kim K, Kolesar J, Huang W, Havighurst TC, Wollmer BW, Stublaski J, Downs T, Muktar H, House MG, Parnes HL, Bailey HH (2017) A phase II randomized, double-blind, presurgical trial of polyphenon E in bladder cancer patients to evaluate pharmacodynamics and bladder tissue biomarkers. Cancer Prev Res (Phila) 10:298–307

    CAS  PubMed Central  Google Scholar 

  • Ghițu A, Schwiebs A, Radeke HH, Avram S, Zupko I, Bor A, Pavel IZ, Dehelean CA, Oprean C, Bojin F, Farcas C, Soica C, Duicu O, Danciu C (2019) A Comprehensive assessment of apigenin as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. Nutrients 11:858

    PubMed Central  Google Scholar 

  • Giuliano S, Pagès G (2013) Mechanisms of resistance to anti-angiogenesis therapies. Biochimie 95:1110–1119

    CAS  PubMed  Google Scholar 

  • Golubnitschaja O, Yeghiazaryan K, Costigliola V, Trog D, Braun M, Debald M, Kuhn W, Schild HH (2013) Risk assessment, disease prevention and personalised treatments in breast cancer: is clinically qualified integrative approach in the horizon? EPMA J 4:6

    PubMed  PubMed Central  Google Scholar 

  • Golubnitschaja O, Kinkorova J, Costigliola V (2014) Predictive, Preventive and Personalised Medicine as the hardcore of ‘Horizon 2020’: EPMA position paper. EPMA J 5:6

    PubMed  PubMed Central  Google Scholar 

  • Golubnitschaja O, Baban B, Boniolo G, Wang W, Bubnov R, Kapalla M, Krapfenbauer K, Mozaffari MS, Costigliola V (2016) Medicine in the early twenty-first century: paradigm and anticipation—EPMA position paper 2016. EPMA J 7:23

    PubMed  PubMed Central  Google Scholar 

  • Gupta MK, Qin RY (2003) Mechanism and its regulation of tumor-induced angiogenesis. World J Gastroenterol 9:1144–1155

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hassoun SM, Abdel-Rahman N, Eladl EI, El-Shishtawy MM (2017) Antiangiogenic activity of vitexicarpine in experimentally induced hepatocellular carcinoma: impact on vascular endothelial growth factor pathway. Tumor Biol 39:1010428317707376

    Google Scholar 

  • Hegde PS, Wallin JJ, Mancao C (2018) Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol 52:117–124

    CAS  PubMed  Google Scholar 

  • Henning SM, Niu Y, Lee NH, Thames GD, Minutti RR, Wang H, Go VLW, Heber D (2004) Bioavailability and antioxidant activity of tea flavanols after consumption of green tea, black tea, or a green tea extract supplement. Am J Clin Nutr 80:1558–1564

    CAS  PubMed  Google Scholar 

  • Herrscher H, Velten M, Leblanc J, Kalish-Weindling M, Fischbach C, Exinger D, Pivot X, Petit T (2020) Fulvestrant and palbociclib combination in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer patients. Breast Cancer Res Treat 179:371–376

    CAS  PubMed  Google Scholar 

  • Hillen F, Griffioen AW (2007) Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev 26:489–502

    PubMed  PubMed Central  Google Scholar 

  • Hirano T, Higa S, Arimitsu J, Naka T, Ogata A, Shima Y, Fujimoto M, Yamadori T, Ohkawara T, Kuwabara Y, Kawai M, Matsuda H, Yoshikawa M, Maezaki N, Tanaka T, Kawase I, Tanaka T (2006) Luteolin, a flavonoid, inhibits AP-1 activation by basophils. Biochem Biophys Res Commun 340:1–7

    CAS  PubMed  Google Scholar 

  • Horn-Ross PL, John EM, Lee M, Stewart SL, Koo J, Sakoda LC, Shiau AC, Goldstein J, Davis P, Perez-Stable EJ (2001) Phytoestrogen consumption and breast cancer risk in a multiethnic population: the Bay Area Breast Cancer Study. Am J Epidemiol 154:434–441

    CAS  PubMed  Google Scholar 

  • Hosseini A, Ghorbani A (2015) Cancer therapy with phytochemicals: evidence from clinical studies. Avicenna J Phytomed 5:84–97

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Z (2004) Roles of main pro- and anti-angiogenic factors in tumor angiogenesis. World J Gastroenterol 10:463

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang H, Chen AY, Rojanasakul Y, Ye X, Rankin GO, Chen YC (2015) Dietary compounds galangin and myricetin suppress ovarian cancer cell angiogenesis. J Funct Foods 15:464–475

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hung TW, Chen PN, Wu HC, Wu SW, Tsai PY, Hsieh YS, Chang HR (2017) Kaempferol inhibits the invasion and migration of renal cancer cells through the downregulation of AKT and FAK pathways. Int J Med Sci 14:984–993

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jászai J, Schmidt MHH (2019) Trends and challenges in tumor anti-angiogenic therapies. Cells 8:1102

    PubMed Central  Google Scholar 

  • Jayson GC, Kerbel R, Ellis LM, Harris AL (2016) Antiangiogenic therapy in oncology: current status and future directions. Lancet 388:518–529

    CAS  PubMed  Google Scholar 

  • Jegal KH, Ko HL, Park SM, Byun SH, Kang KW, Cho IJ, Kim SC (2016) Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress. Apoptosis 21:642–656

    CAS  PubMed  Google Scholar 

  • Kashyap D, Sharma A, Tuli HS (2018) Apigenin: A natural bioactive flavone-type molecule with promising therapeutic function. J Funct Foods 48:457–471

    CAS  Google Scholar 

  • Katayama Y, Uchino J, Chihara Y, Tamiya N, Kaneko Y, Yamada T, Takayama K (2019) Tumor neovascularization and developments in therapeutics. Cancers 11:316

    CAS  PubMed Central  Google Scholar 

  • Keith B, Simon MC (2015) Tumor angiogenesis. In: Mendelsohn J, Gray JW, Howley PM, Israel MA, Thompson CB (eds) The molecular basis of cancer, 4th edn. Saunders, Philadelphia, pp 257–268

    Google Scholar 

  • Khan KA, Kerbel RS (2018) Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 15:310–324

    CAS  PubMed  Google Scholar 

  • Kim GD (2017) Myricetin inhibits angiogenesis by inducing apoptosis and suppressing PI3K/Akt/mTOR signaling in endothelial cells. J Cancer Prev 22:219–227

    PubMed  PubMed Central  Google Scholar 

  • Ko KP, Kim SW, Ma SH, Park B, Ahn Y, Lee JW, Lee MH, Kang E, Kim LS, Jung Y, Cho YU, Lee B, Lin JH, Park SK (2013) Dietary intake and breast cancer among carriers and noncarriers of BRCA mutations in the Korean Hereditary Breast Cancer Study. Am J Clin Nutr 98:1493–1501

    CAS  PubMed  Google Scholar 

  • Kozłowska A, Szostak-Wegierek D (2014) Flavonoids–food sources and health benefits. Rocz Panstw Zakl Hig 65:79–85

    PubMed  Google Scholar 

  • Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview. Sci World J 2013:162750

    Google Scholar 

  • Lall RK, Adhami VM, Mukhtar H (2016) Dietary flavonoid fisetin for cancer prevention and treatment. Mol Nutr Food Res 60:1396–1405

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lazarevic B, Hammarström C, Yang J, Ramberg H, Diep LM, Karlsen SJ, Kucuk O, Saatcioglu F, Tasken KA, Svindland A (2012) The effects of short-term genistein intervention on prostate biomarker expression in patients with localised prostate cancer before radical prostatectomy. Br J Nutr 108:2138–2147

    CAS  PubMed  Google Scholar 

  • Lee S, Goldfinger LE (2014) RLIP76 regulates HIF-1 activity, VEGF expression and secretion in tumor cells, and secretome transactivation of endothelial cells. FASEB J 28:4158–4168

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lei CS, Hou YC, Pai MH, Lin MT, Yeh SL (2018) Effects of quercetin combined with anticancer drugs on metastasis-associated factors of gastric cancer cells: in vitro and in vivo studies. J Nutr Biochem 51:105–113

    CAS  PubMed  Google Scholar 

  • Li WW, Li VW, Hutnik M, Chiou AS (2012) Tumor angiogenesis as a target for dietary cancer prevention. J Oncol 2012:1–23

    Google Scholar 

  • Li C, Wang Q, Shen S, Wei X, Li G (2019) HIF-1α/VEGF signaling-mediated epithelial-mesenchymal transition and angiogenesis is critically involved in anti-metastasis effect of luteolin in melanoma cells. Phytother Res 33:798–807

    CAS  PubMed  PubMed Central  Google Scholar 

  • Loizzi V, Del Vecchio V, Gargano G, De Liso M, Kardashi A, Naglieri E, Resta L, Cicinelli E, Cormio G (2017) Biological pathways involved in tumor angiogenesis and bevacizumab based anti-angiogenic therapy with special references to ovarian cancer. Int J Mol Sci 18:1967

    PubMed Central  Google Scholar 

  • Lu Y, Qin T, Li J, Wang L, Zhang Q, Jiang Z, Mao J (2017) MicroRNA-140-5p inhibits invasion and angiogenesis through targeting VEGF-A in breast cancer. Cancer Gene Ther 24:386–392

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lugano R, Ramachandran M, Dimberg A (2020) Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77:1745–1770

    CAS  PubMed  Google Scholar 

  • Ma YH, Wang SY, Ren YP, Li J, Guo TJ, Lei W, Zhou TY (2019) Antitumor effect of axitinib combined with dopamine and PK-PD modeling in the treatment of human breast cancer xenograft. Acta Pharmacol Sin 40:243–256

    CAS  PubMed  Google Scholar 

  • Maeda H, Khatami M (2018) Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs. Clin Transl Med 7:11

    PubMed  PubMed Central  Google Scholar 

  • Mancini M, Toker A (2009) NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 9:810–820

    CAS  PubMed  PubMed Central  Google Scholar 

  • McLarty J, Bigelow RLH, Smith M, Elmajian D, Ankem M, Cardelli JA (2009) Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prev Res 2:673–682

    CAS  Google Scholar 

  • Messina M, Hilakivi-Clarke L (2009) Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer. Nutr Cancer 61:792–798

    CAS  PubMed  Google Scholar 

  • Messina M, Nagata C, Wu AH (2006) Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer 55:1–12

    CAS  PubMed  Google Scholar 

  • Minder P, Zajac E, Quigley JP, Deryugina EI (2015) EGFR regulates the development and microarchitecture of intratumoral angiogenic vasculature capable of sustaining cancer cell intravasation. Neoplasia N N 17:634–649

    CAS  Google Scholar 

  • Mirossay L, Varinská L, Mojžiš J (2017) Antiangiogenic effect of flavonoids and chalcones: an update. Int J Mol Sci 19:27

    PubMed Central  Google Scholar 

  • Mirzaaghaei S, Foroughmand AM, Saki G, Shafiei M (2019) Combination of epigallocatechin-3-gallate and silibinin: a novel approach for targeting both tumor and endothelial cells. ACS Omega 4:8421–8430

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morrow DMP, Fitzsimmons PEE, Chopra M, McGlynn H (2001) Dietary supplementation with the anti-tumour promoter quercetin: its effects on matrix metalloproteinase gene regulation. Mutat Res 480–481:269–276

    PubMed  Google Scholar 

  • Mukhtar E, Adhami VM, Sechi M, Mukhtar H (2015) Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett 367:173–183

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mukund V, Saddala MS, Farran B, Mannavarapu M, Alam A, Nagaraju GP (2019) Molecular docking studies of angiogenesis target protein HIF-1α and genistein in breast cancer. Gene 701:169–172

    CAS  PubMed  Google Scholar 

  • Murtaza I, Adhami VM, Hafeez BB, Saleem M, Mukhtar H (2009) Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3 mediated inhibition of NF-κB. Int J Cancer 125:2465–2473

    CAS  PubMed  PubMed Central  Google Scholar 

  • Narayanan G, Bharathidevi SR, Vuyyuru H, Muthuvel B, Konerirajapuram Natrajan S (2013) CTR1 Silencing Inhibits Angiogenesis by Limiting Copper Entry into Endothelial Cells. PLoS ONE 8(9):e71982

    CAS  PubMed  PubMed Central  Google Scholar 

  • Natori T, Sata M, Washida M, Hirata Y, Nagai R, Makuuchi MG (2002) CSF stimulates angiogenesis and promotes tumor growth: potential contribution of bone marrow-derived endothelial progenitor cells. Biochem Biophys Res Commun 297:1058–1061

    CAS  PubMed  Google Scholar 

  • Nechuta SJ, Caan BJ, Chen WY, Lu W, Chen Z, Kwan ML, Flatt SW, Zheng Y, Zheng W, Pierce JP, Shu XO (2012) Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin Nutr 96:123–132

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ninomiya M, Koketsu M (2013) Minor flavonoids (chalcones, flavanones, dihydrochalcones, and aurones). In: Ramawat KG, Mérillon JM (eds) Natural products: phytochemistry, botany and metabolism of alkaloids, phenolics and terpenes. Springer, Berlin, Heidelberg, pp 1867–1900

    Google Scholar 

  • Noh EM, Park YJ, Kim JM, Kim MS, Kim HR, Song HK, Hong OY, So HS, Yang SH, Kim JS, Park SH, Youn HJ, You YO, Choi KB, Kwon KB, Lee YR (2015) Fisetin regulates TPA-induced breast cell invasion by suppressing matrix metalloproteinase-9 activation via the PKC/ROS/MAPK pathways. Eur J Pharmacol 764:79–86

    CAS  PubMed  Google Scholar 

  • Noolu B, Gogulothu R, Bhat M, Qadri SSYH, Reddy VS, Reddy GB, Ismail A (2016) In vivo inhibition of proteasome activity and tumour growth by murraya koenigii leaf extract in breast cancer xenografts and by its active flavonoids in breast cancer cells. Anticancer Agents Med Chem 16:1605–1614

    CAS  PubMed  Google Scholar 

  • Ozturk SA, Alp E, Yar Saglam AS, Konac E, Menevse ES (2018) The effects of thymoquinone and genistein treatment on telomerase activity, apoptosis, angiogenesis, and survival in thyroid cancer cell lines. J Cancer Res Ther 14:328–334

    CAS  PubMed  Google Scholar 

  • Panche AN, Diwan AD, Chandra SR (2016) Flavonoids: an overview. J Nutr Sci 5:e47

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park JY, Park DH, Jeon Y, Kim YJ, Lee J, Shin MS, Kang KS, Hwang GS, Kim HY, Yamabe N (2018) Eupatilin inhibits angiogenesis-mediated human hepatocellular metastasis by reducing MMP-2 and VEGF signaling. Bioorg Med Chem Lett 28:3150–3154

    CAS  PubMed  Google Scholar 

  • Pircher A, Hilbe W, Heidegger I, Drevs J, Tichelli A, Medinger M (2011) Biomarkers in tumor angiogenesis and anti-angiogenic therapy. Int J Mol Sci 12:7077–7099

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qin S, Li A, Yi M, Yu S, Zhang M, Wu K (2019) Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol 12:27

    PubMed  PubMed Central  Google Scholar 

  • Qiu JG, Wang L, Liu WJ (2019) Apigenin inhibits IL-6 transcription and suppresses esophageal carcinogenesis. Front Pharmacol 10:1002

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rajasekar J, Perumal MK, Vallikannan B (2019) A critical review on anti-angiogenic property of phytochemicals. J Nutr Biochem 71:1–15

    CAS  PubMed  Google Scholar 

  • Ren B, Yee KO, Lawle J, Khosravi-Far R (2006) Regulation of tumor angiogenesis by thrombospondin-1. Biochim Biophys Acta 1765:178–188

    CAS  PubMed  Google Scholar 

  • Ríos-Luci C, Díaz-Rodríguez E, Gandullo-Sánchez L, Díaz-Gil L, Ocaña A, Pandiella A (2020) Adaptive resistance to trastuzumab impairs response to neratinib and lapatinib through deregulation of cell death mechanisms. Cancer Lett 470:161–169

    PubMed  Google Scholar 

  • Rodríguez-García C, Sánchez-Quesada C, Gaforio JJ (2019) Dietary flavonoids as cancer chemopreventive agents: an updated review of human studies. Antioxidants 8:137

    PubMed Central  Google Scholar 

  • Rykala J, Przybylowska K, Majsterek I, Pasz-Walczak G, Sygut A, Dziki A, Kruk-Jeromin J (2011) Angiogenesis markers quantification in breast cancer and their correlation with clinicopathological prognostic variables. Pathol Oncol Res 17:809–817

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saifullah B, Buskaran K, Shaikh RB, Barahuie F, Fakurazi S, Moklas MAM, Hussein MZ (2018) Graphene oxide–PEG–protocatechuic acid nanocomposite formulation with improved anticancer properties. Nanomaterials 8:820

    PubMed Central  Google Scholar 

  • Saito K, Matsuo Y, Imafuji H, Okubo T, Maeda Y, Sato T, Shamoto T, Tsuboi K, Morimoto M, Takahashi H, Ishiguro H, Takiguchi S (2018) Xanthohumol inhibits angiogenesis by suppressing nuclear factor-κB activation in pancreatic cancer. Cancer Sci 109:132–140

    CAS  PubMed  Google Scholar 

  • Samuel MS, Satheesh NJ, Ghosh S, Büsselberg D, Majeed Y, Ding H, Triggle CR (2019a) Treatment with a combination of metformin and 2-deoxyglucose upregulates thrombospondin-1 in microvascular endothelial cells: implications in anti-angiogenic cancer therapy. Cancers 11:1737

    CAS  Google Scholar 

  • Samuel SM, Varghese E, Kubatka P, Triggle CR, Büsselberg D (2019b) Metformin: the answer to cancer in a flower? Current knowledge and future prospects of metformin as an anti-cancer agent in breast cancer. Biomolecules 9:846

    CAS  PubMed Central  Google Scholar 

  • Schlüter A, Weller P, Kanaan O, Nel I, Heusgen L, Höing B, Haßkamp P, Zander S, Mandapathil M, Dominas N et al (2018) CD31 and VEGF are prognostic biomarkers in early-stage, but not in late-stage, laryngeal squamous cell carcinoma. BMC Cancer 18:272

    PubMed  PubMed Central  Google Scholar 

  • Sen K, Banerjee S, Mandal M (2019) Dual drug loaded liposome bearing apigenin and 5-Fluorouracil for synergistic therapeutic efficacy in colorectal cancer. Colloids Surf B Biointerfaces 180:9–22

    CAS  PubMed  Google Scholar 

  • Sessa C, Guibal A, Conte GD, Rüegg C (2008) Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nat Clin Pract Oncol 5:378–391

    CAS  PubMed  Google Scholar 

  • Siamakpour-Reihani S, Caster J, Bandhu Nepal D, Courtwright A, Hilliard E, Usary J, Ketelsen D, Darr D, Shen XJ, Patterson C, Klauber-Demore N (2011) The role of calcineurin/NFAT in SFRP2 induced angiogenesis—a Rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus. PLoS ONE 6(6):e20412

    CAS  PubMed  PubMed Central  Google Scholar 

  • Siddiqi A, Saidullah B, Sultana S (2018) Anti-carcinogenic effect of hesperidin against renal cell carcinoma by targeting COX-2/PGE2 pathway in Wistar rats. Environ Toxicol 33:1069–1077

    CAS  PubMed  Google Scholar 

  • Singhal J, Nagaprashantha L, Chikara S, Awasthi S, Horne D, Singhal SS (2017) 2’-Hydroxyflavanone: a novel strategy for targeting breast cancer. Oncotarget 8:75025–75037

    PubMed  PubMed Central  Google Scholar 

  • Šmejkal K (2014) Cytotoxic potential of C-prenylated flavonoids. Phytochem Rev 13:245–275

    Google Scholar 

  • Song W, Zhao X, Xu J, Zhang H (2017) Quercetin inhibits angiogenesis-mediated human retinoblastoma growth by targeting vascular endothelial growth factor receptor. Oncol Lett 14:3343–3348

    PubMed  PubMed Central  Google Scholar 

  • Sun S, Gong F, Liu P, Miao Q (2018a) Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway. Gene 664:50–57

    CAS  PubMed  Google Scholar 

  • Sun D, Zhang F, Qian J, Shen W, Fan H, Tan J, Li L, Xu C, Yang Y, Cheng H (2018b) 4’-hydroxywogonin inhibits colorectal cancer angiogenesis by disrupting PI3K/AKT signaling. Chem Biol Interact 296:26–33

    CAS  PubMed  Google Scholar 

  • Syed DN, Adhami VM, Khan N, Khan MI, Mukhtar H (2016) Exploring the molecular targets of dietary flavonoid fisetin in cancer. Semin Cancer Biol 40–41:130–140

    PubMed  PubMed Central  Google Scholar 

  • Tang MKS, Yue PYK, Ip PP, Huang R-L, Lai H-C, Cheung ANY, Tse KY, Ngan HYS, Wong AST (2018) Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface. Nat Commun 9:1–15

    Google Scholar 

  • Teleanu RI, Chircov C, Grumezescu AM, Teleanu DM (2020) Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. J Clin Med 9:84

    CAS  Google Scholar 

  • Tonini T, Rossi F, Claudio PP (2003) Molecular basis of angiogenesis and cancer. Oncogene 22:6549–6556

    CAS  PubMed  Google Scholar 

  • Treml J, Šmejkal K (2016) Flavonoids as potent scavengers of hydroxyl radicals. Compr Rev Food Sci Food Saf 15:720–738

    CAS  Google Scholar 

  • Uramova S, Kubatka P, Dankova Z, Kapinova A, Zolakova B, Samec M, Zubor P, Zulli A, Valentova V, Kwon TK, Solar P, Kello M, Kajo K, Busselberg D, Pec M, Danko J (2018) Plant natural modulators in breast cancer prevention: status quo and future perspectives reinforced by predictive, preventive, and personalized medical approach. EPMA J 9:403–419

    PubMed  PubMed Central  Google Scholar 

  • Varghese E, Samuel SM, Abotaleb M, Cheema S, Mamtani R, Büsselberg D (2018) The “Yin and Yang” of natural compounds in anticancer therapy of triple-negative breast cancers. Cancers 10:346

    CAS  PubMed Central  Google Scholar 

  • Varghese E, Liskova A, Kubatka P, Mathews Samuel S, Büsselberg D (2020) Anti-angiogenic effects of phytochemicals on mirna regulating breast cancer progression. Biomolecules 10:191

    CAS  PubMed Central  Google Scholar 

  • Wang J, Man GCW, Chan TH, Kwong J, Wang CC (2018a) A prodrug of green tea polyphenol (−)-epigallocatechin-3-gallate (Pro-EGCG) serves as a novel angiogenesis inhibitor in endometrial cancer. Cancer Lett 412:10–20

    CAS  PubMed  Google Scholar 

  • Wang D, Taylor EW, Wang Y, Wan X, Zhang J (2012) Encapsulated nanoepigallocatechin-3-gallate and elemental selenium nanoparticles as paradigms for nanochemoprevention. Int J Nanomed 7:1711–1721

    CAS  Google Scholar 

  • Wang ZL, Wang S, Kuang Y, Hu ZM, Qiao X, Ye M (2018b) A comprehensive review on phytochemistry, pharmacology, and flavonoid biosynthesis of Scutellaria baicalensis. Pharm Biol 56:465–484

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang C, Chen Y, Wang Y, Liu X, Liu Y, Li Y, Chen H, Fan C, Wu D, Yang J (2019) Inhibition of COX-2, mPGES-1 and CYP4A by isoliquiritigenin blocks the angiogenic Akt signaling in glioma through ceRNA effect of miR-194-5p and lncRNA NEAT1. J Exp Clin Cancer Res 38:371

    PubMed  PubMed Central  Google Scholar 

  • Wei R, Mao L, Xu P, Zheng X, Hackman RM, Mackenzie GG, Wang Y (2018) Suppressing glucose metabolism with epigallocatechin-3-gallate (EGCG) reduces breast cancer cell growth in preclinical models. Food Funct 9:5682–5696

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu C, Xu Q, Chen X, Liu J (2019) Delivery luteolin with folacin-modified nanoparticle for glioma therapy. Int J Nanomed 14:7515–7531

    CAS  Google Scholar 

  • Yang F, Jiang X, Song L, Wang H, Mei Z, Xu Z, Xing N (2016a) Quercetin inhibits angiogenesis through thrombospondin-1 upregulation to antagonize human prostate cancer PC-3 cell growth in vitro and in vivo. Oncol Rep 35:1602–1610

    CAS  PubMed  Google Scholar 

  • Yang Y, Zhang J, Xia T, Li G, Tian T, Wang M, Wang R, Zhao L, Yang Y, Lan K, Zhou W (2016b) MicroRNA-210 promotes cancer angiogenesis by targeting fibroblast growth factor receptor-like 1 in hepatocellular carcinoma. Oncol Rep 36:2553–2562

    CAS  PubMed  Google Scholar 

  • Yee EMH, Brandl MB, Pasquier E, Cirillo G, Kimpton K, Kavallaris M, Kumar N, Vittorio O (2017) Dextran-Catechin inhibits angiogenesis by disrupting copper homeostasis in endothelial cells. Sci Rep 7:7638

    PubMed  PubMed Central  Google Scholar 

  • Yin XL, Lv Y, Wang S, Zhang YQ (2018) Morusin suppresses A549 cell migration and induces cell apoptosis by downregulating the expression of COX-2 and VEGF genes. Oncol Rep 40:504–510

    CAS  PubMed  Google Scholar 

  • Yu W, Yang L, Li T, Zhang Y (2019) Cadherin signaling in cancer: its functions and role as a therapeutic target. Front Oncol 9:989

    PubMed  PubMed Central  Google Scholar 

  • Zang M, Hu L, Fan ZY, Wang HX, Zhu ZL, Cao S, Wu XY, Li JF, Su LP, Li C, Zhu ZG, Yan M, Liu BY (2017a) Luteolin suppresses gastric cancer progression by reversing epithelial-mesenchymal transition via suppression of the Notch signaling pathway. J Transl Med 15:52

    PubMed  PubMed Central  Google Scholar 

  • Zang M, Hu L, Zhang B, Zhu Z, Li J, Zhu Z, Yan M, Liu B (2017b) Luteolin suppresses angiogenesis and vasculogenic mimicry formation through inhibiting Notch1-VEGF signaling in gastric cancer. Biochem Biophys Res Commun 490:913–919

    CAS  PubMed  Google Scholar 

  • Zhang J, Su H, Li Q, Li J, Zhao Q (2017) Genistein decreases A549 cell viability via inhibition of the PI3K/AKT/HIF-1α/VEGF and NF-κB/COX-2 signaling pathways. Mol Med Rep 15:2296–2302

    CAS  PubMed  Google Scholar 

  • Zhao X, Wang Q, Yang S (2016) Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer. Eur J Pharmacol 781:60–68

    CAS  PubMed  Google Scholar 

  • Zhao X, Liu J, Feng L, Ge S, Yang S, Chen C, Li X, Peng L, Mu Y, Wang Y, Gu D, Guo Y, Lin G, Deng B, Cheng Z, Cai D (2018) Anti-angiogenic effects of Qingdu granule on breast cancer through inhibiting NFAT signaling pathway. J Ethnopharmacol 222:261–269

    PubMed  Google Scholar 

  • Zhao Z, Liu B, Sun J, Lu L, Liu L, Qiu J, Li Q, Yan C, Jiang S, Mohammadtursun N, Ma W, Li M, Dong J, Gong W (2019) Scutellaria flavonoids effectively inhibit the malignant phenotypes of non-small cell lung cancer in an Id1-dependent manner. Int J Biol Sci 15:1500–1513

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhuang Z, Ye G, Huang B (2017) Kaempferol alleviates the interleukin-1β-induced inflammation in rat osteoarthritis chondrocytes via suppression of NF-κB. Med Sci Monit 23:3925–3931

    PubMed  PubMed Central  Google Scholar 

  • Zuazo-Gaztelu I, Casanovas O (2018) Unraveling the role of angiogenesis in cancer ecosystems. Front Oncol 8:248

    PubMed  PubMed Central  Google Scholar 

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Funding

The Qatar National Library funded the publication of this article. This work is supported by the Scientific Grant Agency of the Ministry of Education of the Slovak Republic under the contracts no. VEGA 1/0136/19 and the Slovak Research and Development Agency under the contract no. APVV-16-0021. This publication is the result of the project implementation: "CENTER OF EXCELLENCE FOR RESEARCH IN PERSONALIZED THERAPY (CEVYPET)", ITMS: 26220120053 supported by the Operational Programme Research and Innovation funded by the ERDF.

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Liskova, A., Koklesova, L., Samec, M. et al. Implications of flavonoids as potential modulators of cancer neovascularity. J Cancer Res Clin Oncol 146, 3079–3096 (2020). https://doi.org/10.1007/s00432-020-03383-8

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