Flavonoids and Cancer Stem Cells Maintenance and Growth

  • Kushal Kandhari
  • Hina Agraval
  • Arpana Sharma
  • Umesh C. S. Yadav
  • Rana P. SinghEmail author


Normal stem cells are known to possess three important characteristics of self-renewal, restriction on stem cell numbers and ability to divide and differentiate. Compared to normal stem cells, the cancer stem cells (CSCs) have no control on the stem cell numbers. CSCs constitute a miniscule number of cells in the tumour and are responsible for tumour growth, recurrence and progression. CSCs play a vital role in drug resistance, EMT and metastasis, which are responsible for approximately 90% of cancer-related deaths. Thus, targeting CSCs has now gained significant importance in the control and treatment of various cancers. Traditional cancer therapy regimens have not been successful against cancer drug resistance and metastasis. In the recent past, numerous dietary compounds derived from natural sources have been found effective in chemoprevention and treatment of various cancers. Flavonoids are one of such naturally occurring polyphenolic compounds that are found abundantly in fruits, vegetables, tea, seeds, grains, nuts and some traditional medicinal herbs. Various flavonoids have also been shown to have an inhibitory effect on the self-renewal potential and survival of cancer stem cells of different origins. The aim of this chapter is to focus on cancer stem cells and their role in tumour progression and drug resistance and how chemoprevention using flavonoids can become an effective tool to control cancer growth.


Cancer stem cells EMT Metastasis Drug resistance Chemoprevention 



The fellowships from UGC to KK, CSIR to AS and DST INSPIRE to HA and Ramanujan Fellowship Award from DST to UCSY are thankfully acknowledged.


  1. 1.
    Nassar D, Blanpain C (2016) Cancer stem cells: basic concepts and therapeutic implications. Annu Rev Pathol 11:47–76. CrossRefPubMedGoogle Scholar
  2. 2.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111. CrossRefPubMedGoogle Scholar
  3. 3.
    Pattabiraman DR, Weinberg RA (2014) Tackling the cancer stem cells – what challenges do they pose? Nat Rev Drug Discov 13(7):497–512. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sell S (2009) History of Cancer Stem Cells. In: Rajasekhar VK, Vemuri MC (eds) Regulatory networks in stem cells. Humana Press, Totowa, pp 495–503. CrossRefGoogle Scholar
  5. 5.
    Joosse SA, Gorges TM, Pantel K (2015) Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol Med 7(1):1–11. CrossRefPubMedGoogle Scholar
  6. 6.
    Jordan NV, Johnson GL, Abell AN (2011) Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle 10(17):2865–2873. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Krantz SB, Shields MA, Dangi-Garimella S, Munshi HG, Bentrem DJ (2012) Contribution of epithelial-to-mesenchymal transition and cancer stem cells to pancreatic cancer progression. J Surg Res 173(1):105–112. CrossRefPubMedGoogle Scholar
  8. 8.
    Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Khan S, Karmokar A, Howells L, Thomas AL, Bayliss R, Gescher A, Brown K (2016) Targeting cancer stem-like cells using dietary-derived agents – Where are we now? Mol Nutr Food Res 60(6):1295–1309. CrossRefPubMedGoogle Scholar
  10. 10.
    Sporn MB, Suh N (2002) Chemoprevention: an essential approach to controlling cancer. Nat Rev Cancer 2(7):537–543. CrossRefPubMedGoogle Scholar
  11. 11.
    Lee BM, Park KK (2003) Beneficial and adverse effects of chemopreventive agents. Mutat Res 523–524:265–278CrossRefGoogle Scholar
  12. 12.
    Egert S, Rimbach G (2011) Which sources of flavonoids: complex diets or dietary supplements? Adv Nutr 2(1):8–14. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yang CS, Landau JM, Huang MT, Newmark HL (2001) Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr 21:381–406. CrossRefPubMedGoogle Scholar
  14. 14.
    Oh J, Hlatky L, Jeong YS, Kim D (2016) Therapeutic effectiveness of anticancer phytochemicals on cancer stem cells. Toxins (Basel) 8(7):199. CrossRefGoogle Scholar
  15. 15.
    Batra P, Sharma AK (2013) Anti-cancer potential of flavonoids: recent trends and future perspectives. 3 Biotech 3(6):439–459. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sak K, Everaus H (2015) Role of flavonoids in future anticancer therapy by eliminating the cancer stem cells. Curr Stem Cell Res Ther 10(3):271–282CrossRefGoogle Scholar
  17. 17.
    Almendro V, Marusyk A, Polyak K (2013) Cellular heterogeneity and molecular evolution in cancer. Annu Rev Pathol 8:277–302. CrossRefPubMedGoogle Scholar
  18. 18.
    Kreso A, Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14(3):275–291. CrossRefPubMedGoogle Scholar
  19. 19.
    Blanpain C, Fuchs E (2014) Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration. Science 344(6189):1242281. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737CrossRefGoogle Scholar
  21. 21.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988. CrossRefPubMedGoogle Scholar
  22. 22.
    Lobo NA, Shimono Y, Qian D, Clarke MF (2007) The biology of cancer stem cells. Annu Rev Cell Dev Biol 23:675–699. CrossRefPubMedGoogle Scholar
  23. 23.
    Chen K, Huang YH, Chen JL (2013) Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 34(6):732–740. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Meng X, Li M, Wang X, Wang Y, Ma D (2009) Both CD133+ and CD133- subpopulations of A549 and H446 cells contain cancer-initiating cells. Cancer Sci 100(6):1040–1046. CrossRefPubMedGoogle Scholar
  25. 25.
    Miyata T, Yoshimatsu T, So T, Oyama T, Uramoto H, Osaki T, Nakanishi R, Tanaka F, Nagaya H, Gotoh A (2015) Cancer stem cell markers in lung cancer. Personal Med Universe 4:40–45. CrossRefGoogle Scholar
  26. 26.
    Pine SR, Marshall B, Varticovski L (2008) Lung cancer stem cells. Dis Markers 24(4–5):257–266. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN (2013) Cancer stem cells in lung cancer: evidence and controversies. Respirology 18(5):757–764. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Meyer MJ, Fleming JM, Lin AF, Hussnain SA, Ginsburg E, Vonderhaar BK (2010) CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer. Cancer Res 70(11):4624–4633. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wu X, Chen H, Wang X (2012) Can lung cancer stem cells be targeted for therapies? Cancer Treat Rev 38(6):580–588. CrossRefPubMedGoogle Scholar
  30. 30.
    Leung EL, Fiscus RR, Tung JW, Tin VP, Cheng LC, Sihoe AD, Fink LM, Ma Y, Wong MP (2010) Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One 5(11):e14062. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Louie E, Nik S, Chen JS, Schmidt M, Song B, Pacson C, Chen XF, Park S, Ju J, Chen EI (2010) Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res 12(6):R94. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sullivan JP, Spinola M, Dodge M, Raso MG, Gao B, Schuster K, Shao C, Larsen JE, Laura A, Honorio S, Xie Y, Scaglioni PP, Dimaio JM, Gazdar F, Shay JW, Wistuba II, Minna JD (2011) NIH public access. Cancer 70(23):9937–9948. CrossRefGoogle Scholar
  33. 33.
    Huang CP, Tsai MF, Chang TH, Tang WC, Chen SY, Lai HH, Lin TY, Yang JC, Yang PC, Shih JY, Lin SB (2013) ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Cancer Lett 328(1):144–151. CrossRefPubMedGoogle Scholar
  34. 34.
    Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, Mori M (2006) Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 24(3):506–513. CrossRefPubMedGoogle Scholar
  35. 35.
    Zhou S, Morris JJ, Barnes Y, Lan L, Schuetz JD, Sorrentino BP (2002) Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proc Natl Acad Sci USA 99(19):12339–12344. CrossRefPubMedGoogle Scholar
  36. 36.
    Leccia F, Del Vecchio L, Mariotti E, Di Noto R, Morel AP, Puisieux A, Salvatore F, Ansieau S (2014) ABCG2, a novel antigen to sort luminal progenitors of BRCA1- breast cancer cells. Mol Cancer 13:213. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cariati M, Naderi A, Brown JP, Smalley MJ, Pinder SE, Caldas C, Purushotham AD (2008) Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int J Cancer 122(2):298–304. CrossRefPubMedGoogle Scholar
  38. 38.
    Vaillant F, Asselin-Labat ML, Shackleton M, Forrest NC, Lindeman GJ, Visvader JE (2008) The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res 68(19):7711–7717. CrossRefPubMedGoogle Scholar
  39. 39.
    Ribeiro AS, Paredes J (2014) P-cadherin linking breast cancer stem cells and invasion: a promising marker to identify an “intermediate/metastable” EMT state. Front Oncol 4:371. CrossRefPubMedGoogle Scholar
  40. 40.
    Messam CA, Hou J, Major EO (2000) Coexpression of nestin in neural and glial cells in the developing human CNS defined by a human-specific anti-nestin antibody. Exp Neurol 161(2):585–596. CrossRefPubMedGoogle Scholar
  41. 41.
    Okano H, Imai T, Okabe M (2002) Musashi: a translational regulator of cell fate. J Cell Sci 115(Pt 7):1355–1359PubMedGoogle Scholar
  42. 42.
    Toda M, Iizuka Y, Yu W, Imai T, Ikeda E, Yoshida K, Kawase T, Kawakami Y, Okano H, Uyemura K (2001) Expression of the neural RNA-binding protein Musashi1 in human gliomas. Glia 34(1):1–7CrossRefGoogle Scholar
  43. 43.
    Capela A, Temple S (2002) LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35(5):865–875CrossRefGoogle Scholar
  44. 44.
    Read T-A, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW, Febbo PG, Wechsler-Reya RJ (2009) Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15(2):135–147CrossRefGoogle Scholar
  45. 45.
    Soltanian S, Matin MM (2011) Cancer stem cells and cancer therapy. Tumour Biol 32(3):425–440. CrossRefPubMedGoogle Scholar
  46. 46.
    Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115. CrossRefPubMedGoogle Scholar
  47. 47.
    Vilchez V, Turcios L, Zaytseva Y, Stewart R, Lee EY, Maynard E, Shah MB, Daily MF, Tzeng CW, Davenport D, Castellanos AL, Krohmer S, Hosein PJ, Evers BM, Gedaly R (2016) Cancer stem cell marker expression alone and in combination with microvascular invasion predicts poor prognosis in patients undergoing transplantation for hepatocellular carcinoma. Am J Surg 212(2):238–245. CrossRefPubMedGoogle Scholar
  48. 48.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401. CrossRefGoogle Scholar
  49. 49.
    Boman BM, Wicha MS (2008) Cancer stem cells: a step toward the cure. J Clin Oncol 26(17):2795–2799. CrossRefPubMedGoogle Scholar
  50. 50.
    Kure S, Matsuda Y, Hagio M, Ueda J, Naito Z, Ishiwata T (2012) Expression of cancer stem cell markers in pancreatic intraepithelial neoplasias and pancreatic ductal adenocarcinomas. Int J Oncol 41(4):1314–1324. CrossRefPubMedGoogle Scholar
  51. 51.
    Shien K, Toyooka S, Ichimura K, Soh J, Furukawa M, Maki Y, Muraoka T, Tanaka N, Ueno T, Asano H, Tsukuda K, Yamane M, Oto T, Kiura K, Miyoshi S (2012) Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy. Lung Cancer 77(1):162–167. CrossRefPubMedGoogle Scholar
  52. 52.
    Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S, Roz E, Caserini R, Lo Vullo S, Camerini T, Mariani L, Delia D, Calabro E, Pastorino U, Sozzi G (2009) Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci USA 106(38):16281–16286. CrossRefPubMedGoogle Scholar
  53. 53.
    Annabi B, Rojas-Sutterlin S, Laflamme C, Lachambre MP, Rolland Y, Sartelet H, Beliveau R (2008) Tumor environment dictates medulloblastoma cancer stem cell expression and invasive phenotype. Mol Cancer Res 6(6):907–916. CrossRefPubMedGoogle Scholar
  54. 54.
    Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, Van Belle PA, Xu X, Elder DE, Herlyn M (2005) A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65(20):9328–9337. CrossRefPubMedGoogle Scholar
  55. 55.
    Svachova H, Pour L, Sana J, Kovarova L, Raja KR, Hajek R (2011) Stem cell marker nestin is expressed in plasma cells of multiple myeloma patients. Leuk Res 35(8):1008–1013. CrossRefPubMedGoogle Scholar
  56. 56.
    Shabahang M, Buras RR, Davoodi F, Schumaker LM, Nauta RJ, Evans SR (1993) 1,25-Dihydroxyvitamin D3 receptor as a marker of human colon carcinoma cell line differentiation and growth inhibition. Cancer Res 53(16):3712–3718PubMedGoogle Scholar
  57. 57.
    Klonisch T, Wiechec E, Hombach-Klonisch S, Ande SR, Wesselborg S, Schulze-Osthoff K, Los M (2008) Cancer stem cell markers in common cancers – therapeutic implications. Trends Mol Med 14(10):450–460. CrossRefPubMedGoogle Scholar
  58. 58.
    O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110. CrossRefPubMedGoogle Scholar
  59. 59.
    Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, Reilly JG, Chandra D, Zhou J, Claypool K, Coghlan L, Tang DG (2006) Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25(12):1696–1708. CrossRefPubMedGoogle Scholar
  60. 60.
    Salnikov AV, Gladkich J, Moldenhauer G, Volm M, Mattern J, Herr I (2010) CD133 is indicative for a resistance phenotype but does not represent a prognostic marker for survival of non-small cell lung cancer patients. Int J Cancer 126(4):950–958. CrossRefPubMedGoogle Scholar
  61. 61.
    Isfoss BL, Busch C, Hermelin H, Vermedal AT, Kile M, Braathen GJ, Majak B, Berner A (2014) Stem cell marker-positive stellate cells and mast cells are reduced in benign-appearing bladder tissue in patients with urothelial carcinoma. Virchows Arch 464(4):473–488. CrossRefPubMedGoogle Scholar
  62. 62.
    Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564. CrossRefPubMedGoogle Scholar
  63. 63.
    Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273. CrossRefPubMedGoogle Scholar
  64. 64.
    Fabregat I, Malfettone A, Soukupova J (2016) New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med 5(3):37CrossRefGoogle Scholar
  65. 65.
    Yang JY, Zong CS, Xia W, Wei Y, Ali-Seyed M, Li Z, Broglio K, Berry DA, Hung MC (2006) MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation. Mol Cell Biol 26(19):7269–7282. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Scheel C, Weinberg RA (2012) Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol 22(5-6):396–403. CrossRefPubMedGoogle Scholar
  67. 67.
    Wu KJ (2011) Direct activation of Bmi1 by Twist1: implications in cancer stemness, epithelial-mesenchymal transition, and clinical significance. Chang Gung Med J 34(3):229–238PubMedGoogle Scholar
  68. 68.
    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939. CrossRefPubMedGoogle Scholar
  69. 69.
    Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22(6):725–736. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Ocana OH, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S, Barrallo-Gimeno A, Cano A, Nieto MA (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22(6):709–724. CrossRefPubMedGoogle Scholar
  71. 71.
    Celia-Terrassa T, Meca-Cortes O, Mateo F, Martinez de Paz A, Rubio N, Arnal-Estape A, Ell BJ, Bermudo R, Diaz A, Guerra-Rebollo M, Lozano JJ, Estaras C, Ulloa C, Alvarez-Simon D, Mila J, Vilella R, Paciucci R, Martinez-Balbas M, de Herreros AG, Gomis RR, Kang Y, Blanco J, Fernandez PL, Thomson TM (2012) Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Invest 122(5):1849–1868. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD, Herold CI, Marcom PK, George DJ, Garcia-Blanco MA (2011) Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res 9(8):997–1007. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12(19):5615–5621. CrossRefPubMedGoogle Scholar
  75. 75.
    Liu H, Patel MR, Prescher JA, Patsialou A, Qian D, Lin J, Wen S, Chang YF, Bachmann MH, Shimono Y, Dalerba P, Adorno M, Lobo N, Bueno J, Dirbas FM, Goswami S, Somlo G, Condeelis J, Contag CH, Gambhir SS, Clarke MF (2010) Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci USA 107(42):18115–18120. CrossRefPubMedGoogle Scholar
  76. 76.
    Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323. CrossRefPubMedGoogle Scholar
  77. 77.
    Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A, Hajjar KA, Stainier DY, Chen EI, Lyden D, Bissell MJ (2013) The perivascular niche regulates breast tumour dormancy. Nature Cell Biol 15(7):807–817. CrossRefPubMedGoogle Scholar
  78. 78.
    Moitra K (2015) Overcoming multidrug resistance in cancer stem cells. Biomed Res Int 2015:635745. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Hall MD, Handley MD, Gottesman MM (2009) Is resistance useless? Multidrug resistance and collateral sensitivity. Trends Pharmacol Sci 30(10):546–556. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Thomas ML, Coyle KM, Sultan M, Marcato P (2015) Cancer stem cells and chemoresistance: strategies to overcome therapeutic resistance. In: Babashah S (ed) Cancer stem cells: emerging concepts and future perspectives in translational oncology. Springer, Cham, pp 477–518. CrossRefGoogle Scholar
  81. 81.
    Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627. CrossRefPubMedGoogle Scholar
  82. 82.
    Keshet GI, Goldstein I, Itzhaki O, Cesarkas K, Shenhav L, Yakirevitch A, Treves AJ, Schachter J, Amariglio N, Rechavi G (2008) MDR1 expression identifies human melanoma stem cells. Biochem Biophys Res Commun 368(4):930–936. CrossRefPubMedGoogle Scholar
  83. 83.
    Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH (2008) Identification of cells initiating human melanomas. Nature 451(7176):345–349. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Shaffer BC, Gillet JP, Patel C, Baer MR, Bates SE, Gottesman MM (2012) Drug resistance: still a daunting challenge to the successful treatment of AML. Drug Resist Updat 15(1–2):62–69. CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Trock BJ, Leonessa F, Clarke R (1997) Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst 89(13):917–931CrossRefGoogle Scholar
  86. 86.
    Lizard-Nacol S, Genne P, Coudert B, Riedinger JM, Arnal M, Sancy C, Brunet-Lecomte P, Fargeot P (1999) MDR1 and thymidylate synthase (TS) gene expressions in advanced breast cancer: relationships to drug exposure, p53 mutations, and clinical outcome of the patients. Anticancer Res 19(4C):3575–3581PubMedGoogle Scholar
  87. 87.
    Rudas M, Filipits M, Taucher S, Stranzl T, Steger GG, Jakesz R, Pirker R, Pohl G (2003) Expression of MRP1, LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy. Breast Cancer Res Treat 81(2):149–157. CrossRefPubMedGoogle Scholar
  88. 88.
    Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95(26):15665–15670CrossRefGoogle Scholar
  89. 89.
    van den Heuvel-Eibrink MM, Wiemer EA, Prins A, Meijerink JP, Vossebeld PJ, van der Holt B, Pieters R, Sonneveld P (2002) Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML). Leukemia 16(5):833–839. CrossRefPubMedGoogle Scholar
  90. 90.
    Rentala S, Mangamoori LN (2010) Isolation, characterization and mobilization of prostate cancer tissue derived CD133+ MDR1+ cells. J Stem Cells 5(2):75–81PubMedGoogle Scholar
  91. 91.
    Fong MY, Kakar SS (2010) The role of cancer stem cells and the side population in epithelial ovarian cancer. Histol Histopathol 25(1):113–120PubMedGoogle Scholar
  92. 92.
    Nakai E, Park K, Yawata T, Chihara T, Kumazawa A, Nakabayashi H, Shimizu K (2009) Enhanced MDR1 expression and chemoresistance of cancer stem cells derived from glioblastoma. Cancer Investig 27(9):901–908. CrossRefGoogle Scholar
  93. 93.
    Ho MM, Hogge DE, Ling V (2008) MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid leukemia. Exp Hematol 36(4):433–442. CrossRefPubMedGoogle Scholar
  94. 94.
    Raaijmakers MH, de Grouw EP, Heuver LH, van der Reijden BA, Jansen JH, Scheper RJ, Scheffer GL, de Witte TJ, Raymakers RA (2005) Breast cancer resistance protein in drug resistance of primitive CD34+38- cells in acute myeloid leukemia. Clin Cancer Res 11(6):2436–2444. CrossRefPubMedGoogle Scholar
  95. 95.
    Ikawa M, Impraim CC, Wang G, Yoshida A (1983) Isolation and characterization of aldehyde dehydrogenase isozymes from usual and atypical human livers. J Biol Chem 258(10):6282–6287PubMedGoogle Scholar
  96. 96.
    Marchitti SA, Brocker C, Stagos D, Vasiliou V (2008) Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol 4(6):697–720. CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Abdullah LN, Chow EK (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2(1):3. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, Pickell K, Aguilar J, Lazetic S, Smith-Berdan S, Clarke MF, Hoey T, Lewicki J, Gurney AL (2008) Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One 3(6):e2428. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Duong HQ, Hwang JS, Kim HJ, Kang HJ, Seong YS, Bae I (2012) Aldehyde dehydrogenase 1A1 confers intrinsic and acquired resistance to gemcitabine in human pancreatic adenocarcinoma MIA PaCa-2 cells. Int J Oncol 41(3):855–861. CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Pegoraro L, Palumbo A, Erikson J, Falda M, Giovanazzo B, Emanuel BS, Rovera G, Nowell PC, Croce CM (1984) A 14;18 and an 8;14 chromosome translocation in a cell line derived from an acute B-cell leukemia. Proc Natl Acad Sci USA 81(22):7166–7170CrossRefGoogle Scholar
  102. 102.
    Graninger WB, Seto M, Boutain B, Goldman P, Korsmeyer SJ (1987) Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. J Clin Investig 80(5):1512–1515. CrossRefPubMedGoogle Scholar
  103. 103.
    Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67. CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Shervington A, Lu C (2008) Expression of multidrug resistance genes in normal and cancer stem cells. Cancer Investig 26(5):535–542. CrossRefGoogle Scholar
  105. 105.
    Madjd Z, Mehrjerdi AZ, Sharifi AM, Molanaei S, Shahzadi SZ, Asadi-Lari M (2009) CD44+ cancer cells express higher levels of the anti-apoptotic protein Bcl-2 in breast tumours. Cancer Immun 9:4PubMedPubMedCentralGoogle Scholar
  106. 106.
    Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY (2008) CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27(12):1749–1758. CrossRefPubMedGoogle Scholar
  107. 107.
    Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, Stassi G (2007) Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1(4):389–402. CrossRefPubMedGoogle Scholar
  108. 108.
    Cammareri P, Scopelliti A, Todaro M, Eterno V, Francescangeli F, Moyer MP, Agrusa A, Dieli F, Zeuner A, Stassi G (2010) Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells. Cancer Res 70(11):4655–4665. CrossRefPubMedGoogle Scholar
  109. 109.
    Gonzalez C (2002) Aurora-A in cell fate control. Sci STKE: Signal Transduct Knowl Environ 2002(162):pe48. CrossRefGoogle Scholar
  110. 110.
    Olcina M, Lecane PS, Hammond EM (2010) Targeting hypoxic cells through the DNA damage response. Clin Cancer Res 16(23):5624–5629. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ (2002) Hypoxia links ATR and p53 through replication arrest. Mol Cell Biol 22(6):1834–1843CrossRefGoogle Scholar
  112. 112.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760. CrossRefGoogle Scholar
  113. 113.
    Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL (2003) A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423(6938):409–414. CrossRefPubMedGoogle Scholar
  114. 114.
    Bisson I, Prowse DM (2009) WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res 19(6):683–697. CrossRefPubMedGoogle Scholar
  115. 115.
    Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, Zhang SH, Huang DD, Tang L, Kong XN, Chen C, Liu SQ, Wu MC, Wang HY (2008) Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68(11):4287–4295. CrossRefPubMedGoogle Scholar
  116. 116.
    Flahaut M, Meier R, Coulon A, Nardou KA, Niggli FK, Martinet D, Beckmann JS, Joseph JM, Muhlethaler-Mottet A, Gross N (2009) The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/beta-catenin pathway. Oncogene 28(23):2245–2256. CrossRefPubMedGoogle Scholar
  117. 117.
    Chau WK, Ip CK, Mak AS, Lai HC, Wong AS (2013) c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/beta-catenin-ATP-binding cassette G2 signaling. Oncogene 32(22):2767–2781. CrossRefPubMedGoogle Scholar
  118. 118.
    Meng RD, Shelton CC, Li YM, Qin LX, Notterman D, Paty PB, Schwartz GK (2009) gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res 69(2):573–582. CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    McAuliffe SM, Morgan SL, Wyant GA, Tran LT, Muto KW, Chen YS, Chin KT, Partridge JC, Poole BB, Cheng KH, Daggett J Jr, Cullen K, Kantoff E, Hasselbatt K, Berkowitz J, Muto MG, Berkowitz RS, Aster JC, Matulonis UA, Dinulescu DM (2012) Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc Natl Acad Sci USA 109(43):E2939–E2948. CrossRefPubMedGoogle Scholar
  120. 120.
    Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH, Nephew KP (2008) Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 68(11):4311–4320. CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Leizer AL, Alvero AB, Fu HH, Holmberg JC, Cheng YC, Silasi DA, Rutherford T, Mor G (2011) Regulation of inflammation by the NF-kappaB pathway in ovarian cancer stem cells. Am J Reprod Immunol 65(4):438–447. CrossRefPubMedGoogle Scholar
  122. 122.
    Mahomoodally MF, Gurib-Fakim A, Subratty AH (2008) Antimicrobial activities and phytochemical profiles of endemic medicinal plants of Mauritius. Pharm BiolGoogle Scholar
  123. 123.
    Middleton E Jr (1998) Effect of plant flavonoids on immune and inflammatory cell function. In: Manthey JA, Buslig BS (eds) Flavonoids in the living system. Springer, Boston, pp 175–182CrossRefGoogle Scholar
  124. 124.
    Kuhnau J (1976) The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet 24:117–191CrossRefGoogle Scholar
  125. 125.
    Herrmann K (1976) Flavonols and flavones in food plants: a review. Int J Food Sc Technol 11(5):433–448CrossRefGoogle Scholar
  126. 126.
    Pierpoint WS (1986) Flavonoids in the human diet. Prog Clin Biol Res 213:125–140PubMedGoogle Scholar
  127. 127.
    Mazur W, Fotsis T, Wahala K, Ojala S, Salakka A, Adlercreutz H (1996) Isotope dilution gas chromatographic-mass spectrometric method for the determination of isoflavonoids, coumestrol, and lignans in food samples. Anal Biochem 233(2):169–180. CrossRefPubMedGoogle Scholar
  128. 128.
    Yao LH, Jiang YM, Shi J, Tomas-Barberan FA, Datta N, Singanusong R, Chen SS (2004) Flavonoids in food and their health benefits. Plant Foods Hum Nutr 59(3):113–122CrossRefGoogle Scholar
  129. 129.
    Cook N (1996) Flavonoids?Chemistry, metabolism, cardioprotective effects, and dietary sources. J Eur Ceram Soc 7(2):66–76. CrossRefGoogle Scholar
  130. 130.
    Rice-Evans CA, Miller NJ, Bolwell PG, Bramley PM, Pridham JB (1995) The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res 22(4):375–383CrossRefGoogle Scholar
  131. 131.
    Nijveldt RJ (2001) Flavonoids: a review of probable mechanism of action and potential applications. Am J Clin Nutr 74:418–425CrossRefGoogle Scholar
  132. 132.
    Shashank K, Abhay KP (2013) Review article chemistry and biological activities of flavonoids: an overview. Sci World J 4(2):32–48Google Scholar
  133. 133.
    Fukumoto LR, Mazza G (2000) Assessing antioxidant and prooxidant activities of phenolic compounds. J Agric Food Chem 48(8):3597–3604CrossRefGoogle Scholar
  134. 134.
    Heim KE, Tagliaferro AR, Bobilya DJ (2002) Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 13(10):572–584CrossRefGoogle Scholar
  135. 135.
    Mishra A, Kumar S, Pandey AK (2013) Scientific validation of the medicinal efficacy of Tinospora cordifolia. Sci World J 2013:292934. CrossRefGoogle Scholar
  136. 136.
    Land ET (2009) Free radicals in biology and medicine. Int J Radiat Biol 58(4):725–725. CrossRefGoogle Scholar
  137. 137.
    Brown JE, Khodr H, Hider RC, Rice-Evans CA (1998) Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties. Biochem J 330(Pt 3):1173–1178CrossRefGoogle Scholar
  138. 138.
    van Acker SA, van den Berg DJ, Tromp MN, Griffioen DH, van Bennekom WP, van der Vijgh WJ, Bast A (1996) Structural aspects of antioxidant activity of flavonoids. Free Radic Biol Med 20(3):331–342CrossRefGoogle Scholar
  139. 139.
    Mishra A, Sharma AK, Kumar S, Saxena AK, Pandey AK (2013) Bauhinia variegata leaf extracts exhibit considerable antibacterial, antioxidant, and anticancer activities. Biomed Res Int 2013:915436. CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 74(4):418–425CrossRefGoogle Scholar
  141. 141.
    Dames J, Bourdon V, Remacle-Uolon G, Lecomte J (1985) Pro-inflammatory flavonoids which are inhibitors of prostaglandin biosynthesis. Prostaglandins Leukot Med 19(1):11–24. CrossRefGoogle Scholar
  142. 142.
    Kim HP, Mani I, Iversen L, Ziboh VA (1998) Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostaglandins Leukot Essent Fatty Acids 58(1):17–24CrossRefGoogle Scholar
  143. 143.
    Tordera M, Ferrandiz ML, Alcaraz MJ (1994) Influence of anti-inflammatory flavonoids on degranulation and arachidonic acid release in rat neutrophils. Zeitschrift fur Naturforschung C. J Biosci 49(3–4):235–240Google Scholar
  144. 144.
    Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D (1993) Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 342(8878):1007–1011CrossRefGoogle Scholar
  145. 145.
    Fuhrman B, Aviram M (2001) Flavonoids protect LDL from oxidation and attenuate atherosclerosis. Curr Opin Lipidol 12(1):41–48CrossRefGoogle Scholar
  146. 146.
    Fuhrman B, Lavy A, Aviram M (1995) Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation. Am J Clin Nutr 61(3):549–554CrossRefGoogle Scholar
  147. 147.
    Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R, Kinae N (2000) Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 130(9):2243–2250CrossRefGoogle Scholar
  148. 148.
    Hodgson JM, Croft KD (2006) Dietary flavonoids: effects on endothelial function and blood pressure. J Sci Food Agric 86(15):2492–2498. CrossRefGoogle Scholar
  149. 149.
    Lou FQ, Zhang MF, Zhang XG, Liu JM, Yuan WL (1989) A study on tea-pigment in prevention of atherosclerosis. Chin Med J (Engl) 102(8):579–583Google Scholar
  150. 150.
    Rein D, Paglieroni TG, Pearson DA, Wun T, Schmitz HH, Gosselin R, Keen CL (2000) Cocoa and wine polyphenols modulate platelet activation and function. J Nutr 130(8S Suppl):2120S–2126SCrossRefGoogle Scholar
  151. 151.
    Xiao ZP, Peng ZY, Peng MJ, Yan WB, Ouyang YZ, Zhu HL (2011) Flavonoids health benefits and their molecular mechanism. Mini Rev Med Chem 11(2):169–177CrossRefGoogle Scholar
  152. 152.
    Gibellini L, Pinti M, Nasi M, Montagna JP, De Biasi S, Roat E, Bertoncelli L, Cooper EL, Cossarizza A (2011) Quercetin and cancer chemoprevention. Evid-Based Complement Alternat Med 2011:591356. CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Park E-J, Pezzuto JM (2012) Flavonoids in cancer prevention. Anti-Cancer Agents Med Chem 12(8):836–851. CrossRefGoogle Scholar
  154. 154.
    Es-Safi NE, Ghidouche S, Ducrot PH (2007) Flavonoids: hemisynthesis, reactivity, characterization and free radical scavenging activity. Molecules 12(9):2228–2258CrossRefGoogle Scholar
  155. 155.
    Tan S, Wang C, Lu C, Zhao B, Cui Y, Shi X, Ma X (2009) Quercetin is able to demethylate the p16INK4a gene promoter. Chemotherapy 55(1):6–10. CrossRefPubMedGoogle Scholar
  156. 156.
    Zhang G, Yang P, Guo P, Miele L, Sarkar FH, Wang Z, Zhou Q (2013) Unraveling the mystery of cancer metabolism in the genesis of tumor-initiating cells and development of cancer. Biochim Biophys Acta 1836(1):49–59. CrossRefPubMedGoogle Scholar
  157. 157.
    Li Y, Wicha MS, Schwartz SJ, Sun D (2011) Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem 22(9):799–806. CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, Paulson KE, Yee AS (2006) Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J Biol Chem 281(16):10865–10875. CrossRefPubMedGoogle Scholar
  159. 159.
    Reguart N, He B, Taron M, You L, Jablons DM, Rosell R (2005) The role of Wnt signaling in cancer and stem cells. Future Oncol 1(6):787–797. CrossRefPubMedGoogle Scholar
  160. 160.
    Montales MT, Rahal OM, Kang J, Rogers TJ, Prior RL, Wu X, Simmen RC (2012) Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells. Carcinogenesis 33(3):652–660. CrossRefPubMedGoogle Scholar
  161. 161.
    Zhou W, Kallifatidis G, Baumann B, Rausch V, Mattern J, Gladkich J, Giese N, Moldenhauer G, Wirth T, Buchler MW, Salnikov AV, Herr I (2010) Dietary polyphenol quercetin targets pancreatic cancer stem cells. Int J Oncol 37(3):551–561PubMedGoogle Scholar
  162. 162.
    Subramaniam D, Ponnurangam S, Ramamoorthy P, Standing D, Battafarano RJ, Anant S, Sharma P (2012) Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. PLoS One 7(2):e30590. CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Shakibaei M, Buhrmann C, Kraehe P, Shayan P, Lueders C, Goel A (2014) Curcumin chemosensitizes 5-fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures. PLoS One 9(1):e85397. CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Sun XD, Liu XE, Huang DS (2013) Curcumin reverses the epithelial-mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway. Oncol Rep 29(6):2401–2407. CrossRefPubMedGoogle Scholar
  165. 165.
    Dandawate P, Subramaniam D, Anant S (2016) Targeting cancer stem cells by functional foods and their constituents. In: Food toxicology. CRC Press, Boca Raton, pp 433–460. doi: CrossRefGoogle Scholar
  166. 166.
    Zhang Y, Li Q, Zhou D, Chen H (2013) Genistein, a soya isoflavone, prevents azoxymethane-induced up-regulation of WNT/beta-catenin signalling and reduces colon pre-neoplasia in rats. Br J Nutr 109(1):33–42. CrossRefPubMedGoogle Scholar
  167. 167.
    Zhang Y, Chen H (2011) Genistein attenuates WNT signaling by up-regulating sFRP2 in a human colon cancer cell line. Exp Biol Med (Maywood) 236(6):714–722. CrossRefGoogle Scholar
  168. 168.
    Fan P, Fan S, Wang H, Mao J, Shi Y, Ibrahim MM, Ma W, Yu X, Hou Z, Wang B, Li L (2013) Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway. Stem Cell Res Ther 4(6):146. CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Pahlke G, Ngiewih Y, Kern M, Jakobs S, Marko D, Eisenbrand G (2006) Impact of quercetin and EGCG on key elements of the Wnt pathway in human colon carcinoma cells. J Agric Food Chem 54(19):7075–7082. CrossRefPubMedGoogle Scholar
  170. 170.
    Tang SN, Fu J, Nall D, Rodova M, Shankar S, Srivastava RK (2012) Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int J Cancer 131(1):30–40. CrossRefPubMedGoogle Scholar
  171. 171.
    Nautiyal J, Kanwar SS, Yu Y, Majumdar AP (2011) Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. J Mol Signal 6:7. CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Lin L, Liu Y, Li H, Li PK, Fuchs J, Shibata H, Iwabuchi Y, Lin J (2011) Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030. Br J Cancer 105(2):212–220. CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Yu Y, Kanwar SS, Patel BB, Nautiyal J, Sarkar FH, Majumdar AP (2009) Elimination of colon cancer stem-like cells by the combination of curcumin and FOLFOX. Transl Oncol 2(4):321–328CrossRefGoogle Scholar
  174. 174.
    Kanwar SS, Yu Y, Nautiyal J, Patel BB, Padhye S, Sarkar FH, Majumdar AP (2011) Difluorinated-curcumin (CDF): a novel curcumin analog is a potent inhibitor of colon cancer stem-like cells. Pharm Res 28(4):827–838. CrossRefPubMedGoogle Scholar
  175. 175.
    Bao B, Ali S, Kong D, Sarkar SH, Wang Z, Banerjee S, Aboukameel A, Padhye S, Philip PA, Sarkar FH (2011) Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer. PLoS One 6(3):e17850. CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS, Kong D, Ahmad A, Li Y, Padhye S, Sarkar FH (2012) Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res 72(1):335–345. CrossRefPubMedGoogle Scholar
  177. 177.
    Bao B, Wang Z, Ali S, Kong D, Banerjee S, Ahmad A, Li Y, Azmi AS, Miele L, Sarkar FH (2011) Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem 112(9):2296–2306. CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    To KK, Yu L, Liu S, Fu J, Cho CH (2012) Constitutive AhR activation leads to concomitant ABCG2-mediated multidrug resistance in cisplatin-resistant esophageal carcinoma cells. Mol Carcinog 51(6):449–464. CrossRefPubMedGoogle Scholar
  179. 179.
    Cook MT, Liang Y, Besch-Williford C, Goyette S, Mafuvadze B, Hyder SM (2015) Luteolin inhibits progestin-dependent angiogenesis, stem cell-like characteristics, and growth of human breast cancer xenografts. SpringerPlus 4:444. CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Mineva ND, Paulson KE, Naber SP, Yee AS, Sonenshein GE (2013) Epigallocatechin-3-gallate inhibits stem-like inflammatory breast cancer cells. PLoS One 8(9):e73464. CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Dandawate P, Padhye S, Ahmad A, Sarkar FH (2013) Novel strategies targeting cancer stem cells through phytochemicals and their analogs. Drug Deliv Transl Res 3(2):165–182. CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Kawasaki BT, Hurt EM, Mistree T, Farrar WL (2008) Targeting cancer stem cells with phytochemicals. Mol Interv 8(4):174–184. CrossRefPubMedGoogle Scholar
  183. 183.
    Li YJ, Wu SL, Lu SM, Chen F, Guo Y, Gan SM, Shi YL, Liu S, Li SL (2015) (-)-Epigallocatechin-3-gallate inhibits nasopharyngeal cancer stem cell self-renewal and migration and reverses the epithelial-mesenchymal transition via NF-kappaB p65 inactivation. Tumour Biol 36(4):2747–2761. CrossRefPubMedGoogle Scholar
  184. 184.
    Johnson JJ, Bailey HH, Mukhtar H (2010) Green tea polyphenols for prostate cancer chemoprevention: a translational perspective. Phytomedicine 17(1):3–13. CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Tang SN, Singh C, Nall D, Meeker D, Shankar S, Srivastava RK (2010) The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition. J Mol Signal 5:14. CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Yu R, Jiao JJ, Duh JL, Gudehithlu K, Tan TH, Kong AN (1997) Activation of mitogen-activated protein kinases by green tea polyphenols: potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression. Carcinogenesis 18(2):451–456CrossRefGoogle Scholar
  187. 187.
    Amado NG, Fonseca BF, Cerqueira DM, Neto VM, Abreu JG (2011) Flavonoids: potential Wnt/beta-catenin signaling modulators in cancer. Life Sci 89(15-16):545–554. CrossRefPubMedGoogle Scholar
  188. 188.
    Zhou Q, Ye M, Lu Y, Zhang H, Chen Q, Huang S, Su S (2015) Curcumin improves the tumoricidal effect of mitomycin C by suppressing ABCG2 expression in stem cell-like breast cancer cells. PLoS One 10(8):e0136694. CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Chung SS, Vadgama JV (2015) Curcumin and epigallocatechin gallate inhibit the cancer stem cell phenotype via down-regulation of STAT3-NFkappaB signaling. Anticancer Res 35(1):39–46PubMedPubMedCentralGoogle Scholar
  190. 190.
    Zhang J, Du Y, Wu C, Ren X, Ti X, Shi J, Zhao F, Yin H (2010) Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186* signaling pathway. Oncol Rep 24(5):1217–1223PubMedGoogle Scholar
  191. 191.
    James MI, Iwuji C, Irving G, Karmokar A, Higgins JA, Griffin-Teal N, Thomas A, Greaves P, Cai H, Patel SR, Morgan B, Dennison A, Metcalfe M, Garcea G, Lloyd DM, Berry DP, Steward WP, Howells LM, Brown K (2015) Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy. Cancer Lett 364(2):135–141. CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Kantara C, O’Connell M, Sarkar S, Moya S, Ullrich R, Singh P (2014) Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siRNA. Cancer Res 74(9):2487–2498. CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Park CH, Hahm ER, Park S, Kim HK, Yang CH (2005) The inhibitory mechanism of curcumin and its derivative against beta-catenin/Tcf signaling. FEBS Lett 579(13):2965–2971. CrossRefPubMedGoogle Scholar
  194. 194.
    Jaiswal AS, Marlow BP, Gupta N, Narayan S (2002) Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 21(55):8414–8427. CrossRefPubMedGoogle Scholar
  195. 195.
    Marquardt JU, Gomez-Quiroz L, Arreguin Camacho LO, Pinna F, Lee YH, Kitade M, Dominguez MP, Castven D, Breuhahn K, Conner EA, Galle PR, Andersen JB, Factor VM, Thorgeirsson SS (2015) Curcumin effectively inhibits oncogenic NF-kappaB signaling and restrains stemness features in liver cancer. J Hepatol 63(3):661–669. CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH (2006) Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 106(11):2503–2513. CrossRefPubMedGoogle Scholar
  197. 197.
    Hong M, Tan HY, Li S, Cheung F, Wang N, Nagamatsu T, Feng Y (2016) Cancer stem cells: the potential targets of chinese medicines and their active compounds. Int J Mol Sci 17(6). CrossRefGoogle Scholar
  198. 198.
    Surh YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3(10):768–780. CrossRefPubMedGoogle Scholar
  199. 199.
    Fong D, Yeh A, Naftalovich R, Choi TH, Chan MM (2010) Curcumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals. Cancer Lett 293(1):65–72. CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Adikrisna R, Tanaka S, Muramatsu S, Aihara A, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Yamaoka S, Arii S (2012) Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents. Gastroenterology 143(1):234–245 e237. CrossRefPubMedGoogle Scholar
  201. 201.
    Atashpour S, Fouladdel S, Movahhed TK, Barzegar E, Ghahremani MH, Ostad SN, Azizi E (2015) Quercetin induces cell cycle arrest and apoptosis in CD133(+) cancer stem cells of human colorectal HT29 cancer cell line and enhances anticancer effects of doxorubicin. Iran J Basic Med Sci 18(7):635–643PubMedPubMedCentralGoogle Scholar
  202. 202.
    Chang WW, Hu FW, Yu CC, Wang HH, Feng HP, Lan C, Tsai LL, Chang YC (2013) Quercetin in elimination of tumor initiating stem-like and mesenchymal transformation property in head and neck cancer. Head Neck 35(3):413–419. CrossRefPubMedGoogle Scholar
  203. 203.
    Imai Y, Tsukahara S, Asada S, Sugimoto Y (2004) Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. Cancer Res 64(12):4346–4352. CrossRefPubMedGoogle Scholar
  204. 204.
    Pan H, Zhou W, He W, Liu X, Ding Q, Ling L, Zha X, Wang S (2012) Genistein inhibits MDA-MB-231 triple-negative breast cancer cell growth by inhibiting NF-kappaB activity via the Notch-1 pathway. Int J Mol Med 30(2):337–343. CrossRefPubMedGoogle Scholar
  205. 205.
    Chen Y, Zaman MS, Deng G, Majid S, Saini S, Liu J, Tanaka Y, Dahiya R (2011) MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer. Cancer Prev Res (Phila) 4(1):76–86. CrossRefGoogle Scholar
  206. 206.
    Zhang L, Li L, Jiao M, Wu D, Wu K, Li X, Zhu G, Yang L, Wang X, Hsieh JT, He D (2012) Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway. Cancer Lett 323(1):48–57. CrossRefPubMedGoogle Scholar
  207. 207.
    Xia J, Duan Q, Ahmad A, Bao B, Banerjee S, Shi Y, Ma J, Geng J, Chen Z, Rahman KM, Miele L, Sarkar FH, Wang Z (2012) Genistein inhibits cell growth and induces apoptosis through up-regulation of miR-34a in pancreatic cancer cells. Curr Drug Targets 13(14):1750–1756CrossRefGoogle Scholar
  208. 208.
    Hirata H, Ueno K, Nakajima K, Tabatabai ZL, Hinoda Y, Ishii N, Dahiya R (2013) Genistein downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells. Br J Cancer 108(10):2070–2078. CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Yu D, Shin HS, Lee YS, Lee D, Kim S, Lee YC (2014) Genistein attenuates cancer stem cell characteristics in gastric cancer through the downregulation of Gli1. Oncol Rep 31(2):673–678. CrossRefPubMedGoogle Scholar
  210. 210.
    Ning Y, Luo C, Ren K, Quan M, Cao J (2014) FOXO3a-mediated suppression of the self-renewal capacity of sphere-forming cells derived from the ovarian cancer SKOV3 cell line by 7-difluoromethoxyl-5,4’-di-n-octyl genistein. Mol Med Rep 9(5):1982–1988. CrossRefPubMedGoogle Scholar
  211. 211.
    Kim TH, Woo JS, Kim YK, Kim KH (2014) Silibinin induces cell death through reactive oxygen species-dependent downregulation of notch-1/ERK/Akt signaling in human breast cancer cells. J Pharmacol Exp Ther 349(2):268–278. CrossRefPubMedGoogle Scholar
  212. 212.
    Lu W, Lin C, King TD, Chen H, Reynolds RC, Li Y (2012) Silibinin inhibits Wnt/beta-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells. Cell Signal 24(12):2291–2296. CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Kumar S, Raina K, Agarwal C, Agarwal R (2014) Silibinin strongly inhibits the growth kinetics of colon cancer stem cell-enriched spheroids by modulating interleukin 4/6-mediated survival signals. Oncotarget 5(13):4972–4989. CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Ting H, Deep G, Agarwal R (2013) Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer. AAPS J 15(3):707–716. CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Kim B, Jung N, Lee S, Sohng JK, Jung HJ (2016) Apigenin inhibits cancer stem cell-like phenotypes in human glioblastoma cells via suppression of c-Met signaling. Phytother Res 30(11):1833–1840. CrossRefPubMedGoogle Scholar
  216. 216.
    Ketkaew Y, Osathanon T, Pavasant P, Sooampon S (2016) Apigenin inhibited hypoxia induced stem cell marker expression in a head and neck squamous cell carcinoma cell line. Arch Oral Biol 74:69–74. CrossRefPubMedGoogle Scholar
  217. 217.
    Erdogan S, Doganlar O, Doganlar ZB, Serttas R, Turkekul K, Dibirdik I, Bilir A (2016) The flavonoid apigenin reduces prostate cancer CD44(+) stem cell survival and migration through PI3K/Akt/NF-kappaB signaling. Life Sci 162:77–86. CrossRefPubMedGoogle Scholar
  218. 218.
    Quan MF, Xiao LH, Liu ZH, Guo H, Ren KQ, Liu F, Cao JG, Deng XY (2013) 8-bromo-7-methoxychrysin inhibits properties of liver cancer stem cells via downregulation of beta-catenin. World J Gastroenterol 19(43):7680–7695. CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Ren KQ, Cao XZ, Liu ZH, Guo H, Quan MF, Liu F, Jiang L, Xiang HL, Deng XY, Cao JG (2013) 8-bromo-5-hydroxy-7-methoxychrysin targeting for inhibition of the properties of liver cancer stem cells by modulation of Twist signaling. Int J Oncol 43(5):1719–1729. CrossRefPubMedGoogle Scholar
  220. 220.
    Syed DN, Afaq F, Maddodi N, Johnson JJ, Sarfaraz S, Ahmad A, Setaluri V, Mukhtar H (2011) Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/beta-catenin signaling and decreased Mitf levels. J Invest Dermatol 131(6):1291–1299. CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Sun DW, Zhang HD, Mao L, Mao CF, Chen W, Cui M, Ma R, Cao HX, Jing CW, Wang Z, Wu JZ, Tang JH (2015) Luteolin inhibits breast cancer development and progression in vitro and in vivo by suppressing notch signaling and regulating MiRNAs. Cell Physiol Biochem 37(5):1693–1711. CrossRefPubMedGoogle Scholar
  222. 222.
    Pandurangan AK, Dharmalingam P, Sadagopan SK, Ganapasam S (2014) Luteolin inhibits matrix metalloproteinase 9 and 2 in azoxymethane-induced colon carcinogenesis. Hum Exp Toxicol 33(11):1176–1185. CrossRefPubMedGoogle Scholar
  223. 223.
    Tu DG, Lin WT, Yu CC, Lee SS, Peng CY, Lin T, Yu CH (2016) Chemotherapeutic effects of luteolin on radio-sensitivity enhancement and interleukin-6/signal transducer and activator of transcription 3 signaling repression of oral cancer stem cells. J Formos Med Assoc 115:1032. CrossRefPubMedGoogle Scholar
  224. 224.
    Choi C-H (2005) ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 5(1):1CrossRefGoogle Scholar
  225. 225.
    Tan B, Piwnica-Worms D, Ratner L (2000) Multidrug resistance transporters and modulation. Curr Opin Oncol 12(5):450–458CrossRefGoogle Scholar
  226. 226.
    Tan B, Piwnica-Worms D, Ratner L (2000) Multidrug resistance transporters and modulation. Curr Opin Oncol 12(5):450–458CrossRefGoogle Scholar
  227. 227.
    Schumacher M, Hautzinger A, Rossmann A, Holzhauser S, Popovic D, Hertrampf A, Kuntz S, Boll M, Wenzel U (2010) Chrysin blocks topotecan-induced apoptosis in Caco-2 cells in spite of inhibition of ABC-transporters. Biochem Pharmacol 80(4):471–479CrossRefGoogle Scholar
  228. 228.
    De Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V (2008) Effect of grapefruit juice, naringin, naringenin, and bergamottin on the intestinal carrier-mediated transport of talinolol in rats. J Agric Food Chem 56(12):4840–4845CrossRefGoogle Scholar
  229. 229.
    Zhang S, Wang X, Sagawa K, Morris ME (2005) Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (–/–) mice. Drug Metab Dispos 33(3):341–348CrossRefGoogle Scholar
  230. 230.
    Jodoin J, Demeule M, Béliveau R (2002) Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta 1542(1):149–159CrossRefGoogle Scholar
  231. 231.
    Mei Y, Wei D, Liu J (2003) Reversal of cancer multidrug resistance by tea polyphenol in KB cells. J Chemother 15(3):260–265. CrossRefPubMedGoogle Scholar
  232. 232.
    Zhu A, Wang X, Guo Z (2001) Study of tea polyphenol as a reversal agent for carcinoma cell lines’ multidrug resistance (study of TP as a MDR reversal agent). Nucl Med Biol 28(6):735–740. CrossRefPubMedGoogle Scholar
  233. 233.
    Ekhart C, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD (2009) An overview of the relations between polymorphisms in drug metabolising enzymes and drug transporters and survival after cancer drug treatment. Cancer Treat Rev 35(1):18–31CrossRefGoogle Scholar
  234. 234.
    Peng SX, Ritchie DM, Cousineau M, Danser E, Dewire R, Floden J (2006) Altered oral bioavailability and pharmacokinetics of P-glycoprotein substrates by coadministration of biochanin A. J Pharm Sci 95(9):1984–1993. CrossRefPubMedGoogle Scholar
  235. 235.
    Li Y, Revalde JL, Reid G, Paxton JW (2010) Interactions of dietary phytochemicals with ABC transporters: possible implications for drug disposition and multidrug resistance in cancer. Drug Metab Rev 42(4):590–611. CrossRefPubMedGoogle Scholar
  236. 236.
    Kioka N, Hosokawa N, Komano T, Hirayoshi K, Nagate K, Ueda K (1992) Quercetin, a bioflavonoid, inhibits the increase of human multidrug resistance gene (MDR1) expression caused by arsenite. FEBS Lett 301(3):307–309CrossRefGoogle Scholar
  237. 237.
    Di Pietro A, Dayan G, Conseil G, Steinfels E, Krell T, Trompier D, Baubichon-Cortay H, Jault J-M (1999) P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships. Braz J Med Biol Res 32(8):925–939CrossRefGoogle Scholar
  238. 238.
    Shapiro AB, Ling V (1997) Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochem Pharmacol 53(4):587–596CrossRefGoogle Scholar
  239. 239.
    Wu CP, Calcagno AM, Hladky SB, Ambudkar SV, Barrand MA (2005) Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). FEBS J 272(18):4725–4740CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Kushal Kandhari
    • 1
  • Hina Agraval
    • 1
  • Arpana Sharma
    • 1
  • Umesh C. S. Yadav
    • 1
  • Rana P. Singh
    • 2
    Email author
  1. 1.School of Life SciencesCentral University of GujaratGandhinagarIndia
  2. 2.Cancer Biology Laboratory, School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia

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