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Resistance and DNA Repair Mechanisms of Cancer Stem Cells: Potential Molecular Targets for Therapy

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Abstract

Cancer stem cells (CSCs) are small subpopulations of cells within tumors that are intricately related to both de novo and acquired resistance to conventional therapies leading to tumor recurrence and metastasis. A majority of cancers initially respond to chemotherapeutic agents, as well as radiation therapy, but eventually develop resistance. An increased understanding of CSCs has led to the discovery that current treatments target the differentiated cancer cells leaving the CSCs unscathed due to their robust signaling pathways. Further, maintenance of genomic fidelity is important for normal functioning and survival of cells, including cancer cells and the CSCs. In this chapter, we will discuss several such pathways/phenomena which help CSCs resist therapies. These include increased quiescence and up-regulated drug transporters, activated DNA repair mechanisms and activation of several key cellular signaling pathways (Fig. 3.1). A better understanding of these resistance pathways is a necessary prerequisite towards the ultimate goal of developing novel strategies specifically targeting CSCs. Better designed therapies could ultimately reverse their resistance and thereby eliminate the potential of tumor recurrence and metastasis.

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References

  1. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212–236

    Article  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  3. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 66:9339–9344

    Article  PubMed  CAS  Google Scholar 

  4. Farnie G, Clarke RB (2007) Mammary stem cells and breast cancer—role of Notch signalling. Stem Cell Rev 3:169–175

    Article  PubMed  CAS  Google Scholar 

  5. Wang Z, Li Y, Banerjee S, Sarkar FH (2009) Emerging role of Notch in stem cells and cancer. Cancer Lett 279:8–12

    Article  PubMed  CAS  Google Scholar 

  6. Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, Miele L (2010) Targeting Notch to target cancer stem cells. Clin Cancer Res 16:3141–152

    Article  PubMed  CAS  Google Scholar 

  7. Katoh M, Katoh M (2007) WNT signaling pathway and stem cell signaling network. Clin Cancer Res 13:4042–4045

    Article  PubMed  CAS  Google Scholar 

  8. Katoh Y, Katoh M (2006) Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review). Int J Mol Med 18:1019–1023

    PubMed  CAS  Google Scholar 

  9. Medina V, Calvo MB, az-Prado S, Espada, J (2009) Hedgehog signalling as a target in cancer stem cells. Clin Transl Oncol 11:199–207

    Article  PubMed  CAS  Google Scholar 

  10. Cerdan C, Bhatia M (2010) Novel roles for Notch, Wnt and Hedgehog in hematopoesis derived from human pluripotent stem cells. Int J Dev Biol 54:955–963

    Article  PubMed  CAS  Google Scholar 

  11. Takebe N, Harris PJ, Warren RQ, Ivy SP (2011) Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 8:97–106

    Article  PubMed  CAS  Google Scholar 

  12. Mathews LA, Cabarcas SM, Farrar WL (2011) DNA repair: the culprit for tumor-initiating cell survival? Cancer Metastasis Rev 30:185–197

    Article  PubMed  Google Scholar 

  13. Blanpain C, Mohrin M, Sotiropoulou PA, Passegue E (2011) DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell 8:16–29

    Article  PubMed  CAS  Google Scholar 

  14. Lacerda L, Pusztai L, Woodward WA (2010) The role of tumor initiating cells in drug resistance of breast cancer: implications for future therapeutic approaches. Drug Resist Updat 13:99–108

    Article  PubMed  CAS  Google Scholar 

  15. Wang Z, Li Y, Ahmad A, Azmi AS, Kong D, Banerje S, Sarkar FH (2010) Targeting miRNAs involved in cancer stem cell and EMT regulation: an emerging concept in overcoming drug resistance. Drug Resist Updat 13:109–118

    Article  PubMed  CAS  Google Scholar 

  16. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284

    Article  PubMed  CAS  Google Scholar 

  17. Moore N, Lyle S (2011) Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance. J Oncol (PMID: 20936110; doi:10.1155/2011/396076, http://www.hindawi.com/journals/jo/2011/396076/)

    Google Scholar 

  18. Viale A, Pelicci PG (2009) Awaking stem cells from dormancy: growing old and fighting cancer. EMBO Mol Med 1:88–91

    Article  PubMed  CAS  Google Scholar 

  19. Li L, Bhatia R (2011) Stem cell quiescence. Clin Cancer Res 17:4936–4941

    Article  PubMed  CAS  Google Scholar 

  20. Dembinski JL, Kraus S (2009) Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma. Clin Exp Metastasis 26:611–623

    Article  PubMed  CAS  Google Scholar 

  21. Gao MQ, Choi YP, Kang S, Youn JH, Cho NH (2010) CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene 29:2672–2680

    Article  PubMed  CAS  Google Scholar 

  22. Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A, Basu D, Gimotty P, Vogt T, Herlyn M (2010) A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141:583–594

    Article  PubMed  CAS  Google Scholar 

  23. Forsberg EC, Passegue E, Prohaska SS, Wagers AJ, Koeva M, Stuart JM, Weissman IL (2010) Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic stem cells. PLoS One 5:e8785

    Article  PubMed  CAS  Google Scholar 

  24. Ichihara E, Kaneda K, Saito Y, Yamakawa N, Morishita K (2011) Angiopoietin1 contributes to the maintenance of cell quiescence in EVI1(high) leukemia cells. Biochem Biophys Res Commun 416:239–245

    Google Scholar 

  25. Roth S, Fodde R (2011) Quiescent stem cells in intestinal homeostasis and cancer. Cell Commun Adhes 18:33–44

    Article  PubMed  CAS  Google Scholar 

  26. Buczacki S, Davies RJ, Winton DJ (2011) Stem cells, quiescence and rectal carcinoma: an unexplored relationship and potential therapeutic target. Br J Cancer 105:1253–1259

    Article  PubMed  CAS  Google Scholar 

  27. Havard M, Dautry F, Tchenio T (2011) A dormant state modulated by osmotic pressure controls clonogenicity of prostate cancer cells. J Biol Chem 286:44177–44186

    Google Scholar 

  28. Dean M, Allikmets R (1995) Evolution of ATP-binding cassette transporter genes. Curr Opin Genet Dev 5:779–785

    Article  PubMed  CAS  Google Scholar 

  29. Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58

    Article  PubMed  CAS  Google Scholar 

  30. Dean M (2009) ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia 14:3–9

    Article  PubMed  Google Scholar 

  31. Ueda K, Cardarelli C, Gottesman MM, Pastan I (1987) Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci USA 84:3004–3008

    Article  PubMed  CAS  Google Scholar 

  32. Scharenberg CW, Harkey MA, Torok-Storb B (2002) The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 99:507–512

    Article  PubMed  CAS  Google Scholar 

  33. Kim M, Turnquist H, Jackson J, Sgagias M, Yan Y, Gong M, Dean M, Sharp JG, Cowan K. (2002) The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 8:22–28

    PubMed  CAS  Google Scholar 

  34. Lou H, Dean M (2007) Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene 26:1357–1360

    Article  PubMed  CAS  Google Scholar 

  35. An Y, Ongkeko WM (2009) ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol 5:1529–1542

    Article  PubMed  CAS  Google Scholar 

  36. Elliot A, Adams J, Al-Haj M (2010) The ABCs of cancer stem cell drug resistance. I Drugs 13:632–635

    PubMed  Google Scholar 

  37. Loebinger MR, Giangreco A, Groot KR, Prichard L, Allen K, Simpson C, Bazley L, Navani N, Tibrewal S, Davies D, Janes SM (2008) Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade. Br J Cancer 98:380–387

    Article  PubMed  CAS  Google Scholar 

  38. Bleau AM, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW, Holland EC (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4:226–235

    Article  PubMed  CAS  Google Scholar 

  39. Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, Li J (2010) Cancer stem/progenitor cells are highly enriched in CD133+ CD44+ population in hepatocellular carcinoma. Int J Cancer 126:2067–2078

    Article  PubMed  CAS  Google Scholar 

  40. Rizzo S, Hersey JM, Mellor P, Dai W, Santos-Silva A, Liber D, Luk L, Titley I, Carden CP, Box G, Hudson DL, Kaye SB, Brown R (2011) Ovarian cancer stem cell-like side populations are enriched following chemotherapy and overexpress EZH2. Mol Cancer Ther 10:325–335

    Article  PubMed  CAS  Google Scholar 

  41. Jeong HW, Cui W, Yang, Y, Lu J, He J, Li A, Song D, Guo Y, Liu BH, Chai L (2011) SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes. PLoS One 6:e18372

    Article  PubMed  CAS  Google Scholar 

  42. Schinkel AH, Smit JJ, van TO, Beijnen JH, Wagenaar E, van DL, Mol CA, van dV Robanus-Maandag EC, te Riele HP (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502

    Article  PubMed  CAS  Google Scholar 

  43. Moitra K, Lou H, Dean M (2011) Multidrug efflux pumps and cancer stem cells: insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther 89:491–502

    Article  PubMed  CAS  Google Scholar 

  44. Lee CH (2010) Reversing agents for ATP-binding cassette drug transporters. Methods Mol Biol 596:325–340

    Article  PubMed  CAS  Google Scholar 

  45. Hambardzumyan D, Squatrito M, Holland EC (2006) Radiation resistance and stem-like cells in brain tumors. Cancer Cell 10:454–456

    Article  PubMed  CAS  Google Scholar 

  46. Vlashi E, McBride WH, Pajonk F (2009) Radiation responses of cancer stem cells. J Cell Biochem 108:339–342

    Article  PubMed  CAS  Google Scholar 

  47. Bauman M, Krause M, Hil R (2008) Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545–554

    Article  CAS  Google Scholar 

  48. 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 444:756–760

    Article  PubMed  CAS  Google Scholar 

  49. Phillips TM, McBride WH, Pajonk F (2006) The response of CD24(−/low)/CD44+breast cancer-initiating cells to radiation. J Natl Cancer Inst 98:1777–1785

    Article  PubMed  Google Scholar 

  50. Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM (2007) WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA 104:618–623

    Article  PubMed  CAS  Google Scholar 

  51. Bao S, Wu Q, Sathornsumete S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:7843–7848

    Article  PubMed  CAS  Google Scholar 

  52. Rich JN (2007) Cancer stem cells in radiation resistance. Cancer Res 67:8980–8984

    Article  PubMed  CAS  Google Scholar 

  53. Gieni RS, Ismail IH, Campbel S, Hendzel MJ (2011) Polycomb group proteins in the DNA damage response: a link between radiation resistance and “stemness”. Cell Cycle 10:883–894

    Article  PubMed  CAS  Google Scholar 

  54. Facchino S, Abdouh M, Chato W, Bernier G (2010) BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci 30:10096–10111

    Article  PubMed  CAS  Google Scholar 

  55. Yin H, Glas J (2011) The phenotypic radiation resistance of CD44+/CD24(−or low) breast cancer cells is mediated through the enhanced activation of ATM signaling. PLoS One 6:e24080

    Article  PubMed  CAS  Google Scholar 

  56. Wei L, Liu TT, Wang HH, Hong HM, Yu AL, Feng HP, Chang WW (2011) Hsp27 participates in the maintenance of breast cancer stem cells through regulation of epithelial-mesenchymal transition and nuclear factor-kappa B. Breast Cancer Res 13:R101

    Article  PubMed  CAS  Google Scholar 

  57. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27:2059–2068

    Article  PubMed  CAS  Google Scholar 

  58. Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C, Kusunoki M (2009) Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 16:3488–3498

    Article  PubMed  Google Scholar 

  59. Yu CC, Chiou GY, Le YY, Chang YL, Huang PI, Cheng YW, Tai LK, Ku HH, Chiou SH, Wong TT (2010) Medulloblastoma-derived tumor stem-like cells acquired resistance to TRAIL-induced apoptosis and radiosensitivity. Childs Nerv Syst 26:897–904

    Article  PubMed  Google Scholar 

  60. Mihatsch J, Toulany M, Bareis PM, Grim S, Lengerke C, Kehlbach R, Rodeman HP (2011) Selection of radioresistant tumor cells and presence of ALDH1 activity in vitro. Radiother Oncol 99:300–306

    Article  PubMed  CAS  Google Scholar 

  61. Croker AK, Allan AL (2012) Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDH(hi)CD44 (+) human breast cancer cells. Breast Cancer Res Treat 133:75–87

    Google Scholar 

  62. D’Andrea FP, Safwat A, Kassem M, Gautier L, Overgaard J, Horsman MR (2011) Cancer stem cell overexpression of nicotinamide N-methyltransferase enhances cellular radiation resistance. Radiother Oncol 99:373–378

    Article  PubMed  CAS  Google Scholar 

  63. Choi S, Ku JL (2011) Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression. Biochem Biophys Res Commun 412:207–213

    Article  PubMed  CAS  Google Scholar 

  64. Lin L, Fuchs J, Li C, Olson V, Bekaii-Saab T, Lin J (2011) STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH(+)/CD133(+) stem cell-like human colon cancer cells. Biochem Biophys Res Commun 416:246–251

    Google Scholar 

  65. Kim RK, Yoon CH, Hyun KH, Le H, An S, Park MJ, Kim MJ, Le SJ (2010) Role of lymphocyte-specific protein tyrosine kinase (LCK) in the expansion of glioma-initiating cells by fractionated radiation. Biochem Biophys Res Commun 402:631–636

    Article  PubMed  CAS  Google Scholar 

  66. Ma HI, Chiou SH, Hueng DY, Tai LK, Huang PI, Kao CL, Chen YW, Sytwu HK (2011) Celecoxib and radioresistant glioblastoma-derived CD133+ cells: improvement in radiotherapeutic effects. Lab Inves J Neurosurg 114:651–662.

    CAS  Google Scholar 

  67. Zhuang W, Li B, Long L, Chen L, Huang Q, Liang Z (2011) Induction of autophagy promotes differentiation of glioma-initiating cells and their radiosensitivity. Int J Cancer 129:2720–2731

    Article  PubMed  CAS  Google Scholar 

  68. Kim Y, Kim KH, Le J, Le YA, Kim M, Le SJ, Park K, Yang H, Jin J, Jo KM, Le J, Nam DH (2012) Wnt activation is implicated in glioblastoma radioresistance. Lab Invest 92:466–473

    Google Scholar 

  69. Yang YP, Chien Y, Chiou GY, Cherng JY, Wang ML, Lo WL, Chang YL, Huang PI, Chen YW, Shih YH, Chen MT, Chiou SH (2012) Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI. Biomaterials 33:1462–1476

    Google Scholar 

  70. Pajonk F, Vlashi E, McBride WH (2010) Radiation resistance of cancer stem cells: the 4 R’s of radiobiology revisited. Stem Cells 28:639–648

    Article  PubMed  CAS  Google Scholar 

  71. Debeb BG, Xu W, Woodward WA (2009) Radiation resistance of breast cancer stem cells: understanding the clinical framework. J Mammary Gland Biol Neoplasia 14:11–17

    Article  PubMed  Google Scholar 

  72. Cripe TP, Wang PY, Marcato P, Mahller YY, Le PW (2009) Targeting cancer-initiating cells with oncolytic viruses. Mol Ther 17:1677–1682

    Article  PubMed  CAS  Google Scholar 

  73. Frosina G (2009) DNA repair and resistance of gliomas to chemotherapy and radiotherapy. Mol Cancer Res 7:989–999

    Article  PubMed  CAS  Google Scholar 

  74. Morrison R, Schleicher SM, Sun Y, Nierman KJ, Kim S, Sprat DE, Chung CH, Lu B (2011) Targeting the mechanisms of resistance to chemotherapy and radiotherapy with the cancer stem cell hypothesis. J Oncol 2011:941876

    Article  PubMed  CAS  Google Scholar 

  75. Roos WP, Kaina B (2006) DNA damage-induced cell death by apoptosis. Trends Mol Med 12:440–450

    Article  PubMed  CAS  Google Scholar 

  76. Xu Y, Price BD (2011) Chromatin dynamics and the repair of DNA double strand breaks. Cell Cycle 10:261–267

    Article  PubMed  CAS  Google Scholar 

  77. Rossetto D, Truman AW, Kron SJ, Cote J (2010) Epigenetic modifications in double-strand break DNA damage signaling and repair. Clin Cancer Res 16:4543–4552

    Article  PubMed  CAS  Google Scholar 

  78. Frosina G (2009) DNA repair in normal and cancer stem cells, with special reference to the central nervous system. Curr Med Chem 16:854–866

    Article  PubMed  CAS  Google Scholar 

  79. Ropolo M, Daga A, Griffero F, Foresta M, Casartelli G, Zunino A, Poggi A, Cappelli E, Zona G, Spaziante R, Corte G, Frosina G (2009) Comparative analysis of DNA repair in stem and nonstem glioma cell cultures. Mol Cancer Res 7:383–392

    Article  PubMed  CAS  Google Scholar 

  80. Jalal S, Earley JN, Turchi JJ (2011) DNA repair: from genome maintenance to biomarker and therapeutic target. Clin Cancer Res 17:6973–6984

    Article  PubMed  CAS  Google Scholar 

  81. Frosina G (2010) The bright and the dark sides of DNA repair in stem cells. J Biomed Biotechnol 2010:845396

    Article  PubMed  CAS  Google Scholar 

  82. Rabik CA, Dolan ME (2007) Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33:9–23

    Article  PubMed  CAS  Google Scholar 

  83. Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4:307–320

    Article  PubMed  CAS  Google Scholar 

  84. Johannessen TC, Bjerkvig R, Tysnes BB (2008) DNA repair and cancer stem-like cells-potential partners in glioma drug resistance? Cancer Treat Rev 34:558–567

    Article  PubMed  CAS  Google Scholar 

  85. Di BG, Alessio N, Dell’Aversana C, Casale F, Teti D, Cipollaro M, Altucci L, Galderisi U (2010) Impact of histone deacetylase inhibitors SAHA and MS-275 on DNA repair pathways in human mesenchymal stem cells. J Cell Physiol 225:537–544

    Article  CAS  Google Scholar 

  86. Bartucci M, Svensson S, Romania P, Dattilo R, Patrizi M, Signore M, Navarra S, Lotti F, Biffoni M, Pilozzi E, Duranti E, Martinelli S, Rinaldo C, Zeuner A, Maugeri-Sacca M, Eramo A, De MR (2012) Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy. Cell Death Differ 19:768–778

    Google Scholar 

  87. Viale A, De FF, Orleth A, Cambiaghi V, Giuliani V, Bossi D, Ronchini C, Ronzoni S, Muradore I, Monestiroli S, Gobbi A, Alcalay M, Minucci S, Pelicci PG (2009) Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 457:51–56

    Article  PubMed  CAS  Google Scholar 

  88. Zhuang W, Li B, Long L, Chen L, Huang Q, Liang ZQ (2011) Knockdown of the DNA-dependent protein kinase catalytic subunit radiosensitizes glioma-initiating cells by inducing autophagy. Brain Res 1371:7–15

    Article  PubMed  CAS  Google Scholar 

  89. Karimi-Busheri F, Rasouli-Nia A, Mackey JR, Weinfeld M (2010) Senescence evasion by MCF-7 human breast tumor-initiating cells. Breast Cancer Res 12:R31

    Article  PubMed  CAS  Google Scholar 

  90. Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrel F, Edwards D, Medina D, Tsimelzon A, Hilsenbeck S, Green JE, Michalowska AM, Rosen JM (2008) Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res 68:4674–4682

    Article  PubMed  CAS  Google Scholar 

  91. Fan J, Robert C, Jang YY, Liu H, Sharkis S, Baylin SB, Rassool FV (2011) Human induced pluripotent cells resemble embryonic stem cells demonstrating enhanced levels of DNA repair and efficacy of nonhomologous end-joining. Mutat Res 713:8–17

    Article  PubMed  CAS  Google Scholar 

  92. Sarkar FH, Li Y, Wang Z, Kong D (2009) Cellular signaling perturbation by natural products. Cell Signal 21:1541–1547

    Article  PubMed  CAS  Google Scholar 

  93. Sarkar FH, Li Y (2009) Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics. Cancer Treat Rev 35:597–607

    Article  PubMed  CAS  Google Scholar 

  94. Sarkar FH, Li Y, Wang Z, Padhye S (2010) Lesson learned from nature for the development of novel anti-cancer agents: implication of isoflavone, curcumin, and their synthetic analogs. Curr Pharm Des 16:1801–1812

    Article  PubMed  CAS  Google Scholar 

  95. Sarkar FH, Li Y, Wang Z, Kong D (2010) The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer. Cancer Metastasis Rev 29:383–394

    Article  PubMed  CAS  Google Scholar 

  96. Kawasaki BT, Hurt EM, Mistre T, Farrar WL (2008) Targeting cancer stem cells with phytochemicals. Mol Interv 8:174–184

    Article  PubMed  CAS  Google Scholar 

  97. 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 22:799–806

    Article  PubMed  CAS  Google Scholar 

  98. Ghantous A, Gali-Muhtasib H, Vuorela H, Saliba NA, Darwiche N (2010) What made sesquiterpene lactones reach cancer clinical trials? Drug Discov Today 15:668–678

    Article  PubMed  CAS  Google Scholar 

  99. Guzman ML, Rossi RM, Karnischky L, Li X, Peterson DR, Howard DS, Jordan CT (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105:4163–169

    Article  PubMed  CAS  Google Scholar 

  100. Guzman ML, Rossi RM, Neelakantan S, Li X, Corbet CA, Hassane DC, Becker MW, Bennet JM, Sullivan E, Lachowicz JL, Vaughan A, Sweeney CJ, Matthews W, Carrol M, Liesveld JL, Crooks PA, Jordan CT (2007) An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 110:4427–4435

    Article  PubMed  CAS  Google Scholar 

  101. Kim YR, Eom JI, Kim SJ, Jeung HK, Cheong JW, Kim JS, Min YH (2010) Myeloperoxidase expression as a potential determinant of parthenolide-induced apoptosis in leukemia bulk and leukemia stem cells. J Pharmacol Exp Ther 335:389–400

    Article  PubMed  CAS  Google Scholar 

  102. Zhou J, Zhang H, Gu P, Bai J, Margolick JB, Zhang Y (2008) NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells. Breast Cancer Res Treat 111:419–427

    Article  PubMed  CAS  Google Scholar 

  103. Liu Y, Lu WL, Guo J, Du J, Li T, Wu JW, Wang GL, Wang JC, Zhang X, Zhang Q (2008) A potential target associated with both cancer and cancer stem cells: a combination therapy for eradication of breast cancer using vinorelbine stealthy liposomes plus parthenolide stealthy liposomes. J Control Release 129:18–25

    Article  PubMed  CAS  Google Scholar 

  104. Kawasaki BT, Hurt EM, Kalathur M, Duhagon MA, Milner JA, Kim YS, Farrar WL (2009) Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: an integrated molecular profiling approach. Prostate 69:827–837

    Article  PubMed  CAS  Google Scholar 

  105. Zuch D, Giang AH, Shapovalov Y, Schwarz E, Rosier R, O’Keefe R, Eliseev RA (2011) Targeting radioresistant osteosarcoma cells with parthenolide. J Cell Biochem (PMID: 22109788; doi: 10.1002/jcb.24002)

    Google Scholar 

  106. Gun EJ, Williams JT, Huynh, DT, Iannotti MJ, Han C, Barrios FJ, Kendal S, Glackin CA, Colby DA, Kirshner J (2011) The natural products parthenolide and andrographolide exhibit anti-cancer stem cell activity in multiple myeloma. Leuk Lymphoma 52:1085–1097

    Article  CAS  Google Scholar 

  107. Volate SR, Kawasaki BT, Hurt EM, Milner JA, Kim YS, White J, Farrar WL (2010) Gossypol induces apoptosis by activating p53 in prostate cancer cells and prostate tumor-initiating cells. Mol Cancer Ther 9:461–470

    Article  PubMed  CAS  Google Scholar 

  108. Denissova NG, Nasello CM, Yeung PL, Tischfield JA, Brenneman MA (2012) Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage. Carcinogenesis 33:149–155

    Google Scholar 

  109. Lu KH, Chen YW, Tsai PH, Tsai ML, Le YY, Chiang CY, Kao CL, Chiou SH, Ku HH, Lin CH, Chen YJ (2009) Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells. Childs Nerv Syst 25:543–550

    Article  PubMed  Google Scholar 

  110. Yang YP, Chang YL, Huang PI, Chiou GY, Tseng LM, Chiou SH, Chen MH, Chen MT, Shih YH, Chang CH, Hsu CC, Ma HI, Wang CT, Tsai LL, Yu CC, Chang CJ (2012) Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis. J Cell Physiol 227:976–993

    Google Scholar 

  111. Pandey PR, Okuda H, Watabe M, Pai SK, Liu W, Kobayashi A, Xing F, Fukuda K, Hirota S, Sugai T, Wakabayashi G, Koeda K, Kashiwaba M, Suzuki K, Chiba T, Endo M, Fujioka T, Tanji S, Mo YY, Cao D, Wilber AC, Watabe K (2011) Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase. Breast Cancer Res Treat 130:387–398

    Article  PubMed  CAS  Google Scholar 

  112. Shankar S, Nal D, Tang SN, Meeker D, Passarini J, Sharma J, Srivastava RK (2011) Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One 6:e16530

    Article  PubMed  CAS  Google Scholar 

  113. Li Y, Zhang T, Korkaya H, Liu S, Le HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS, Sun D (2010) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 16:2580–2590

    Article  PubMed  CAS  Google Scholar 

  114. Rausch V, Liu L, Kallifatidis G, Bauman B, Mattern J, Gladkich J, Wirth T, Schemmer P, Buchler MW, Zoller M, Salnikov AV, Her I (2010) Synergistic activity of sorafenib and sulforaphane abolishes pancreatic cancer stem cell characteristics. Cancer Res 70:5004–5013

    Article  PubMed  CAS  Google Scholar 

  115. Kallifatidis G, Labsch S, Rausch V, Mattern J, Gladkich J, Moldenhauer G, Buchler MW, Salnikov AV, Her I (2011) Sulforaphane increases drug-mediated cytotoxicity toward cancer stem-like cells of pancreas and prostate. Mol Ther 19:188–195

    Article  PubMed  CAS  Google Scholar 

  116. Srivastava RK, Tang SN, Zhu W, Meeker D, Shankar S (2011) Sulforaphane synergizes with quercetin to inhibit self-renewal capacity of pancreatic cancer stem cells. Front Biosci (Elite Ed) 3:515–528

    Article  Google Scholar 

  117. Zhou W, Kallifatidis G, Bauman B, Rausch V, Mattern J, Gladkich J, Giese N, Moldenhauer G, Wirth T, Buchler MW, Salnikov AV, Her I (2010) Dietary polyphenol quercetin targets pancreatic cancer stem cells. Int J Oncol 37:551–561

    PubMed  CAS  Google Scholar 

  118. Tang SN, Singh C, Nal 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

    Article  PubMed  CAS  Google Scholar 

  119. Tang SN, Fu J, Nal 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 131:30–40

    Google Scholar 

  120. Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122:777–785

    Article  PubMed  CAS  Google Scholar 

  121. 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 2:321–328

    PubMed  Google Scholar 

  122. 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 293:65–72

    Article  PubMed  CAS  Google Scholar 

  123. Padhye S, Yang H, Jamadar A, Cui QC, Chavan D, Dominiak K, McKinney J, Banerje S, Dou QP, Sarkar FH (2009) New difluoro Knoevenagel condensates of curcumin, their Schiff bases and copper complexes as proteasome inhibitors and apoptosis inducers in cancer cells. Pharm Res 26:1874–1880

    Article  PubMed  CAS  Google Scholar 

  124. Padhye S, Banerje S, Chavan D, Pandye S, Swamy KV, Ali S, Li J, Dou QP, Sarkar FH (2009) Fluorocurcumins as cyclooxygenase-2 inhibitor: molecular docking, pharmacokinetics and tissue distribution in mice. Pharm Res 26:2438–2445

    Article  PubMed  CAS  Google Scholar 

  125. 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 28:827–838

    Article  PubMed  CAS  Google Scholar 

  126. Bao B, Ali S, Kong D, Sarkar SH, Wang Z, Banerje 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:e17850

    Article  PubMed  CAS  Google Scholar 

  127. Bao B, Ali S, Banerje S, Wang Z, Logna F, Azmi AS, Kong D, Ahmad A, Li Y, Padhye S, Sarkar FH (2012) Curcumin analog CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res 72:335–345

    Google Scholar 

  128. Lim KJ, Bisht S, Bar EE, Maitra A, Eberhart CG (2011) A polymeric nanoparticle formulation of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain tumors. Cancer Biol Ther 11:464–473

    Article  PubMed  CAS  Google Scholar 

  129. 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 105:212–20

    Article  PubMed  CAS  Google Scholar 

  130. Freitas AA, de Magalhaes JP (2011) A review and appraisal of the DNA damage theory of ageing. Mutat Res 728:12–22

    Article  PubMed  CAS  Google Scholar 

  131. Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361:1475–1485

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Aamir Ahmad .

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Ahmad, A., Li, Y., Bao, B., Sarkar, F. (2013). Resistance and DNA Repair Mechanisms of Cancer Stem Cells: Potential Molecular Targets for Therapy. In: Mathews, L., Cabarcas, S., Hurt, E. (eds) DNA Repair of Cancer Stem Cells. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4590-2_3

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