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Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis

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Abstract

Carcinogenesis is a multi-step process which could be prevented by phytochemicals. Phytochemicals from dietary plants and other plant sources such as herbs are becoming increasingly important sources of anticancer drugs or compounds for cancer chemoprevention or adjuvant chemotherapy. Phytochemicals can prevent cancer initiation, promotion, and progression by exerting anti-inflammatory and anti-oxidative stress effects which are mediated by integrated Nrf2, NF-κB, and AP-1 signaling pathways. In addition, phytochemicals from herbal medicinal plants and/or some dietary plants developed in recent years have been shown to induce apoptosis in cancer cells and inhibition of tumor growth in vivo. In advanced tumors, a series of changes involving critical signaling molecules that would drive tumor cells undergoing epithelial–mesenchymal transition and becoming invasive. In this review, we will discuss the potential molecular targets and signaling pathways that mediate tumor onset and metastasis. In addition, we will shed light on some of the phytochemicals that are capable of targeting these signaling pathways which would make them potentially applicable to cancer chemoprevention, treatment and control of cancer progression.

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References

  1. Boyd, J. A., & Barrett, J. C. (1990). Genetic and cellular basis of multistep carcinogenesis. Pharmacology & Therapeutics, 46(3), 469–486.

    Article  CAS  Google Scholar 

  2. Armitage, P. (1985). Multistage models of carcinogenesis. Environmental Health Perspectives, 63, 195–201.

    Article  CAS  PubMed  Google Scholar 

  3. Fimognari, C., Lenzi, M., & Hrelia, P. (2008). Chemoprevention of cancer by isothiocyanates and anthocyanins: mechanisms of action and structure-activity relationship. Current Medicinal Chemistry, 15(5), 440–447.

    Article  CAS  PubMed  Google Scholar 

  4. Ottini, L., et al. (2006). Patterns of genomic instability in gastric cancer: clinical implications and perspectives. Annals of Oncology, 17(Suppl 7), vii97–vii102.

    Article  PubMed  Google Scholar 

  5. Kelloff, G. J., et al. (1999). Progress in cancer chemoprevention. Annals of the New York Academy of Sciences, 889, 1–13.

    Article  CAS  PubMed  Google Scholar 

  6. Sporn, M. B., et al. (1976). Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Federation Proceedings, 35(6), 1332–1338.

    CAS  PubMed  Google Scholar 

  7. Wattenberg, L. W. (1966). Chemoprophylaxis of carcinogenesis: a review. Cancer Research, 26(7), 1520–1526.

    CAS  PubMed  Google Scholar 

  8. Tsao, A. S., Kim, E. S., & Hong, W. K. (2004). Chemoprevention of cancer. CA: A Cancer Journal for Clinicians, 54(3), 150–180.

    Article  Google Scholar 

  9. Greenwald, P. (2002). Cancer chemoprevention. BMJ, 324(7339), 714–718.

    Article  CAS  PubMed  Google Scholar 

  10. Johnson, S. M., Wang, X., & Mark Evers, B. (2009). Triptolide inhibits proliferation and migration of colon cancer cells by inhibition of cell cycle regulators and cytokine receptors. Journal of Surgical Research. doi:10.1016/j.jss.2009.07.002.

  11. Ganther, H. E. (1999). Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. Carcinogenesis, 20(9), 1657–1666.

    Article  CAS  PubMed  Google Scholar 

  12. Cheung, K. L., et al. (2010). Differential in vivo mechanism of chemoprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM. Carcinogenesis, 31(5), 880–885.

    Article  CAS  PubMed  Google Scholar 

  13. Sarkar, F. H., & Li, Y. (2002). Mechanisms of cancer chemoprevention by soy isoflavone genistein. Cancer and Metastasis Reviews, 21(3-4), 265–280.

    Article  CAS  PubMed  Google Scholar 

  14. Chin, Y. W., et al. (2006). Drug discovery from natural sources. The AAPS Journal, 8(2), E239–E253.

    CAS  PubMed  Google Scholar 

  15. Jiang, J., & Hu, C. (2009). Evodiamine: a novel anti-cancer alkaloid from Evodia rutaecarpa. Molecules, 14(5), 1852–1859.

    Article  CAS  PubMed  Google Scholar 

  16. Kumar, N. B., Allen, K., & Bell, H. (2005). Perioperative herbal supplement use in cancer patients: potential implications and recommendations for presurgical screening. Cancer Control, 12(3), 149–157.

    PubMed  Google Scholar 

  17. Shord, S. S., Shah, K., & Lukose, A. (2009). Drug-botanical interactions: a review of the laboratory, animal, and human data for 8 common botanicals. Integrative Cancer Therapies, 8(3), 208–227.

    CAS  PubMed  Google Scholar 

  18. Ho, E., Clarke, J. D., & Dashwood, R. H. (2009). Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention. The Journal of Nutrition, 139(12), 2393–2396.

    Article  CAS  PubMed  Google Scholar 

  19. Bode, A. M., & Dong, Z. (2004). Targeting signal transduction pathways by chemopreventive agents. Mutation Research, 555(1-2), 33–51.

    CAS  PubMed  Google Scholar 

  20. Newman, D. J., Cragg, G. M., & Snader, K. M. (2000). The influence of natural products upon drug discovery. Natural Product Reports, 17(3), 215–234.

    Article  CAS  PubMed  Google Scholar 

  21. van Der Heijden, R., et al. (2004). The Catharanthus alkaloids: pharmacognosy and biotechnology. Current Medicinal Chemistry, 11(5), 607–628.

    Article  Google Scholar 

  22. Oberlies, N. H., & Kroll, D. J. (2004). Camptothecin and taxol: historic achievements in natural products research. Journal of Natural Products, 67(2), 129–135.

    Article  CAS  PubMed  Google Scholar 

  23. Wall, M. E., & Wani, M. C. (1996). Camptothecin and taxol: from discovery to clinic. Journal of Ethnopharmacology, 51(1-3), 239–253. discussion 253–4.

    Article  CAS  PubMed  Google Scholar 

  24. Aggarwal, B. B., Kumar, A., & Bharti, A. C. (2003). Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Research, 23(1A), 363–398.

    CAS  PubMed  Google Scholar 

  25. Bar-Sela, G., Epelbaum, R., & Schaffer, M. (2010). Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications. Current Medicinal Chemistry, 17(3), 190–197.

    Article  CAS  PubMed  Google Scholar 

  26. Swami, S., et al. (2009). Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients. International Journal of Cancer, 124(9), 2050–2059.

    Article  CAS  Google Scholar 

  27. Itokawa, H., et al. (2008). Plant-derived natural product research aimed at new drug discovery. Journal of Natural Medicines, 62(3), 263–280.

    Article  CAS  PubMed  Google Scholar 

  28. Lu, Y., Li, C. S., & Dong, Q. (2008). Chinese herb related molecules of cancer-cell-apoptosis: a minireview of progress between Kanglaite injection and related genes. Journal of Experimental & Clinical Cancer Research, 27, 31.

    Article  CAS  Google Scholar 

  29. Balunas, M. J., & Kinghorn, A. D. (2005). Drug discovery from medicinal plants. Life Sciences, 78(5), 431–441.

    Article  CAS  PubMed  Google Scholar 

  30. Johnson, I. T. (2007). Phytochemicals and cancer. The Proceedings of the Nutrition Society, 66(2), 207–215.

    Article  CAS  PubMed  Google Scholar 

  31. Rushmore, T. H., & Pickett, C. B. (1993). Glutathione S-transferases, structure, regulation, and therapeutic implications. The Journal of Biological Chemistry, 268(16), 11475–11478.

    CAS  PubMed  Google Scholar 

  32. Miao, W., et al. (2005). Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. The Journal of Biological Chemistry, 280(21), 20340–20348.

    Article  CAS  PubMed  Google Scholar 

  33. McMahon, M., et al. (2001). The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Research, 61(8), 3299–3307.

    CAS  PubMed  Google Scholar 

  34. Chan, K., Han, X. D., & Kan, Y. W. (2001). An important function of Nrf2 in combating oxidative stress:detoxification of acetaminophen. Proceedings of the National Academy of Sciences of the United States of America, 98(8), 4611–4616.

    Article  CAS  PubMed  Google Scholar 

  35. Rushmore, T. H., Morton, M. R., & Pickett, C. B. (1991). The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. The Journal of Biological Chemistry, 266(18), 11632–11639.

    CAS  PubMed  Google Scholar 

  36. Li, W., et al. (2008). Activation of Nrf2–antioxidant signaling attenuates NFkappaB–inflammatory response and elicits apoptosis. Biochemical Pharmacology, 76(11), 1485–1489.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang, D. D. (2006). Mechanistic studies of the Nrf2–Keap1 signaling pathway. Drug Metabolism Reviews, 38(4), 769–789.

    Article  CAS  PubMed  Google Scholar 

  38. Lin, W., et al. (2006). Regulation of Nrf2 transactivation domain activity by p160 RAC3/SRC3 and other nuclear co–regulators. Journal of Biochemistry and Molecular Biology, 39(3), 304–310.

    CAS  PubMed  Google Scholar 

  39. Copple, I. M., et al. (2010). The keap1–nrf2 cellular defense pathway: mechanisms of regulation and role in protection against drug–induced toxicity. Handbook of Experimental Pharmacology, 196, 233–266.

    Article  CAS  PubMed  Google Scholar 

  40. Cullinan, S. B., et al. (2004). The Keap1–BTB protein is an adaptor that bridges Nrf2 to a Cul3–based E3 ligase: oxidative stress sensing by a Cul3–Keap1 ligase. Molecular and Cellular Biology, 24(19), 8477–8486.

    Article  CAS  PubMed  Google Scholar 

  41. Li, W., et al. (2010). An internal ribosomal entry site mediates redox–sensitive translation of Nrf2. Nucleic Acids Research, 38(3), 778–788.

    Article  PubMed  CAS  Google Scholar 

  42. Dinkova-Kostova, A. T., et al. (2002). Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proceedings of the National Academy of Sciences of the United States of America, 99(18), 11908–11913.

    Article  CAS  PubMed  Google Scholar 

  43. Dinkova-Kostova, A. T., Holtzclaw, W. D., & Wakabayashi, N. (2005). Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry, 44(18), 6889–6899.

    Article  CAS  PubMed  Google Scholar 

  44. Li, W., & Kong, A. N. (2009). Molecular mechanisms of Nrf2–mediated antioxidant response. Molecular Carcinogenesis, 48(2), 91–104.

    Article  CAS  PubMed  Google Scholar 

  45. Nguyen, T., et al. (2003). Increased protein stability as a mechanism that enhances Nrf2–mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26S proteasome. The Journal of Biological Chemistry, 278(7), 4536–4541.

    Article  CAS  PubMed  Google Scholar 

  46. Huang, H. C., Nguyen, T., & Pickett, C. B. (2002). Phosphorylation of Nrf2 at Ser–40 by protein kinase C regulates antioxidant response element–mediated transcription. The Journal of Biological Chemistry, 277(45), 42769–42774.

    Article  CAS  PubMed  Google Scholar 

  47. Nakaso, K., et al. (2003). PI3K is a key molecule in the Nrf2–mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Letters, 546(2–3), 181–184.

    Article  CAS  PubMed  Google Scholar 

  48. Zipper, L. M., & Mulcahy, R. T. (2003). Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells. Toxicological Sciences, 73(1), 124–134.

    Article  CAS  PubMed  Google Scholar 

  49. Zipper, L. M., & Mulcahy, R. T. (2000). Inhibition of ERK and p38 MAP kinases inhibits binding of Nrf2 and induction of GCS genes. Biochemical and Biophysical Research Communications, 278(2), 484–492.

    Article  CAS  PubMed  Google Scholar 

  50. Shen, G., et al. (2004). Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen–activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB– binding protein. The Journal of Biological Chemistry, 279(22), 23052–23060.

    Article  CAS  PubMed  Google Scholar 

  51. Cheung, K. L., Khor, T. O., & Kong, A. N. (2009). Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation. Pharmaceutical Research, 26(1), 224–231.

    Article  CAS  PubMed  Google Scholar 

  52. Xu, C., et al. (2006). Mechanism of action of isothiocyanates: the induction of ARE–regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. Molecular Cancer Therapeutics, 5(8), 1918–1926.

    Article  CAS  PubMed  Google Scholar 

  53. Balogun, E., et al. (2003). Curcumin activates the haem oxygenase–1 gene via regulation of Nrf2 and the antioxidant–responsive element. The Biochemical Journal, 371(Pt 3), 887–895.

    Article  CAS  PubMed  Google Scholar 

  54. Na, H. K., et al. (2008). (-)-Epigallocatechin gallate induces Nrf2–mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Archives of Biochemistry and Biophysics, 476(2), 171–177.

    Article  CAS  PubMed  Google Scholar 

  55. Hong, F., Freeman, M. L., & Liebler, D. C. (2005). Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chemical Research in Toxicology, 18(12), 1917–1926.

    Article  CAS  PubMed  Google Scholar 

  56. Mantovani, A., et al. (2008). Cancer–related inflammation. Nature, 454(7203), 436–444.

    Article  CAS  PubMed  Google Scholar 

  57. Mantovani, A. (2010). Molecular pathways linking inflammation and cancer. Current Molecular Medicine, 10(4), 369–373.

    Article  CAS  PubMed  Google Scholar 

  58. Colotta, F., et al. (2009). Cancer–related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 30(7), 1073–1081.

    Article  CAS  PubMed  Google Scholar 

  59. Greten, F. R., et al. (2004). IKKbeta links inflammation and tumorigenesis in a mouse model of colitis–associated cancer. Cell, 118(3), 285–296.

    Article  CAS  PubMed  Google Scholar 

  60. Sen, R., & Baltimore, D. (1986). Inducibility of kappa immunoglobulin enhancer–binding protein Nf–kappa B by a posttranslational mechanism. Cell, 47(6), 921–928.

    Article  CAS  PubMed  Google Scholar 

  61. Pahl, H. L. (1999). Activators and target genes of Rel/NF–kappaB transcription factors. Oncogene, 18(49), 6853–6866.

    Article  CAS  PubMed  Google Scholar 

  62. Karin, M., & Ben-Neriah, Y. (2000). Phosphorylation meets ubiquitination: the control of NF–[kappa]B activity. Annual Review of Immunology, 18, 621–663.

    Article  CAS  PubMed  Google Scholar 

  63. Inoue, J., et al. (1992). I kappa B gamma, a 70 kd protein identical to the C–terminal half of p110 NF–kappa B: a new member of the I kappa B family. Cell, 68(6), 1109–1120.

    Article  CAS  PubMed  Google Scholar 

  64. Jacobs, M. D., & Harrison, S. C. (1998). Structure of an IkappaBalpha/NF–kappaB complex. Cell, 95(6), 749–758.

    Article  CAS  PubMed  Google Scholar 

  65. Bonizzi, G., & Karin, M. (2004). The two NF–kappaB activation pathways and their role in innate and adaptive immunity. Trends in Immunology, 25(6), 280–288.

    Article  CAS  PubMed  Google Scholar 

  66. Luedde, T., et al. (2007). Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell, 11(2), 119–132.

    Article  CAS  PubMed  Google Scholar 

  67. Garg, A., & Aggarwal, B. B. (2002). Nuclear transcription factor–kappaB as a target for cancer drug development. Leukemia, 16(6), 1053–1068.

    Article  CAS  PubMed  Google Scholar 

  68. Sethi, G., Sung, B., & Aggarwal, B. B. (2008). Nuclear factor–kappaB activation: from bench to bedside. Experimental Biology and Medicine (Maywood), 233(1), 21–31.

    Article  CAS  Google Scholar 

  69. Sica, A., et al. (2008). Macrophage polarization in tumour progression. Seminars in Cancer Biology, 18(5), 349–355.

    Article  CAS  PubMed  Google Scholar 

  70. Biswas, S. K., Sica, A., & Lewis, C. E. (2008). Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. Journal of Immunology, 180(4), 2011–2017.

    CAS  Google Scholar 

  71. Pollard, J. W. (2004). Tumour–educated macrophages promote tumour progression and metastasis. Nature Reviews. Cancer, 4(1), 71–78.

    Article  CAS  PubMed  Google Scholar 

  72. Lewis, C. E., & Pollard, J. W. (2006). Distinct role of macrophages in different tumor microenvironments. Cancer Research, 66(2), 605–612.

    Article  CAS  PubMed  Google Scholar 

  73. Mancino, A., & Lawrence, T. (2010). Nuclear factor–kappaB and tumor–associated macrophages. Clinical Cancer Research, 16(3), 784–789.

    Article  CAS  PubMed  Google Scholar 

  74. Lin, W., et al. (2008). Sulforaphane suppressed LPS–induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway. Biochemical Pharmacology, 76(8), 967–973.

    Article  CAS  PubMed  Google Scholar 

  75. Chun, K. S., et al. (2003). Curcumin inhibits phorbol ester–induced expression of cyclooxygenase–2 in mouse skin through suppression of extracellular signal–regulated kinase activity and NF–kappaB activation. Carcinogenesis, 24(9), 1515–1524.

    Article  CAS  PubMed  Google Scholar 

  76. Reuter, S., et al. (2008). Modulation of anti–apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochemical Pharmacology, 76(11), 1340–1351.

    Article  CAS  PubMed  Google Scholar 

  77. Sun, D. I., et al. (2008). Bisacurone inhibits adhesion of inflammatory monocytes or cancer cells to endothelial cells through down–regulation of VCAM–1 expression. International Immunopharmacology, 8(9), 1272–1281.

    Article  CAS  PubMed  Google Scholar 

  78. Wang, C., Li, S., & Wang, M. W. (2010). Evodiamine–induced human melanoma A375–S2 cell death was mediated by PI3K/Akt/caspase and Fas–L/NF–kappaB signaling pathways and augmented by ubiquitin–proteasome inhibition. Toxicology In Vitro, 24(3), 898–904.

    Article  CAS  PubMed  Google Scholar 

  79. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70.

    Article  CAS  PubMed  Google Scholar 

  80. Li, L. Y., Luo, X., & Wang, X. (2001). Endonuclease G is an apoptotic DNase when released from mitochondria. Nature, 412(6842), 95–99.

    Article  CAS  PubMed  Google Scholar 

  81. Wang, X. (2001). The expanding role of mitochondria in apoptosis. Genes & Development, 15(22), 2922–2933.

    CAS  Google Scholar 

  82. Danial, N. N., & Korsmeyer, S. J. (2004). Cell death: critical control points. Cell, 116(2), 205–219.

    Article  CAS  PubMed  Google Scholar 

  83. Scorrano, L., et al. (2003). BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science, 300(5616), 135–139.

    Article  CAS  PubMed  Google Scholar 

  84. Suzuki, M., Youle, R. J., & Tjandra, N. (2000). Structure of Bax: coregulation of dimer formation and intracellular localization. Cell, 103(4), 645–654.

    Article  CAS  PubMed  Google Scholar 

  85. Letai, A. (2005). Pharmacological manipulation of Bcl–2 family members to control cell death. The Journal of Clinical Investigation, 115(10), 2648–2655.

    Article  CAS  PubMed  Google Scholar 

  86. Ashkenazi, A., & Dixit, V. M. (1998). Death receptors: signaling and modulation. Science, 281(5381), 1305–1308.

    Article  CAS  PubMed  Google Scholar 

  87. Sprick, M. R., & Walczak, H. (2004). The interplay between the Bcl–2 family and death receptor–mediated apoptosis. Biochimica et Biophysica Acta, 1644(2–3), 125–132.

    CAS  PubMed  Google Scholar 

  88. Ashkenazi, A. (2008). Targeting the extrinsic apoptosis pathway in cancer. Cytokine & Growth Factor Reviews, 19(3–4), 325–331.

    Article  CAS  Google Scholar 

  89. Barnhart, B. C., & Peter, M. E. (2003). The TNF receptor 1: a split personality complex. Cell, 114(2), 148–150.

    Article  CAS  PubMed  Google Scholar 

  90. Kischkel, F. C., et al. (1995). Cytotoxicity–dependent APO–1 (Fas/CD95)–associated proteins form a death–inducing signaling complex (DISC) with the receptor. The EMBO Journal, 14(22), 5579–5588.

    CAS  PubMed  Google Scholar 

  91. Kischkel, F. C., et al. (2000). Apo2L/TRAIL–dependent recruitment of endogenous FADD and caspase–8 to death receptors 4 and 5. Immunity, 12(6), 611–620.

    Article  CAS  PubMed  Google Scholar 

  92. Barnhart, B. C., Alappat, E. C., & Peter, M. E. (2003). The CD95 type I/type II model. Seminars in Immunology, 15(3), 185–193.

    Article  CAS  PubMed  Google Scholar 

  93. Ma, J., et al. (2001). Apoptosis induced by isoliquiritigenin in human gastric cancer MGC–803 cells. Planta Medica, 67(8), 754–757.

    Article  CAS  PubMed  Google Scholar 

  94. Tang, W., et al. (2006). Ganoderic acid T from Ganoderma lucidum mycelia induces mitochondria mediated apoptosis in lung cancer cells. Life Sciences, 80(3), 205–211.

    Article  CAS  PubMed  Google Scholar 

  95. Cheung, J. Y., et al. (2005). Polyphyllin D is a potent apoptosis inducer in drug–resistant HepG2 cells. Cancer Letters, 217(2), 203–211.

    Article  PubMed  CAS  Google Scholar 

  96. Lee, M. S., et al. (2005). Effects of polyphyllin D, a steroidal saponin in Paris polyphylla, in growth inhibition of human breast cancer cells and in xenograft. Cancer Biology & Therapy, 4(11), 1248–1254.

    CAS  Google Scholar 

  97. Ma, D. D., et al. (2009). Polyphyllin D exerts potent anti–tumour effects on Lewis cancer cells under hypoxic conditions. The Journal of International Medical Research, 37(3), 631–640.

    CAS  PubMed  Google Scholar 

  98. Mace, T. A., et al. (2006). The potential of the tumor microenvironment to influence Apo2L/TRAIL induced apoptosis. Immunological Investigations, 35(3–4), 279–296.

    Article  CAS  PubMed  Google Scholar 

  99. Ashkenazi, A. (2002). Targeting death and decoy receptors of the tumour–necrosis factor superfamily. Nature Reviews. Cancer, 2(6), 420–430.

    Article  CAS  PubMed  Google Scholar 

  100. Naka, T., et al. (2002). Effects of tumor necrosis factor–related apoptosis–inducing ligand alone and in combination with chemotherapeutic agents on patients' colon tumors grown in SCID mice. Cancer Research, 62(20), 5800–5806.

    CAS  PubMed  Google Scholar 

  101. Ravi, R., & Bedi, A. (2002). Requirement of BAX for TRAIL/Apo2L–induced apoptosis of colorectal cancers: synergism with sulindac–mediated inhibition of Bcl–x(L). Cancer Research, 62(6), 1583–1587.

    CAS  PubMed  Google Scholar 

  102. Clarke, N., et al. (2005). TRAIL: at the center of drugable anti–tumor pathways. Cell Cycle, 4(7), 914–918.

    CAS  PubMed  Google Scholar 

  103. Zhang, L., et al. (2010). Chemoprevention of colorectal cancer by targeting APC–deficient cells for apoptosis. Nature, 464(7291), 1058–1061.

    Article  CAS  PubMed  Google Scholar 

  104. Wicker, C. A., et al. (2010). BITC sensitizes pancreatic adenocarcinomas to TRAIL–induced apoptosis. Cancer Growth Metastasis, 2009(2), 45–55.

    PubMed  Google Scholar 

  105. Lee, D. H., Rhee, J. G., & Lee, Y. J. (2009). Reactive oxygen species up–regulate p53 and Puma; a possible mechanism for apoptosis during combined treatment with TRAIL and wogonin. British Journal of Pharmacology, 157(7), 1189–1202.

    Article  CAS  PubMed  Google Scholar 

  106. Hart, I. R., & Fidler, I. J. (1981). The implications of tumor heterogeneity for studies on the biology of cancer metastasis. Biochimica et Biophysica Acta, 651(1), 37–50.

    CAS  PubMed  Google Scholar 

  107. Eccles, S. A., & Welch, D. R. (2007). Metastasis: recent discoveries and novel treatment strategies. Lancet, 369(9574), 1742–1757.

    Article  CAS  PubMed  Google Scholar 

  108. Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Reviews. Cancer, 3(6), 453–458.

    Article  CAS  PubMed  Google Scholar 

  109. Karnoub, A. E., et al. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 449(7162), 557–563.

    Article  CAS  PubMed  Google Scholar 

  110. Chambers, A. F. (2009). Influence of diet on metastasis and tumor dormancy. Clinical & Experimental Metastasis, 26(1), 61–66.

    Article  CAS  Google Scholar 

  111. Cameron, M. D., et al. (2000). Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Research, 60(9), 2541–2546.

    CAS  PubMed  Google Scholar 

  112. Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial–mesenchymal transition. The Journal of Clinical Investigation, 119(6), 1420–1428.

    Article  CAS  PubMed  Google Scholar 

  113. Tarin, D., Thompson, E. W., & Newgreen, D. F. (2005). The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Research, 65(14), 5996–6000. discussion 6000–6001.

    Article  CAS  PubMed  Google Scholar 

  114. Thiery, J. P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature Reviews. Cancer, 2(6), 442–454.

    Article  CAS  PubMed  Google Scholar 

  115. Yang, J., & Weinberg, R. A. (2008). Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental Cell, 14(6), 818–829.

    Article  CAS  PubMed  Google Scholar 

  116. Hugo, H., et al. (2007). Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. Journal of Cellular Physiology, 213(2), 374–383.

    Article  CAS  PubMed  Google Scholar 

  117. Bissell, M. J., Kenny, P. A., & Radisky, D. C. (2005). Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes. Cold Spring Harbor Symposia on Quantitative Biology, 70, 343–356.

    Article  CAS  PubMed  Google Scholar 

  118. Tse, J. C., & Kalluri, R. (2007). Mechanisms of metastasis: epithelial–to–mesenchymal transition and contribution of tumor microenvironment. Journal of Cellular Biochemistry, 101(4), 816–829.

    Article  CAS  PubMed  Google Scholar 

  119. Zhao, A., et al. (2000). The effects of the expression of VEGF and KDR on the angiogenesis, growth and metastasis of hepatocellular carcinoma. Zhonghua Wai Ke Za Zhi, 38(6), 453–456.

    CAS  PubMed  Google Scholar 

  120. Gallo, O., et al. (2001). Cyclooxygenase–2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia, 3(1), 53–61.

    Article  CAS  PubMed  Google Scholar 

  121. Mukherjee, T., et al. (2003). Ets–1 and VEGF expression correlates with tumor angiogenesis, lymph node metastasis, and patient survival in esophageal squamous cell carcinoma. Journal of Cancer Research and Clinical Oncology, 129(7), 430–436.

    Article  CAS  PubMed  Google Scholar 

  122. Zhang, J., et al. (2007). Suppression of breast cancer metastasis through the inhibition of VEGF–mediated tumor angiogenesis. Cancer Therapy, 5, 273–286.

    PubMed  Google Scholar 

  123. Hanyu, A., et al. (2009). Functional in vivo optical imaging of tumor angiogenesis, growth, and metastasis prevented by administration of anti–human VEGF antibody in xenograft model of human fibrosarcoma HT1080 cells. Cancer Science, 100(11), 2085–2092.

    Article  CAS  PubMed  Google Scholar 

  124. Zheng, H., et al. (2006). Expressions of MMP–2, MMP–9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Research, 26(5A), 3579–3583.

    CAS  PubMed  Google Scholar 

  125. Kurahara, S., et al. (1999). Expression of MMPS, MT–MMP, and TIMPs in squamous cell carcinoma of the oral cavity: correlations with tumor invasion and metastasis. Head & Neck, 21(7), 627–638.

    Article  CAS  Google Scholar 

  126. Morini, M., et al. (2000). The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP–9) activity. International Journal of Cancer, 87(3), 336–342.

    Article  CAS  Google Scholar 

  127. Chen, J. S., et al. (2009). Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP–9. Hepatology Research, 39(2), 177–186.

    Article  CAS  PubMed  Google Scholar 

  128. Zigrino, P., et al. (2009). Stromal expression of MMP–13 is required for melanoma invasion and metastasis. The Journal of Investigative Dermatology, 129(11), 2686–2693.

    Article  CAS  PubMed  Google Scholar 

  129. Tan, C. T., et al. (2008). CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-–dependent invasion via the ERK1/2/AP–1 pathway. Carcinogenesis, 29(8), 1519–1527.

    Article  CAS  PubMed  Google Scholar 

  130. Naglich, J. G., et al. (2001). Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS–275291. Cancer Research, 61(23), 8480–8485.

    CAS  PubMed  Google Scholar 

  131. Shinoda, K., et al. (2003). A novel matrix metalloproteinase inhibitor, FYK–1388 suppresses tumor growth, metastasis and angiogenesis by human fibrosarcoma cell line. International Journal of Oncology, 22(2), 281–288.

    CAS  PubMed  Google Scholar 

  132. Blackburn, J. S., et al. (2007). RNA interference inhibition of matrix metalloproteinase–1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis. Cancer Research, 67(22), 10849–10858.

    Article  CAS  PubMed  Google Scholar 

  133. Pradeep, C. R., & Kuttan, G. (2003). Effect of beta–carotene on the inhibition of lung metastasis in mice. Phytomedicine, 10(2–3), 159–164.

    Article  CAS  PubMed  Google Scholar 

  134. Huang, C. S., Liao, J. W., & Hu, M. L. (2008). Lycopene inhibits experimental metastasis of human hepatoma SK–Hep–1 cells in athymic nude mice. The Journal of Nutrition, 138(3), 538–543.

    PubMed  Google Scholar 

  135. Chow, C. K. (2008). The relative efficacy of lycopene and beta–carotene in inhibiting experimental metastasis of human hepatoma SK–Hep–1 cells in athymic nude mice. The Journal of Nutrition, 138(11), 2289. author reply 2290.

    CAS  PubMed  Google Scholar 

  136. Gude, R. P., Menon, L. G., & Rao, S. G. (2001). Effect of Caffeine, a xanthine derivative, in the inhibition of experimental lung metastasis induced by B16F10 melanoma cells. Journal of Experimental & Clinical Cancer Research, 20(2), 287–292.

    CAS  Google Scholar 

  137. Yang, H., et al. (2004). Caffeine suppresses metastasis in a transgenic mouse model: a prototype molecule for prophylaxis of metastasis. Clinical & Experimental Metastasis, 21(8), 719–735.

    Article  CAS  Google Scholar 

  138. Lim, Y. C., et al. (2008). (–)–Epigallocatechin–3–gallate (EGCG) inhibits HGF–induced invasion and metastasis in hypopharyngeal carcinoma cells. Cancer Letters, 271(1), 140–152.

    Article  CAS  PubMed  Google Scholar 

  139. Shankar, S., et al. (2008). EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. Frontiers in Bioscience, 13, 440–452.

    Article  PubMed  Google Scholar 

  140. Kimura, Y., & Okuda, H. (2001). Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor–induced neovascularization in Lewis lung carcinoma– bearing mice. The Journal of Nutrition, 131(6), 1844–1849.

    CAS  PubMed  Google Scholar 

  141. Weng, Y. L., et al. (2010). Oral administration of resveratrol in suppression of pulmonary metastasis of BALB/c mice challenged with CT26 colorectal adenocarcinoma cells. Molecular Nutrition & Food Research, 54(2), 259–67.

    Article  CAS  Google Scholar 

  142. Wu, H., et al. (2008). Resveratrol inhibits hypoxia–induced metastasis potential enhancement by restricting hypoxia–induced factor–1 alpha expression in colon carcinoma cells. Biomedicine & Pharmacotherapy, 62(9), 613–621.

    Article  CAS  Google Scholar 

  143. Connolly, J. M., Liu, X. H., & Rose, D. P. (1997). Effects of dietary menhaden oil, soy, and a cyclooxygenase inhibitor on human breast cancer cell growth and metastasis in nude mice. Nutrition and Cancer, 29(1), 48–54.

    Article  CAS  PubMed  Google Scholar 

  144. Yan, L., Li, D., & Yee, J. A. (2002). Dietary supplementation with isolated soy protein reduces metastasis of mammary carcinoma cells in mice. Clinical & Experimental Metastasis, 19(6), 535–540.

    Article  CAS  Google Scholar 

  145. Li, D., et al. (2004). Dietary supplementation with high–selenium soy protein reduces pulmonary metastasis of melanoma cells in mice. The Journal of Nutrition, 134(6), 1536–1540.

    CAS  PubMed  Google Scholar 

  146. Singh, A. V., et al. (2006). Soy phytochemicals prevent orthotopic growth and metastasis of bladder cancer in mice by alterations of cancer cell proliferation and apoptosis and tumor angiogenesis. Cancer Research, 66(3), 1851–1858.

    Article  CAS  PubMed  Google Scholar 

  147. Menon, L. G., et al. (1998). Effect of isoflavones genistein and daidzein in the inhibition of lung metastasis in mice induced by B16F–10 melanoma cells. Nutrition and Cancer, 30(1), 74–77.

    Article  CAS  PubMed  Google Scholar 

  148. Vantyghem, S. A., et al. (2005). Dietary genistein reduces metastasis in a postsurgical orthotopic breast cancer model. Cancer Research, 65(8), 3396–3403.

    CAS  PubMed  Google Scholar 

  149. Schleicher, R. L., et al. (1999). The inhibitory effect of genistein on the growth and metastasis of a transplantable rat accessory sex gland carcinoma. Cancer Letters, 136(2), 195–201.

    Article  CAS  PubMed  Google Scholar 

  150. Iishi, H., et al. (2000). Genistein attenuates peritoneal metastasis of azoxymethane–induced intestinal adenocarcinomas in Wistar rats. International Journal of Cancer, 86(3), 416–420.

    Article  CAS  Google Scholar 

  151. Li, Y., et al. (2004). Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia, 6(4), 354–363.

    Article  CAS  PubMed  Google Scholar 

  152. Lee, W. Y., et al. (2007). Alterations of metastasis–related genes identified using an oligonucleotide microarray of genistein–treated HCC1395 breast cancer cells. Nutrition and Cancer, 58(2), 239–246.

    CAS  PubMed  Google Scholar 

  153. El Touny, L. H., & Banerjee, P. P. (2007). Genistein induces the metastasis suppressor kangai–1 which mediates its anti–invasive effects in TRAMP cancer cells. Biochemical and Biophysical Research Communications, 361(1), 169–175.

    Article  PubMed  CAS  Google Scholar 

  154. Gu, Y., et al. (2009). Inhibitory effects of genistein on metastasis of human hepatocellular carcinoma. World Journal of Gastroenterology, 15(39), 4952–4957.

    Article  CAS  PubMed  Google Scholar 

  155. Lakshman, M., et al. (2008). Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Research, 68(6), 2024–2032.

    Article  CAS  PubMed  Google Scholar 

  156. Young, M. R., et al. (1995). Treating tumor–bearing mice with vitamin D3 diminishes tumor–induced myelopoiesis and associated immunosuppression, and reduces tumor metastasis and recurrence. Cancer Immunology, Immunotherapy, 41(1), 37–45.

    CAS  PubMed  Google Scholar 

  157. Getzenberg, R. H., et al. (1997). Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system. Urology, 50(6), 999–1006.

    Article  CAS  PubMed  Google Scholar 

  158. Grant, W. B. (2008). Vitamin D may reduce prostate cancer metastasis by several mechanisms including blocking Stat3. The American Journal of Pathology, 173(5), 1589–1590.

    Article  PubMed  Google Scholar 

  159. Ooi, L. L., et al. (2010). Vitamin D deficiency promotes human breast cancer growth in a murine model of bone metastasis. Cancer Research, 70(5), 1835–1844.

    Article  CAS  PubMed  Google Scholar 

  160. El Abdaimi, K., et al. (2000). The vitamin D analogue EB 1089 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breast cancer cells. Cancer Research, 60(16), 4412–4418.

    PubMed  Google Scholar 

  161. Li-Weber, M. (2009). New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treatment Reviews, 35(1), 57–68.

    Article  CAS  PubMed  Google Scholar 

  162. Chen, Q., Peng, W., & Xu, A. (2002). Apoptosis of a human non–small cell lung cancer (NSCLC) cell line, PLA–801, induced by acutiaporberine, a novel bisalkaloid derived from Thalictrum acutifolium (Hand.–Mazz.) Boivin. Biochemical Pharmacology, 63(8), 1389–1396.

    Article  CAS  PubMed  Google Scholar 

  163. Zhao, F., et al. (2008). Anti–tumor activities of andrographolide, a diterpene from Andrographis paniculata, by inducing apoptosis and inhibiting VEGF level. Journal of Asian Natural Products Research, 10(5–6), 467–473.

    Article  PubMed  CAS  Google Scholar 

  164. Sheeja, K., & Kuttan, G. (2007). Modulation of natural killer cell activity, antibody–dependent cellular cytotoxicity, and antibody–dependent complement–mediated cytotoxicity by andrographolide in normal and Ehrlich ascites carcinoma–bearing mice. Integrative Cancer Therapies, 6(1), 66–73.

    Article  CAS  PubMed  Google Scholar 

  165. Li, P. C., et al. (2008). Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Research, 68(11), 4347–4351.

    Article  CAS  PubMed  Google Scholar 

  166. Efferth, T., et al. (2001). The anti–malarial artesunate is also active against cancer. International Journal of Oncology, 18(4), 767–773.

    CAS  PubMed  Google Scholar 

  167. Konkimalla, V. B., et al. (2008). Effect of artemisinins and other endoperoxides on nitric oxide–related signaling pathway in RAW 264.7 mouse macrophage cells. Nitric Oxide, 19(2), 184–191.

    Article  CAS  PubMed  Google Scholar 

  168. Li, S., et al. (2009). Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NFkappaB p65. International Journal of Hematology, 90(4), 513–521.

    Article  CAS  PubMed  Google Scholar 

  169. Hou, J., et al. (2008). Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clinical Cancer Research, 14(17), 5519–5530.

    Article  CAS  PubMed  Google Scholar 

  170. Efferth, T., et al. (2002). Activity of ascaridol from the anthelmintic herb Chenopodium anthelminticum L. against sensitive and multidrug–resistant tumor cells. Anticancer Research, 22(6C), 4221–4224.

    CAS  PubMed  Google Scholar 

  171. Bezerra, D. P., et al. (2009). Antitumor activity of the essential oil from the leaves of Croton regelianus and its component ascaridole. Chemistry & Biodiversity, 6(8), 1224–1231.

    Article  CAS  Google Scholar 

  172. Sun, D. I., et al. (2008). Bisacurone inhibits adhesion of inflammatory monocytes or cancer cells to endothelial cells through down–regulation of VCAM–1 expression. International Immunopharmacology, 8(9), 1272–1281.

    Article  CAS  PubMed  Google Scholar 

  173. Jing, Y., et al. (1999). Boswellic acid acetate induces differentiation and apoptosis in leukemia cell lines. Leukemia Research, 23(1), 43–50.

    Article  CAS  PubMed  Google Scholar 

  174. Batra, S., et al. (2010). Benzyl isothiocyanate–mediated inhibition of histone deacetylase leads to NF–kappaB turnoff in human pancreatic carcinoma cells. Molecular Cancer Therapeutics, 9(6), 1596–1608.

    Article  CAS  PubMed  Google Scholar 

  175. Wicker, C. A., et al. (2010). BITC sensitizes pancreatic adenocarcinomas to TRAIL–induced apoptosis. Cancer Growth Metastasis, 2009(2), 45–55.

    PubMed  Google Scholar 

  176. Warin, R., et al. (2010). Inhibition of human breast cancer xenograft growth by cruciferous vegetable constituent benzyl isothiocyanate. Molecular Carcinogenesis, 49(5), 500–507.

    Article  CAS  PubMed  Google Scholar 

  177. Chun, K. S., et al. (2003). Curcumin inhibits phorbol ester–induced expression of cyclooxygenase–2 in mouse skin through suppression of extracellular signal–regulated kinase activity and NF–kappaB activation. Carcinogenesis, 24(9), 1515–1524.

    Article  CAS  PubMed  Google Scholar 

  178. Reuter, S., et al. (2008). Modulation of anti–apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochemical Pharmacology, 76(11), 1340–1351.

    Article  CAS  PubMed  Google Scholar 

  179. Aggarwal, B. B., Kumar, A., & Bharti, A. C. (2003). Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Research, 23(1A), 363–398.

    CAS  PubMed  Google Scholar 

  180. Deeb, D., et al. (2003). Curcumin (diferuloyl–methane) enhances tumor necrosis factor–related apoptosis–inducing ligand–induced apoptosis in LNCaP prostate cancer cells. Molecular Cancer Therapeutics, 2(1), 95–103.

    CAS  PubMed  Google Scholar 

  181. Barve, A., et al. (2008). Murine prostate cancer inhibition by dietary phytochemicals–curcumin and phenyethylisothiocyanate. Pharmaceutical Research, 25(9), 2181–2189.

    Article  CAS  PubMed  Google Scholar 

  182. Pandey, M., & Gupta, S. (2009). Green tea and prostate cancer: from bench to clinic. Frontiers in Bioscience (Elite Ed), 1, 13–25.

    Google Scholar 

  183. Jeong, W. S., et al. (2004). Modulation of AP–1 by natural chemopreventive compounds in human colon HT–29 cancer cell line. Pharmaceutical Research, 21(4), 649–660.

    Article  CAS  PubMed  Google Scholar 

  184. Jagtap, S., et al. (2009). Chemoprotective mechanism of the natural compounds, epigallocatechin–3–O–gallate, quercetin and curcumin against cancer and cardiovascular diseases. Current Medicinal Chemistry, 16(12), 1451–1462.

    Article  CAS  PubMed  Google Scholar 

  185. Liao, S., & Hiipakka, R. A. (1995). Selective inhibition of steroid 5 alpha–reductase isozymes by tea epicatechin–3–gallate and epigallocatechin–3–gallate. Biochemical and Biophysical Research Communications, 214(3), 833–838.

    Article  CAS  PubMed  Google Scholar 

  186. Yang, Z. G., Chen, A. Q., & Liu, B. (2009). Antiproliferation and apoptosis induced by evodiamine in human colorectal carcinoma cells (COLO–205). Chemistry & Biodiversity, 6(6), 924–933.

    Article  CAS  Google Scholar 

  187. Wang, C., Li, S., & Wang, M. W. (2010). Evodiamine–induced human melanoma A375–S2 cell death was mediated by PI3K/Akt/caspase and Fas–L/NF–kappaB signaling pathways and augmented by ubiquitin–proteasome inhibition. Toxicology In Vitro, 24(3), 898–904.

    Article  CAS  PubMed  Google Scholar 

  188. Takada, Y., Kobayashi, Y., & Aggarwal, B. B. (2005). Evodiamine abolishes constitutive and inducible NF–kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF–kappaB–regulated antiapoptotic and metastatic gene expression, up–regulating apoptosis, and inhibiting invasion. The Journal of Biological Chemistry, 280(17), 17203–17212.

    Article  CAS  PubMed  Google Scholar 

  189. Liao, C. H., et al. (2005). Antitumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus, in human multiple–drug resistant breast cancer NCI/ADR–RES cells in vitro and in vivo. Carcinogenesis, 26(5), 968–975.

    Article  CAS  PubMed  Google Scholar 

  190. Liu, Z., et al. (2009). Modulation of DNA methylation by a sesquiterpene lactone parthenolide. The Journal of Pharmacology and Experimental Therapeutics, 329(2), 505–514.

    Article  CAS  PubMed  Google Scholar 

  191. Koprowska, K., & Czyz, M. (2010). Molecular mechanisms of parthenolide's action: old drug with a new face. Postępy Higieny i Medycyny Doświadczalnej (Online), 64, 100–114.

    Google Scholar 

  192. Shanmugam, R., et al. (2006). Restoring chemotherapy and hormone therapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model. The Prostate, 66(14), 1498–1511.

    Article  CAS  PubMed  Google Scholar 

  193. Tang, W., et al. (2006). Ganoderic acid T from Ganoderma lucidum mycelia induces mitochondria mediated apoptosis in lung cancer cells. Life Sciences, 80(3), 205–211.

    Article  CAS  PubMed  Google Scholar 

  194. Kim, S. O., et al. (2005). [6]–Gingerol inhibits COX–2 expression by blocking the activation of p38 MAP kinase and NF–kappaB in phorbol ester–stimulated mouse skin. Oncogene, 24(15), 2558–2567.

    Article  CAS  PubMed  Google Scholar 

  195. Ishiguro, K., et al. (2007). Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms. Biochemical and Biophysical Research Communications, 362(1), 218–223.

    Article  CAS  PubMed  Google Scholar 

  196. Park, K. K., et al. (1998). Inhibitory effects of [6]–gingerol, a major pungent principle of ginger, on phorbol ester–induced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice. Cancer Letters, 129(2), 139–144.

    Article  CAS  PubMed  Google Scholar 

  197. Liu, W. K., Xu, S. X., & Che, C. T. (2000). Anti–proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sciences, 67(11), 1297–1306.

    Article  CAS  PubMed  Google Scholar 

  198. Yun, T. K. (2003). Experimental and epidemiological evidence on non–organ specific cancer preventive effect of Korean ginseng and identification of active compounds. Mutation Research, 523–524, 63–74.

    PubMed  Google Scholar 

  199. Nakata, H., et al. (1998). Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells. Japanese Journal of Cancer Research, 89(7), 733–740.

    CAS  PubMed  Google Scholar 

  200. Shinkai, K., et al. (1996). Inhibition of in vitro tumor cell invasion by ginsenoside Rg3. Japanese Journal of Cancer Research, 87(4), 357–362.

    CAS  PubMed  Google Scholar 

  201. Lin, S. Y., et al. (2002). Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA synthesis and activating apoptosis. Journal of Cellular Biochemistry, 84(3), 532–544.

    Article  PubMed  CAS  Google Scholar 

  202. Liu, H., et al. (2008). Anti–tumor effect of honokiol alone and in combination with other anti–cancer agents in breast cancer. European Journal of Pharmacology, 591(1–3), 43–51.

    Article  CAS  PubMed  Google Scholar 

  203. Lee, S. J., et al. (2007). Aqueous extract of Magnolia officinalis mediates proliferative capacity, p21WAF1 expression and TNF–alpha–induced NF–kappaB activity in human urinary bladder cancer 5637 cells; involvement of p38 MAP kinase. Oncology Reports, 18(3), 729–736.

    PubMed  Google Scholar 

  204. Hahm, E. R., & Singh, S. V. (2007). Honokiol causes G0–G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity. Molecular Cancer Therapeutics, 6(10), 2686–2695.

    Article  CAS  PubMed  Google Scholar 

  205. Hahm, E. R., et al. (2008). Honokiol, a constituent of oriental medicinal herb magnolia officinalis, inhibits growth of PC–3 xenografts in vivo in association with apoptosis induction. Clinical Cancer Research, 14(4), 1248–1257.

    Article  CAS  PubMed  Google Scholar 

  206. Takai, N., et al. (2008). Beta–hydroxyisovalerylshikonin has a profound anti–growth activity in human endometrial and ovarian cancer cells. Gynecologic Oncology, 109(1), 107–114.

    Article  CAS  PubMed  Google Scholar 

  207. Komi, Y., et al. (2009). Mechanism of inhibition of tumor angiogenesis by beta–hydroxyisovalerylshikonin. Cancer Science, 100(2), 269–277.

    Article  CAS  PubMed  Google Scholar 

  208. Ma, P., et al. (2006). Inducement effect of synthetic indiosides from Solanum indicum L.on apoptosis of human hepatocarcinoma cell line Bel–7402 and its mechanism. Ai Zheng, 25(4), 438–442.

    CAS  PubMed  Google Scholar 

  209. Lv, W., et al. (2008). Jaceosidin induces apoptosis in human ovary cancer cells through mitochondrial pathway. Journal of Biomedicine & Biotechnology, 2008, 394802.

    Google Scholar 

  210. Ma, J., et al. (2001). Apoptosis induced by isoliquiritigenin in human gastric cancer MGC–803 cells. Planta Medica, 67(8), 754–757.

    Article  CAS  PubMed  Google Scholar 

  211. Fu, Y., et al. (2004). Licochalcone–A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late–G1 arrests in androgen–independent PC–3 prostate cancer cells. Biochemical and Biophysical Research Communications, 322(1), 263–270.

    Article  CAS  PubMed  Google Scholar 

  212. Yo, Y. T., et al. (2009). Licorice and licochalcone–A induce autophagy in LNCaP prostate cancer cells by suppression of Bcl–2 expression and the mTOR pathway. Journal of Agricultural and Food Chemistry, 57(18), 8266–8273.

    Article  CAS  PubMed  Google Scholar 

  213. Lee, C. K., et al. (2008). Licochalcone A inhibits the growth of colon carcinoma and attenuates cisplatin–induced toxicity without a loss of chemotherapeutic efficacy in mice. Basic & Clinical Pharmacology & Toxicology, 103(1), 48–54.

    Article  CAS  Google Scholar 

  214. Liu, X. S., & Jiang, J. (2006). Molecular mechanism of matrine–induced apoptosis in leukemia K562 cells. The American Journal of Chinese Medicine, 34(6), 1095–1103.

    Article  CAS  PubMed  Google Scholar 

  215. Ma, L., et al. (2008). Anticancer effects of the Chinese medicine matrine on murine hepatocellular carcinoma cells. Planta Medica, 74(3), 245–251.

    Article  CAS  PubMed  Google Scholar 

  216. Ma, D. D., et al. (2009). Polyphyllin D exerts potent anti–tumour effects on Lewis cancer cells under hypoxic conditions. The Journal of International Medical Research, 37(3), 631–640.

    CAS  PubMed  Google Scholar 

  217. Huang, Q., Shen, H. M., & Ong, C. N. (2004). Inhibitory effect of emodin on tumor invasion through suppression of activator protein–1 and nuclear factor–kappaB. Biochemical Pharmacology, 68(2), 361–371.

    Article  CAS  PubMed  Google Scholar 

  218. Liu, J. J., et al. (2004). Anti–proliferative effects of oridonin on SPC–A–1 cells and its mechanism of action. The Journal of International Medical Research, 32(6), 617–625.

    CAS  PubMed  Google Scholar 

  219. Leung, C. H., et al. (2005). Novel mechanism of inhibition of nuclear factor–kappa B DNA–binding activity by diterpenoids isolated from Isodon rubescens. Molecular Pharmacology, 68(2), 286–297.

    CAS  PubMed  Google Scholar 

  220. Hsieh, T. C., et al. (2005). Differential control of growth, cell cycle progression, and expression of NF–kappaB in human breast cancer cells MCF–7, MCF–10A, and MDA–MB–231 by ponicidin and oridonin, diterpenoids from the chinese herb Rabdosia rubescens. Biochemical and Biophysical Research Communications, 337(1), 224–231.

    Article  CAS  PubMed  Google Scholar 

  221. Liu, J. J., et al. (2005). Antiproliferation effects of ponicidin on human myeloid leukemia cells in vitro. Oncology Reports, 13(4), 653–657.

    CAS  PubMed  Google Scholar 

  222. Hayashi, K., et al. (2002). Contribution of a combination of ponicidin and acyclovir/ganciclovir to the antitumor efficacy of the herpes simplex virus thymidine kinase gene therapy system. Human Gene Therapy, 13(3), 415–423.

    Article  CAS  PubMed  Google Scholar 

  223. Yang, S., et al. (2003). Triptolide inhibits the growth and metastasis of solid tumors. Molecular Cancer Therapeutics, 2(1), 65–72.

    CAS  PubMed  Google Scholar 

  224. Zhao, F., et al. (267). Triptolide alters histone H3K9 and H3K27 methylation state and induces G0/G1 arrest and caspase–dependent apoptosis in multiple myeloma in vitro. Toxicology, 267(1–3), 70–79.

    Google Scholar 

  225. Yang, M., et al. (2008). Triptolide overcomes dexamethasone resistance and enhanced PS–341–induced apoptosis via PI3k/Akt/NF–kappaB pathways in human multiple myeloma cells. International Journal of Molecular Medicine, 22(4), 489–496.

    CAS  PubMed  Google Scholar 

  226. Lin, J., et al. (2007). Inhibitory effect of triptolide on glioblastoma multiforme in vitro. The Journal of International Medical Research, 35(4), 490–496.

    CAS  PubMed  Google Scholar 

  227. Yu, R., et al. (1998). Chemopreventive isothiocyanates induce apoptosis and caspase–3–like protease activity. Cancer Research, 58(3), 402–408.

    CAS  PubMed  Google Scholar 

  228. Wu, S. J., Ng, L. T., & Lin, C. C. (2005). Effects of antioxidants and caspase–3 inhibitor on the phenylethyl isothiocyanate–induced apoptotic signaling pathways in human PLC/PRF/5 cells. European Journal of Pharmacology, 518(2–3), 96–106.

    Article  CAS  PubMed  Google Scholar 

  229. Trachootham, D., et al. (2006). Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta–phenylethyl isothiocyanate. Cancer Cell, 10(3), 241–252.

    Article  CAS  PubMed  Google Scholar 

  230. Cheung, K. L., & Kong, A. N. (2010). Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention. The AAPS Journal, 12(1), 87–97.

    Article  CAS  PubMed  Google Scholar 

  231. Cheung, K. L., Khor, T. O., & Kong, A. N. (2009). Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation. Pharmaceutical Research, 26(1), 224–231.

    Article  CAS  PubMed  Google Scholar 

  232. Hecht, S. S. (1995). Chemoprevention by isothiocyanates. Journal of Cellular Biochemistry. Supplement, 22, 195–209.

    Article  CAS  PubMed  Google Scholar 

  233. Cheung, K. L., et al. (2010). Differential in vivo mechanism of chemoprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM. Carcinogenesis, 31(5), 880–885.

    Article  CAS  PubMed  Google Scholar 

  234. Khor, T. O., et al. (2006). Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC–3 prostate xenografts in immunodeficient mice. Cancer Research, 66(2), 613–621.

    Article  CAS  PubMed  Google Scholar 

  235. Hecht, S. S. (1999). Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. The Journal of Nutrition, 129(3), 768S–774S.

    CAS  PubMed  Google Scholar 

  236. Powolny, A. A., & Singh, S. V. (2008). Plumbagin–induced apoptosis in human prostate cancer cells is associated with modulation of cellular redox status and generation of reactive oxygen species. Pharmaceutical Research, 25(9), 2171–2180.

    Article  CAS  PubMed  Google Scholar 

  237. Hsu, Y. L., et al. (2006). Plumbagin (5–hydroxy–2–methyl–1,4–naphthoquinone) induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation via c–Jun NH2–terminal kinase–mediated phosphorylation at serine 15 in vitro and in vivo. The Journal of Pharmacology and Experimental Therapeutics, 318(2), 484–494.

    Article  CAS  PubMed  Google Scholar 

  238. Hansen, R. K., et al. (1997). Quercetin inhibits heat shock protein induction but not heat shock factor DNA–binding in human breast carcinoma cells. Biochemical and Biophysical Research Communications, 239(3), 851–856.

    Article  CAS  PubMed  Google Scholar 

  239. HemaIswarya, S., & Doble, M. (2006). Potential synergism of natural products in the treatment of cancer. Phytotherapy Research, 20(4), 239–249.

    Article  CAS  PubMed  Google Scholar 

  240. Jung, Y. H., et al. (2010). Quercetin enhances TRAIL–induced apoptosis in prostate cancer cells via increased protein stability of death receptor 5. Life Sciences, 86(9–10), 351–357.

    Article  CAS  PubMed  Google Scholar 

  241. Kim, Y. H., et al. (2008). Quercetin augments TRAIL–induced apoptotic death: involvement of the ERK signal transduction pathway. Biochemical Pharmacology, 75(10), 1946–1958.

    Article  CAS  PubMed  Google Scholar 

  242. Miyamoto, S., et al. (2010). Dietary flavonoids suppress azoxymethane–induced colonic preneoplastic lesions in male C57BL/KsJ–db/db mice. Chemistry & Biology Interact, 183(2), 276–283.

    Article  CAS  Google Scholar 

  243. Lin, S., et al. (2003). Rhein inhibits TPA–induced activator protein–1 activation and cell transformation by blocking the JNK–dependent pathway. International Journal of Oncology, 22(4), 829–833.

    CAS  PubMed  Google Scholar 

  244. Lai, W. W., et al. (2009). Rhein induced apoptosis through the endoplasmic reticulum stress, caspase– and mitochondria–dependent pathways in SCC–4 human tongue squamous cancer cells. In Vivo, 23(2), 309–316.

    CAS  PubMed  Google Scholar 

  245. Lin, Y. J., & Zhen, Y. S. (2009). Rhein lysinate suppresses the growth of breast cancer cells and potentiates the inhibitory effect of Taxol in athymic mice. Anti-Cancer Drugs, 20(1), 65–72.

    Article  CAS  PubMed  Google Scholar 

  246. Hsu, S. H., et al. (1996). Solamargine purified from Solanum incanum Chinese herb triggers gene expression of human TNFR I which may lead to cell apoptosis. Biochemical and Biophysical Research Communications, 229(1), 1–5.

    Article  CAS  PubMed  Google Scholar 

  247. Liu, L. F., et al. (2004). Action of solamargine on human lung cancer cells—enhancement of the susceptibility of cancer cells to TNFs. FEBS Letters, 577(1–2), 67–74.

    Article  CAS  PubMed  Google Scholar 

  248. Liang, C. H., et al. (2007). Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells. Molecular Nutrition & Food Research, 51(8), 999–1005.

    Article  CAS  Google Scholar 

  249. Liang, C. H., et al. (2004). Action of solamargine on TNFs and cisplatin–resistant human lung cancer cells. Biochemical and Biophysical Research Communications, 322(3), 751–758.

    Article  CAS  PubMed  Google Scholar 

  250. Sestili, P., et al. (2010). Sulforaphane induces DNA single strand breaks in cultured human cells. Mutation Research, 689(1–2), 65–73.

    CAS  PubMed  Google Scholar 

  251. Moon, D. O., et al. (2010). Sulforaphane decreases viability and telomerase activity in hepatocellular carcinoma Hep3B cells through the reactive oxygen species–dependent pathway. Cancer Letter, 295(2), 260–266.

    Article  CAS  Google Scholar 

  252. Ho, E., Clarke, J. D., & Dashwood, R. H. (2009). Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention. The Journal of Nutrition, 139(12), 2393–2396.

    Article  CAS  PubMed  Google Scholar 

  253. Kim, S. H., & Singh, S. V. (2009). D,L–Sulforaphane causes transcriptional repression of androgen receptor in human prostate cancer cells. Molecular Cancer Therapeutics, 8(7), 1946–1954.

    Article  CAS  PubMed  Google Scholar 

  254. Shan, Y., et al. (2009). Sulforaphane down–regulates COX–2 expression by activating p38 and inhibiting NF–kappaB–DNA–binding activity in human bladder T24 cells. International Journal of Oncology, 34(4), 1129–1134.

    CAS  PubMed  Google Scholar 

  255. Shankar, S., Ganapathy, S., & Srivastava, R. K. (2008). Sulforaphane enhances the therapeutic potential of TRAIL in prostate cancer orthotopic model through regulation of apoptosis, metastasis, and angiogenesis. Clinical Cancer Research, 14(21), 6855–6866.

    Article  CAS  PubMed  Google Scholar 

  256. Keum, Y. S., et al. (2009). Pharmacokinetics and pharmacodynamics of broccoli sprouts on the suppression of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: implication of induction of Nrf2, HO–1 and apoptosis and the suppression of Akt–dependent kinase pathway. Pharmaceutical Research, 26(10), 2324–2331.

    Article  CAS  PubMed  Google Scholar 

  257. Myzak, M. C., et al. (2007). Sulforaphane retards the growth of human PC–3 xenografts and inhibits HDAC activity in human subjects. Experimental Biology and Medicine (Maywood), 232(2), 227–234.

    CAS  Google Scholar 

  258. Lee, W. Y., Chiu, L. C., & Yeung, J. H. (2008). Cytotoxicity of major tanshinones isolated from Danshen (Salvia miltiorrhiza) on HepG2 cells in relation to glutathione perturbation. Food and Chemical Toxicology, 46(1), 328–338.

    Article  CAS  PubMed  Google Scholar 

  259. Nizamutdinova, I. T., et al. (2008). Tanshinone I effectively induces apoptosis in estrogen receptor–positive (MCF–7) and estrogen receptor–negative (MDA–MB–231) breast cancer cells. International Journal of Oncology, 33(3), 485–491.

    CAS  PubMed  Google Scholar 

  260. El-Mahdy, M. A., et al. (2005). Thymoquinone induces apoptosis through activation of caspase–8 and mitochondrial events in p53–null myeloblastic leukemia HL–60 cells. International Journal of Cancer, 117(3), 409–417.

    Article  CAS  Google Scholar 

  261. Gali-Muhtasib, H., et al. (2004). Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53–dependent mechanism. International Journal of Oncology, 25(4), 857–866.

    CAS  PubMed  Google Scholar 

  262. Badary, O. A. (1999). Thymoquinone attenuates ifosfamide–induced Fanconi syndrome in rats and enhances its antitumor activity in mice. Journal of Ethnopharmacology, 67(2), 135–142.

    Article  CAS  PubMed  Google Scholar 

  263. Aggarwal, B. B., et al. (2008). Potential of spice–derived phytochemicals for cancer prevention. Planta Medica, 74(13), 1560–1569.

    Article  CAS  PubMed  Google Scholar 

  264. Roepke, M., et al. (2007). Lack of p53 augments thymoquinone–induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biology & Therapy, 6(2), 160–169.

    Article  CAS  Google Scholar 

  265. Shoieb, A. M., et al. (2003). In vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone. International Journal of Oncology, 22(1), 107–113.

    CAS  PubMed  Google Scholar 

  266. Gali-Muhtasib, H., Roessner, A., & Schneider-Stock, R. (2006). Thymoquinone: a promising anti–cancer drug from natural sources. The International Journal of Biochemistry & Cell Biology, 38(8), 1249–1253.

    Article  CAS  Google Scholar 

  267. Yi, T., et al. (2008). Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal–regulated kinase signaling pathways. Molecular Cancer Therapeutics, 7(7), 1789–1796.

    Article  CAS  PubMed  Google Scholar 

  268. Zhang, K., et al. (2008). Wogonin induces the granulocytic differentiation of human NB4 promyelocytic leukemia cells and up–regulates phospholipid scramblase 1 gene expression. Cancer Science, 99(4), 689–695.

    Article  CAS  PubMed  Google Scholar 

  269. Yang, L., et al. (2009). Wogonin induces G1 phase arrest through inhibiting Cdk4 and cyclin D1 concomitant with an elevation in p21Cip1 in human cervical carcinoma HeLa cells. Biochemistry and Cell Biology, 87(6), 933–942.

    Article  CAS  PubMed  Google Scholar 

  270. Lee, E., et al. (2009). Inhibition of P–glycoprotein by wogonin is involved with the potentiation of etoposide–induced apoptosis in cancer cells. Annals of the New York Academy of Sciences, 1171, 132–136.

    Article  CAS  PubMed  Google Scholar 

  271. Chung, H., et al. (2008). Anticancer effects of wogonin in both estrogen receptor–positive and –negative human breast cancer cell lines in vitro and in nude mice xenografts. International Journal of Cancer, 122(4), 816–822.

    Article  CAS  Google Scholar 

  272. Cheung, J. Y., et al. (2005). Polyphyllin D is a potent apoptosis inducer in drug–resistant HepG2 cells. Cancer Letters, 217(2), 203–211.

    Article  PubMed  CAS  Google Scholar 

  273. Lee, M. S., et al. (2005). Effects of polyphyllin D, a steroidal saponin in Paris polyphylla, in growth inhibition of human breast cancer cells and in xenograft. Cancer Biology & Therapy, 4(11), 1248–1254.

    CAS  Google Scholar 

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Acknowledgments

Supported in part by Institutional Funds and by RO1-CA073674, RO1-CA094828 and R01-CA118947 to Dr Ah-Ng Tony Kong from the National Institutes of Health (NIH). We thank all the members in Dr. Tony Kong's lab for their help in discussing and preparing this manuscript.

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Correspondence to Chi Chen or Ah-Ng Kong.

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Shu, L., Cheung, KL., Khor, T.O. et al. Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis. Cancer Metastasis Rev 29, 483–502 (2010). https://doi.org/10.1007/s10555-010-9239-y

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