This overview presents curcumin as a significant chemosensitizer in cancer chemotherapy. Although the review focuses on curcumin and its analogues on multidrug resistance (MDR) reversal, the relevance of curcumin as a nuclear factor (NF)-κB blocker and sensitizer of many chemoresistant cancer cell lines to chemotherapeutic agents will also be discussed. One of the major mechanisms of MDR is the enhanced ability of tumor cells to actively efflux drugs, leading to a decrease in cellular drug accumulation below toxic levels.


Multidrug Resistance Breast Cancer Resistance Protein MDR1 Gene Curcuma Longa MDR1 Gene Expression 
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  1. 1.
    1. H. Lage, ABC-transporters: Implications on drug resistance from microorganisms to human cancers. Int J Antimicrob Agents 22, 188 (2003).PubMedGoogle Scholar
  2. 2.
    2. T. Tsuruo, H. Iida, S. Tsukagoshi, and Y. Sakurai, Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41, 1967 (1981).PubMedGoogle Scholar
  3. 3.
    3. H. A. Bardelmeijer, J. H. Beijnen, K. R. Brouwer, H. Rosing, W. J. Nooijen, J. H. Schellens, Jand O. van Tellingen, Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein. Clin Cancer Res 6, 4416 (2000).PubMedGoogle Scholar
  4. 4.
    4. L. J. Green, P. Marder, and C. A. Slapak, Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells. Biochem Pharmacol 61, 1393 (2001).PubMedGoogle Scholar
  5. 5.
    5. A. L. Cheng, C. H. Hsu, J. K. Lin, M. M. Hsu, Y. F. Ho, T. S. Shen, J. Y. Ko, J. T. Lin, B. R. Lin, W. Ming-Shiang, H. S. Yu, S. H. Jee, G. S. Chen, T. M. Chen, C. A. Chen, M. K. Lai, Y. S. Pu, M. H. Pan, Y. J. Wang, C. C. Tsai, and C. Y. Hsieh, Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21, 2895 (2001).PubMedGoogle Scholar
  6. 6.
    6. M Notarbartolo, P. Poma, D. Perri, L. Dusonchet, M. Cervello, and N. D'Alessandro, Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression. Cancer Lett 224, 53 (2005).PubMedGoogle Scholar
  7. 7.
    7. B. Hill, Drug resistance, and overview of the current state of the art. Int J Oncol 9, 197 (1996).Google Scholar
  8. 8.
    8. P. S. Lacombe, J. A. G. Vicente, J. G. Pages, and P. L. Morselli, Causes and problems of nonresponse or poor response to drugs. Drugs 51, 552 (1996).Google Scholar
  9. 9.
    9. L. J. Goldstein, MDR1 gene expression in solid tumours. Eur J Cancer 32A(6), 1039 (1996).PubMedGoogle Scholar
  10. 10.
    10. M. Volmand J. Mattern, Resistance mechanisms and their regulation in lung cancer. Crit Rev Oncog 7, 227 (1996).Google Scholar
  11. 11.
    11. M. Dietel, What's new in cytostatic drug resistance and pathology. Pathol Res Pract 187, 892 (1991).PubMedGoogle Scholar
  12. 12.
    12. W. T. Beck, Mechanisms of multidrug resistance in human tumor cells. The roles of P-glycoprotein, DNA topoisomerase II, and other factors. Cancer Treat Rev 17(Suppl A), 11 (1990).PubMedGoogle Scholar
  13. 13.
    13. C. S. Morrow and K. H. Cowan, Glutathione S-transferases and drug resistance. Cancer Cells 2, 15 (1990).PubMedGoogle Scholar
  14. 14.
    14. J. R. Hammond, R. M. Johnstone, and P. Gros, Enhanced efflux of [3H]vinblastine from Chinese hamster ovary cells transfected with a full-length complementary DNA clone for the mdr1 gene. Cancer Res 49, 3867 (1989).PubMedGoogle Scholar
  15. 15.
    15. Y. A. Hannun, Apoptosis and the dilemma of cancer chemotherapy. Blood 89, 1845 (1997).PubMedGoogle Scholar
  16. 16.
    16. Y. Y. Liu, T. Y. Han, A. E. Giuliano, and M. C. Cabot, Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 15, 719 (2001).PubMedGoogle Scholar
  17. 17.
    17. R. L. Juliano and V. Ling, A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455, 152 (1976).PubMedGoogle Scholar
  18. 18.
    18. D. Nielson, C. Maare, and T. Skovsgaard, Influx of daunorubicin in multidrug resistance Erlich ascites tumor cells, correlation to expression of P-glycoprotein and efflux. Influence of verapamil. Biochem Pharmacol 50, 443 (1995).Google Scholar
  19. 19.
    19. A. R. Safa, Photoaffinity labeling of p-glycoprotein in multidrug resistance cells. Cancer Invest 10, 295 (1992).Google Scholar
  20. 20.
    20. R. G. Deeley and S. P. Cole, Function, evolution and structure of multidrug resistance protein (MRP). Semin Cancer Biol 8, 193 (1997).PubMedGoogle Scholar
  21. 21.
    21. D. D. Ross, W. Yang, L. V. Abruzzo, W. S. Dalton, E. Schneider, H. Lage, M. Dietel, L. Greenberger, S. P. Cole, and L. A. Doyle, Atypical multidrug resistance: Breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J Natl Cancer Inst 91, 429 (1999).PubMedGoogle Scholar
  22. 22.
    22. Z. E. Sauna, M. M. Smith, M. Muller, K. M. Kerr, and S. V. Ambudkar, The mechanism of action of multidrug-resistance-linked P-glycoprotein. J Bioenerg Biomembr 33, 481 (2001).PubMedGoogle Scholar
  23. 23.
    23. T. Litman, T. E. Druley, W. D. Stein, and S. E. Bates, From MDR to MXR: New understanding of multidrug resistance systems, their properties and clinical significance. Cell Mol Life Sci 58, 931 (2001).PubMedGoogle Scholar
  24. 24.
    24. J. C. Leighton, Jr. and L. J. Goldstein, P-Glycoprotein in adultsolid tumors. Expression and prognostic significance. Hematol Oncol Clin North Am 9, 251 (1995).PubMedGoogle Scholar
  25. 25.
    25. J. P. Marie, P-Glycoprotein in adult hematologic malignancies. Hematol Oncol Clin North Am 9, 239 (1995).PubMedGoogle Scholar
  26. 26.
    26. R. J. Arceci, Clinical significance of P-glycoprotein in multidrug resistance malignancies. Blood 81, 2215 (1993).PubMedGoogle Scholar
  27. 27.
    27. R. Pirker, J. Wallner, K. Geissler, W. Linkesch, O. A. Haas, P. Bettelheim, M. Hopfner, R. Scherrer, P. Valent, L. Havelec, et al., MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst. 83, 708 (1991).PubMedGoogle Scholar
  28. 28.
    28. H. S. Chan, P. S. Thorner, G. Haddad, and V. Ling, Immunohistochemical detection of P-glycoprotein: Prognostic correlation in soft tissue sarcoma of childhood. J Clin Oncol 8, 689 (1990).PubMedGoogle Scholar
  29. 29.
    29. R. S. Weinstein, S. M. Jakate, J. M. Dominguez, M. D. Lebovitz, G. K. Koukoulis, J. R. Kuszak, L. F. Klusens, T. M. Grogan, T. J. Saclarides, I. B. Roninson, et al., Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res. 51, 2720 (1991).PubMedGoogle Scholar
  30. 30.
    30. S. W. Tobe, S. E. Noble-Topham, I. L. Andrulis, R. W. Hartwick, K. L. Skorecki, and E. Warner, Expression of the multiple drug resistance gene in human renal cell carcinoma depends on tumor histology, grade, and stage. Clin Cancer Res 1, 1611 (1995).PubMedGoogle Scholar
  31. 31.
    31. G. Giaccone, S. C. Linn, and H. M. Pinedo, Multidrug resistance in breast cancer, mechanisms, strategies. Eur J Cancer 31A(Suppl 7), S15 (1995).PubMedGoogle Scholar
  32. 32.
    32. H. M. Pinedo and G. Giaccone, P-Glycoprotein: A marker of cancer-cell behavior. N Engl J Med 333, 1417 (1995).PubMedGoogle Scholar
  33. 33.
    33. J. L. Biedler, Genetic aspects of multidrug resistance. Cancer 70, 1799 (1992).PubMedGoogle Scholar
  34. 34.
    34. M. Lehnert, Clinical multidrug resistance in cancer: A multifactorial problem. Eur J Cancer 32A, 912 (1996).PubMedGoogle Scholar
  35. 35.
    35. E. Buschman, R. J. Arceci, J. M. Croop, M. Che, I. M. Arias, D. E. Housman, and P. Gros, mdr2 encodes P-glycoprotein expressed in the bile canalicular membrane as determined by isoform-specific antibodies. J Biol Chem 267, 18,093 (1992).Google Scholar
  36. 36.
    36. C. Cordon-Cardo, J. P. O'Brien, J. Boccia, D. Casals, J. R. Bertino, and M. R. Melamed, Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 38, 1277 (1990).PubMedGoogle Scholar
  37. 37.
    37. J. J. Smit, A. H. Schinkel, C. A. Mol, D. Majoor, W. J. Mooi, A. P. Jongsma, C. R. Lincke, and P. Borst, Tissue distribution of the human MDR3 P-glycoprotein. Lab Invest 71, 638 (1994).PubMedGoogle Scholar
  38. 38.
    38. M. M. Gottesman and I. Pastan, Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62, 385 (1993).PubMedGoogle Scholar
  39. 39.
    39. F. Frezard, E. Pereira-Maia, P. Quidu, W. Priebe, and A. Garnier-Suillerot, P-Glycoprotein preferentially effluxes anthracyclines containing free basic versus charged amine. Eur J Biochem 268, 1561 (2001).PubMedGoogle Scholar
  40. 40.
    40. U. Brinkmann, I. Roots, and M. Eichelbaum, Pharmacogenetics of the human drug-transporter gene MDR1: Impact of polymorphisms on pharmacotherapy. Drug Discov Today 6, 835 (2001).PubMedGoogle Scholar
  41. 41.
    41. P. Gros and C. Shustik, Multidrug resistance: A novel class of membrane-associated transport proteins is identified. Cancer Invest 9, 563 (1991).PubMedGoogle Scholar
  42. 42.
    42. M. M. Cornwell, I. Pastan, and M. M. Gottesman, Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J Biol Chem 262, 2166 (1987).PubMedGoogle Scholar
  43. 43.
    43. T. W. Loo and D. M. Clarke, Functional consequences of glycine mutations in the predicted cytoplasmic loops of P-glycoprotein. J Biol Chem 269, 7243 (1994).PubMedGoogle Scholar
  44. 44.
    44. F. J. Sharom, X. Yu, and C. A. Doige, Functional reconstitution of drug transport and ATPase activity in proteoliposomes containing partially purified P-glycoprotein. J Biol Chem 268, 24,197 (1993).Google Scholar
  45. 45.
    45. P. M. Jones and A. M. George, A new structural model for P-glycoprotein. J Membr Biol 166, 133 (1998).PubMedGoogle Scholar
  46. 46.
    46. K. Ueda, A. Yoshida, and T. Amachi, Recent progress in P-glycoprotein research. Anticancer Drug Des 14, 115 (1999).PubMedGoogle Scholar
  47. 47.
    47. A. F. Castro, J. K. Horton, C. G. Vanoye, and G. A. Altenberg, Mechanism of inhibition of P-glycoprotein-mediated drug transport by protein kinase C blockers. Biochem Pharmacol 58, 1723 (1999).PubMedGoogle Scholar
  48. 48.
    48. G. Conseil, J. M. Perez-Victoria, J. M. Jault, F. Gamarro, A. Goffeau, J. Hofmann, and A. Di Pietro, Protein kinase C effectors bind to multidrug ABC transporters and inhibit their activity. Biochemistry 40, 2564 (2001).PubMedGoogle Scholar
  49. 49.
    49. H. Yabuuchi, S. Takayanagi, K. Yoshinaga, N. Taniguchi, H. Aburatani and T. Ishikawa, ABCC13, an unusual truncated ABC transporter, is highly expressed in fetal human liver. Biochem Biophys Res Common 299, 410 (2002).Google Scholar
  50. 50.
    50. A. C. Lockhart, R. G. Tirona, and R. B. Kim, Pharmacogenetics of ATP-binding cassette transporters in cancer and chemotherapy. Mol Cancer Ther 2, 685 (2003).PubMedGoogle Scholar
  51. 51.
    51. S. P. Cole, G. Bhardwaj, J. H. Gerlach, J. E. Mackie, C. E. Grant, K. C. Almquist, A. J. Stewart, E. U. Kurz, A. M. Duncan, and R. G. Deeley, Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258, 1650 (1992).PubMedGoogle Scholar
  52. 52.
    52. P. Borst, R. Evers, M. Kool, and J. Wijnholds, A family of drug transporters: The multidrug resistance-associated proteins. J Natl Cancer Inst 92, 1295 (2000).PubMedGoogle Scholar
  53. 53.
    53. D. R. Hipfner, R. G. Deeley, and S. P. Cole, Structural, mechanistic and clinical aspects of MRP1. Biochim Biophys Acta 1461, 359 (1999).PubMedGoogle Scholar
  54. 54.
    54. J. Renes, E. G. de Vries, E. F. Nienhuis, P. L. Jansen, and M. Muller, ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1. Br J Pharmacol 126, 681 (1999).PubMedGoogle Scholar
  55. 55.
    55. G. Rappa, A. Lorico, R. A. Flavell, and A. C. Sartorelli, Evidence that the multidrug resistance protein (MRP) functions as a co-transporter of glutathione and natural product toxins. Cancer Res 57, 5232 (1997).PubMedGoogle Scholar
  56. 56.
    56. L. Manciu, X. B. Chang, J. R. Riordan, and J. M. Ruysschaert, Multidrug resistance protein MRP1 reconstituted into lipid vesicles: Secondary structure and nucleotide-induced tertiary structure changes. Biochemistry 39, 13,026 (2000).Google Scholar
  57. 57.
    57. E. M. Leslie, R. G. Deeley, and S. P. Cole, Multidrug resistance proteins, role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204, 216 (2005).PubMedGoogle Scholar
  58. 58.
    58. A. Haimeur, G. Conseil, R. G. Deeley, and S. P. Cole, The MRP-related and BCRP/ABCG2 multidrug resistance proteins: Biology, substrate specificity and regulation. Curr Drug Metab 5, 21 (2004).PubMedGoogle Scholar
  59. 59.
    59. M. Gao, H. R. Cui, D. W. Loe, C. E. Grant, K. C. Almquist, S. P. Cole, and R. G. Deeley, Comparison of the functional characteristics of the nucleotide binding domains of multidrug resistance protein 1. J Biol Chem 275, 13,098 (2000).Google Scholar
  60. 60.
    60. K. Nagata, M. Nishitani, M. Matsuo, N. Kioka, T. Amachi, and K. Ueda, Nonequivalent nucleotide trapping in the two nucleotide binding folds of the human multidrug resistance protein MRP1. J Biol Chem 275, 17,626 (2000).Google Scholar
  61. 61.
    61. K. Barnouin, I. Leier, G. Jedlitschky, A. Pourtier-Manzanedo, J. Konig, W. D. Lehmann, and D. Keppler, Multidrug resistance protein-mediated transport of chlorambucil and melphalan conjugated to glutathione. Br J Cancer 77, 201 (1998).PubMedGoogle Scholar
  62. 62.
    62. N. Ballatori, C. L. Hammond, J. B. Cunningham, S. M. Krance, and R. Marchan, Molecular mechanisms of reduced glutathione transport: Role of the MRP/CFTR/ABCC and OATP/SLC21A families of membrane proteins. Toxicol Appl Pharmacol 204, 238 (2005).PubMedGoogle Scholar
  63. 63.
    63. K. Miyake, L. Mickley, T. Litman, Z. Zhan, R. Robey, B. Cristensen, M. Brangi, L. Greenberger, M. Dean, T. Fojo, and S. E. Bates, Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: Demonstration of homology to ABC transport genes. Cancer Res 59, 8 (1999).PubMedGoogle Scholar
  64. 64.
    64. L. A. Doyle and D. D. Ross, Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22, 7340 (2003).PubMedGoogle Scholar
  65. 65.
    65. R. Allikmets, L. M. Schriml, A. Hutchinson, V. Romano-Spica, and M. Dean, A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res 58, 5337 (1998).PubMedGoogle Scholar
  66. 66.
    66. S. E. Bates, R. Robey, K. Miyake, K. Rao, D. D. Ross, and T. Litman, The role of half-transporters in multidrug resistance. J Bioenerg Biomembr 33, 503 (2001).PubMedGoogle Scholar
  67. 67.
    67. Y. Honjo, C. A. Hrycyna, Q. W. Yan, W. Medina-Perez, R. W. Robey, A. van de Laar, T. Litman, M. Dean, and S. E. Bates, Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Res 61, 6635 (2001).PubMedGoogle Scholar
  68. 68.
    68. R. W. Robey, Y. Honjo, K. Morisaki, T. A. Nadjem, S. Runge, M. Risbood, M. S. Poruchynsky, and S. E. Bates, Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity. Br J Cancer 89, 1971 (2003).PubMedGoogle Scholar
  69. 69.
    69. M. Miwa, S. Tsukahara, E. Ishikawa, S. Asada, Y. Imai, and Y. Sugimoto, Single amino acid substitutions in the transmembrane domains of breast cancer resistance protein (BCRP) alter cross resistance patterns in transfectants. Int J Cancer 107(5), 757 (2003).PubMedGoogle Scholar
  70. 70.
    70. S. Kawabata, M. Oka, K. Shiozawa, K. Tsukamoto, K. Nakatomi, H. Soda, M. Fukuda, Y. Ikegami, K. Sugahara, Y. Yamada, S. Kamihira, L. A. Doyle, D. D. Ross, and S. Kohno, Breast cancer resistance protein directly confers SN-38 resistance of lung cancer cells. Biochem Biophys Res Commun 280, 1216 (2001).PubMedGoogle Scholar
  71. 71.
    71. Q. Mao and J. D. Unadkat, Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J 7, E118 (2005).PubMedGoogle Scholar
  72. 72.
    72. M. C. Raff, Social controls on cell survival and cell death. Nature 356, 397 (1993).Google Scholar
  73. 73.
    73. E. Ruoslahti and J. C. Reed, Anchorage dependence, integrins, and apoptosis. Cell 77, 477 (1994).PubMedGoogle Scholar
  74. 74.
    74. S. M. Frisch and H. Francis, Disruption of epithelial cell–matrix interactions induces apoptosis. J Cell Biol 124, 619 (1994).PubMedGoogle Scholar
  75. 75.
    75. E. A. Harrington M. R. Bennett, A. Fanidi, and G. I. Evan, c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J 13, 3286 (1994).PubMedGoogle Scholar
  76. 76.
    76. S. Nagata, Apoptosis regulated by a death factor and its receptor, Fas ligand and Fas. Phil Trans R Soc Lond B: Biol Sci 345, 281 (1994).Google Scholar
  77. 77.
    77. C. Dive and J. A. Hickman, JDrug-target interactions: Only the first step in the commitment to a programmed cell death? Br J Cancer 64,192 (1991).PubMedGoogle Scholar
  78. 78.
    78. D. E. Fisher, Apoptosis in cancer therapy: Crossing the threshold. Cell 78, 539–542 (1994).PubMedGoogle Scholar
  79. 79.
    79. D. Hockenbery, G. Nunez, C. Milliman, R. D. Schreiber, and S. I. Korsmeyer, Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334 (1990).PubMedGoogle Scholar
  80. 80.
    80. J. C. Reed, Bcl-2 and the regulation of programmed cell death. J Cell Biol 124, 1 (1994).PubMedGoogle Scholar
  81. 81.
    81. X. M. Yin, Z. N. Oltvai, and S. J. Korsmeyer, BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369, 321 (1994).PubMedGoogle Scholar
  82. 82.
    82. E. Yang, J. Zha, J. Jockel, L. H. Boise, C. B. Thompson, and S. J. Korsmeyer, Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285 (1995).PubMedGoogle Scholar
  83. 83.
    83. M. C. Kiefer, M. J. Brauer, V. C. Powers, J. J. Wu, S. R. Umansky, L. D. Tomei, and P. J. Barr, Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature 374, 736 (1995).PubMedGoogle Scholar
  84. 84.
    84. S. N. Farrow, J. H. White, I. Martinou, T. Raven, K. T. Pun, C. J. Grinham, J. C. Martinou, and R. Brown, Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K. Nature 374, 731 (1995).PubMedGoogle Scholar
  85. 85.
    85. T. Chittenden, E. A. Harrington, R. O'Connor, C. Flemington, R. J. Lutz, G. I. Evan, and B. C. Guild, Induction of apoptosis by the Bcl-2 homologue Bak. Nature 374, 733 (1995).PubMedGoogle Scholar
  86. 86.
    86. D. T. Chao, G. P. Linette, L. H. Boise, L. S. White, C. B. Thompson, and S. J. Korsmeyer, Bcl-XL and Bcl-2 repress a common pathway of cell death. J Exp Med 182, 821 (1995).PubMedGoogle Scholar
  87. 87.
    87. A. R. Gottschalk, L. H. Boise, C. B. Thompson, and J. Quintans, Identification of immunosuppressant-induced apoptosis in a murine B-cell line and its prevention by bcl-x but not bcl-2. Proc Natl Acad Sci USA 91, 7350 (1994).PubMedGoogle Scholar
  88. 88.
    88. V. N. Sumantran, M. W. Ealovega, G. Nunez, M. F. Clarke, and M. S. Wicha, Overexpression of Bcl-XS sensitizes MCF-7 cells to chemotherapy-induced apoptosis. Cancer Res 55, 2507 (1995).PubMedGoogle Scholar
  89. 89.
    89. A. R. Clarke, C. A. Purdie, D. J. Harrison, R. G. Morris, C. C. Bird, M. L. Hooper, and A. H. Wyllie, Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 362, 849 (1993).PubMedGoogle Scholar
  90. 90.
    90. S. W. Lowe, E. M. Schmitt, S. W. Smith, B. A. Osborne, and T. Jacks, p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362, 847 (1993).PubMedGoogle Scholar
  91. 91.
    91. A. J. Merritt, C. S. Potten, C. J. Kemp, J. A. Hickman, A. Balmain, D. P. Lane, and P. A. Hall, The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res 54, 614 (1994).PubMedGoogle Scholar
  92. 92.
    92. V. Sandor, T. Fojo, and E. Bates, Future perspectives for the development of P-glycoprotein modulators. Drug Resist Up-dates. 1, 190 (1998).Google Scholar
  93. 93.
    93. F. Gualtieri, Drugs reverting multidrug resistance (chemosenzitizers). Chim. Ind 78, 1233 (1996).Google Scholar
  94. 94.
    94. T. J. Lampidis, A. Krishan, L. Planas, and H. Tapiero, Reversal of intrinsic resistance to adriamycin in normal cells by verapamil. Cancer Drug Deliv 3, 251 (1986).PubMedGoogle Scholar
  95. 95.
    95. E. C. Spoelstra, H. V. Westerhoff, H. M. Pinedo, H. Dekker, and J. Lankelma, The multidrug-resistance-reverser verapamil interferes with cellular P-glycoprotein-mediated pumping of daunorubicin as a non-competing substrate. Eur J Biochem 221, 363 (1994).PubMedGoogle Scholar
  96. 96.
    96. N. J. Chao, M. Aihara, K. G. Blume, and B. I. Sikic, Modulation of etoposide (VP-16) cytotoxicity by verapamil or cyclosporine in multidrug-resistant human leukemic cell lines and normal bone marrow. Exp Hematol 18, 1193 (1990).PubMedGoogle Scholar
  97. 97.
    97. C. Avendano and J. C. Menendez, Inhibitors of multidrug resistance to antitumor agents (MDR). Curr Med Chem 9, 159 (2002).PubMedGoogle Scholar
  98. 98.
    98. P. Atadja, T. Watanabe, H. Xu, and D. Cohen, PSC-833, a frontier in modulation of P-glycoprotein mediated multidrug resistance. Cancer Metastasis Rev 17, 163 (1998).PubMedGoogle Scholar
  99. 99.
    99. U. A. Germann, D. Shlyakhter, V. S. Mason, R. E. Zelle, J. P. Duffy, V. Galullo, D. M. Armistead, J. O. Saunders, J. Boger, and M. W. Harding, Cellular and biochemical characterization of VX-710 as a chemosensitizer: Reversal of P-glycoprotein-mediated multidrug resistance in vitro. Anticancer Drugs 8(2), 125 (1997).PubMedGoogle Scholar
  100. 100.
    100. R. Krishna and L. D. Mayer, Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 11, 265 (2000).PubMedGoogle Scholar
  101. 101.
    101. A. H. Dantzig, K. L. Law, J. Cao, and J. J. Starling, Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. Curr Med Chem 8, 39 (2001).PubMedGoogle Scholar
  102. 102.
    102. A. Stewart, J. Steiner, G. Mellows, B. Laguda, D. Norris, and P. Bevan, Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56/ lymphocytes after oral and intravenous administration. Clin Cancer Res 6, 4186 (2000).PubMedGoogle Scholar
  103. 103.
    103. B. Tan, D. Piwnica-Worms, and L. Ratner, Multidrug resistance transporters and modulation. Curr Opin Oncol 12, 450 (2000).PubMedGoogle Scholar
  104. 104.
    104. L. Payen, L. Delugin, A. Courtois, Y. Trinquart, A. Guillouzo, and O. Fardel, The sulphonylurea glibenclamide inhibits multidrug resistance protein (MRP1) activity in human lung cancer cells. Br J Pharmacol 132, 778 (2001).PubMedGoogle Scholar
  105. 105.
    105. D. Burg, P. Wielinga, N. Zelcer, T. Saeki, G. J. Mulder, and P. Borst, Inhibition of the multidrug resistance protein 1 (MRP1) by peptidomimetic glutathione-conjugate analogs. Mol Pharmacol 62, 1160 (2002).PubMedGoogle Scholar
  106. 106.
    106. J. D. Allen, S. C. Van Dort, M. Buitelaar, O. van Tellingen, and A. H. Schinkel, Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res 63, 1339 (2003).PubMedGoogle Scholar
  107. 107.
    107. M. de Bruin, K. Miyake, T. Litman, R. Robey, and S. E. Bates, Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett 146, 117 (1999).PubMedGoogle Scholar
  108. 108.
    108. C. M. Kruijtzer, J. H. Beijnen, H. Rosing, W. W. ten Bokkel Huinink, M. Schot, R. C. Jewell, E. M. Paul, and J. H. Schellens, Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 20, 2943 (2002).PubMedGoogle Scholar
  109. 109.
    109. S. K. Rabindran, D. D. Ross, L. A. Doyle, W. Yang, and L. M. Greenberger, Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res 60, 47 (2000).PubMedGoogle Scholar
  110. 110.
    110. A. Gupta, Y. Zhang, J. D. Unadkat, and Q. Mao, HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther 310, 334 (2004).PubMedGoogle Scholar
  111. 111.
    111. H. J. Broxterman, H. M. Pinedo, G. J. Schuurhuis, and J. Lankelma, Cyclosporin A and verapamil have different effects on energy metabolism in multidrug-resistant tumour cells. Br J Cancer 62, 85 (1990).PubMedGoogle Scholar
  112. 112.
    112. D. Cohen, Modulation of resistance and P-glycoprotein function in tumor cells. ′ATP Binding cassette (ABC) Transporter: From multidrug resistance to genetic disease. Abstract Book, 1997, p. 46.Google Scholar
  113. 113.
    113. S. P. Cole, K. E. Sparks, K. Fraser, D. W. Loe, C. E. Grant, G. M. Wilson, and R. G. Deeley, Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res 54, 5902 (1994).PubMedGoogle Scholar
  114. 114.
    114. G. Jedlitschky, I. Leier, U. Buchholz, M. Center, and D. Keppler, ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 54, 4833 (1994).PubMedGoogle Scholar
  115. 115.
    115. H. J. Broxterman, G. Giaccone, and J. Lankelma, Multidrug resistance proteins and other drug transport-related resistance to natural product agents. Curr Opin Oncol. 7, 532 (1995).PubMedGoogle Scholar
  116. 116.
    116. P. R. Twentyman and C. H. Versantvoort, Experimental modulation of MRP (multidrug resistance-associated protein)-mediated resistance. Eur J Cancer 32A, 1002 (1996).PubMedGoogle Scholar
  117. 117.
    117. M. K. al-Shawi and A. E. Senior, Characterization of the adenosine triphosphatase activity of Chinese hamster P-glycoprotein. J Biol Chem 268, 4197 (1993).PubMedGoogle Scholar
  118. 118.
    118. M. K. al-Shawi, I. L. Urbatsch, and A. E. Senior, Covalent inhibitors of P-glycoprotein ATPase activity. J Biol Chem 269, 8986 (1994).PubMedGoogle Scholar
  119. 119.
    119. A. B Shapiro and V. Ling, Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochem Pharmacol 53, 587 (1997).PubMedGoogle Scholar
  120. 120.
    120. S. V. Ambudkar, Purification and reconstitution of functional human P-glycoprotein. J Bioenerg Biomembr 27, 23 (1995).PubMedGoogle Scholar
  121. 121.
    121. D. M. Woodcock, S. Jefferson, M. E. Linsenmeyer, P. J. Crowther, G. M. Chojnowski, B. Williams, and I. Bertoncello, Reversal of the multidrug resistance phenotype with cremophor EL, a common vehicle for water-insoluble vitamins and drugs. Cancer Res 50, 4199 (1990).PubMedGoogle Scholar
  122. 122.
    122. K. Ueda, I. Pastan, and M. M. Gottesman, Isolation and sequence of the promoter region of the human multidrug-resistance (P-glycoprotein) gene. J Biol Chem 262, 17,432 (1987).Google Scholar
  123. 123.
    123. Q. Zhu and M. S. Center, Cloning and sequence analysis of the promoter region of the MRP gene of HL60 cells isolated for resistance to adriamycin. Cancer Res 54, 4488 (1994).PubMedGoogle Scholar
  124. 124.
    124. R. Sundseth, G. MacDonald, J. Ting, and A. C. King, DNA elements recognizing NF-Y and Sp1 regulate the human multidrug-resistance gene promoter. Mol Pharmacol 51, 963 (1997).PubMedGoogle Scholar
  125. 125.
    125. T. Ohga, T. Uchiumi, Y. Makino, K. Koike, M. Wada, M. Kuwano, and K. Kohno, Direct involvement of the Y-box binding protein YB-1 in genotoxic stress-induced activation of the human multidrug resistance 1 gene. J Biol Chem 273, 5997 (1998).PubMedGoogle Scholar
  126. 126.
    126. C. Rohlff and R. I. Glazer, Regulation of the MDR1 promoter by cyclic AMP-dependent protein kinase and transcription factor Sp1. Int J Oncol 12, 383 (1998).PubMedGoogle Scholar
  127. 127.
    127. K. Kohno, S. Sato, H. Takano, K. Matsuo, and M. Kuwano, The direct activation of human multidrug resistance gene (MDR1) by anticancer agents. Biochem Biophys Res Commun 165, 1415 (1989).PubMedGoogle Scholar
  128. 128.
    128. N. Kioka, Y. Yamano, T. Komano, and K. Ueda, Heat-shock responsive elements in the induction of the multidrug resistance gene (MDR1). FEBS Lett 301, 37 (1992).PubMedGoogle Scholar
  129. 129.
    129. K. V. Chin, S. Tanaka, G. Darlington, I. Pastan, and M. M. Gottesman, Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J Biol Chem 265, 221 (1990).PubMedGoogle Scholar
  130. 130.
    130. K. V. Chin, K. Ueda, I. Pastan, and M. M. Gottesman, Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science 255, 459 (1992).PubMedGoogle Scholar
  131. 131.
    131. C. Cucco and B. Calabretta, In vitro and in vivo reversal of multidrug resistance in a human leukemia-resistant cell line by mdr1 antisense oligodeoxynucleotides. Cancer Res 56, 4332 (1996).PubMedGoogle Scholar
  132. 132.
    132. J. Bertram, K. Palfner, M Killian, W. Brysch, K. H. Schlingensiepen, W. Hiddemann, and M. Kneba, Reversal of multiple drug resistance in vitro by phosphorothioate oligonucleotides and ribozymes. Anticancer Drugs 6, 124 (1995).PubMedGoogle Scholar
  133. 133.
    133. A. H. Schinkel, S. Kemp, M. Dolle, G. Rudenko, and E. Wagenaar, N-Glycosylation and deletion mutants of the human MDR1 P-glycoprotein. J Biol Chem 268, 7474 (1993).PubMedGoogle Scholar
  134. 134.
    134. H. Lis and N. Sharon, Protein glycosylation. Structural and functional aspects. Eur J Biochem 218, 1 (1993).PubMedGoogle Scholar
  135. 135.
    135. H. R. Goodfellow, A. Sardini, S. Ruetz, R. Callaghan, P. Gros, P. A. McNaughton, and C. F. Higgins, Protein kinase C-mediated phosphorylation does not regulate drug transport by the human multidrug resistance P-glycoprotein. J Biol Chem 271, 13,668 (1996).Google Scholar
  136. 136.
    136. H. P. Ammon and M. A. Wahl, Pharmacology of Curcuma longa. Planta Med 57, 1 (1991).PubMedGoogle Scholar
  137. 137.
    137. R. S. Ramsewak, D. L. DeWitt, and M. G. Nair, Cytotoxicity, antioxidant and anti-inflammatory activities of curcumins I–III from Curcuma longa. Phytomedicine 7, 303 (2000).PubMedGoogle Scholar
  138. 138.
    138. W. Chearwae, S. Anuchapreeda, K. Nandigama, S. V. Ambudkar, and P. Limtrakul, Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder. Biochem Pharmacol 68, 2043 (2004).PubMedGoogle Scholar
  139. 139.
    139. W. Chearwae, C. P. Wu, H. Y. Chu, T. R. Lee, S. V. Ambudkar, and P. Limtrakul, Curcuminoids purified from turmeric powder modulate the function of human multidrug resistance protein 1 (ABCC1). Cancer Chemother Pharmacol 57, 376 (2006).PubMedGoogle Scholar
  140. 140.
    140. L. M. Antunes, M. C. Araujo, J. D. Darin, and M. L. Bianchi, Effects of the antioxidants curcumin and vitamin C on cisplatin-induced clastogenesis in Wistar rat bone marrow cells. Mutat Res 465, 131 (2000).PubMedGoogle Scholar
  141. 141.
    141. T. Kawamori, R. Lubet, V. E. Steele, G. J. Kelloff, R. B. Kaskey, C. V. Rao, and B. S. Reddy, Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 59, 597 (1999).PubMedGoogle Scholar
  142. 142.
    142. M. L. Kuo, T. S. Huang, and J. K. Lin, Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. Biochim Biophys Acta 1317, 95 (1996).PubMedGoogle Scholar
  143. 143.
    143. P. Limtrakul, S. Lipigorngoson, O. Namwong, A. Apisariyakul, and F. W. Dunn, Inhibitory effect of dietary curcumin on skin carcinogenesis in mice. Cancer Lett 116, 197 (1997).PubMedGoogle Scholar
  144. 144.
    144. B. B. Aggarwal, A. Kumar, and A. C. Bharti, Anticancer potential of curcumin: Preclinical and clinical studies. Anticancer Res 23, 363 (2003).PubMedGoogle Scholar
  145. 145.
    145. N. Chainani-Wu, Safety and anti-inflammatory activity of curcumin: A component of tumeric (Curcuma longa). J Altern Complement Med. 9, 161 (2003).PubMedGoogle Scholar
  146. 146.
    146. C. R. Ireson, D. J. Jones, S. Orr, M. W. Coughtrie, D. J. Boocock, M. L. Williams, P. B. Farmer, W. P. Steward, and A. J. Gescher, Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomarkers Prev 11, 105 (2002).PubMedGoogle Scholar
  147. 147.
    147. M. H. Pan, T. M. Huang, and J. K. Lin, Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metab Dispos 27, 486 (1999).PubMedGoogle Scholar
  148. 148.
    148. J. K. Lin, M. H. Pan, and S. Y. Lin-Shiau, Recent studies on the biofunctions and biotransformations of curcumin. Biofactors 13, 153 (2000).PubMedGoogle Scholar
  149. 149.
    149. S. Anuchapreeda, P. Leechanachai, M. M. Smith, S. V. Ambudkar, and P. N. Limtrakul, Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochem Pharmacol 64,573 (2002).PubMedGoogle Scholar
  150. 150.
    150. P. Waiwut, S. Anuchapreeda, and P. Limtrakul, Curcumin inhibits the P-glycoprotein level in carcinoma of cervix cells (KB-carcinoma cell lines) induced by vinblastine, Chiang Mai Med Bull 41, 135 (2002).Google Scholar
  151. 151.
    151. P. Limtrakul, S. Anuchapreeda, and D. Buddhasukh, Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. BMC Cancer 4, 13 (2004).PubMedGoogle Scholar
  152. 152.
    152. N. Romiti, R. Tongiani, F. Cervelli, and E. Chieli Effects of curcumin on P-glycoprotein in primary cultures of rat hepatocytes. Life Sci 62(25), 2349 (1998).PubMedGoogle Scholar
  153. 153.
    153. H. M. Wortelboer, M. Usta, A. E. van der Velde, M. G. Boersma, B. Spenkelink, J. J. van Zanden, I. M. Rietjens, P. J. van Bladeren, and N. H. Cnubben, Interplay between MRP inhibition and metabolism of MRP inhibitors, the case of curcumin. Chem Res Toxicol 16, 1642 (2003).PubMedGoogle Scholar
  154. 154.
    154. J. Hong, J. D. Lambert, S. H. Lee, P. J. Sinko, and C. S. Yang, Involvement of multidrug resistance-associated proteins in regulating cellular levels of (-)-epigallocatechin-3-gallate and its methyl metabolites. Biochem Biophys Res Commun 310, 222 (2003).PubMedGoogle Scholar
  155. 155.
    155. M. E. Egan, M. Pearson, S. A. Weiner, V. Rajendran, D. Rubin, J. Glockner-Pagel, S. Canny, K. Du, G. L. Lukacs, and M. J. Caplan, Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science 304(5670), 600 (2004).PubMedGoogle Scholar
  156. 156.
    156. A. L. Berger, C. O. Randak, L. S. Ostedgaard, P. H. Karp, D. W. Vermeer, and M. J. Welsh, Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl channel activity. J Biol Chem 280, 5221 (2005).PubMedGoogle Scholar
  157. 156a.
    156a. R. C. Bargou, F. Emmerich, D. Krappmann, K. Bommert, M. Y. Mapara, W. Arnold, H. D. Royer, E. Grinstein, A. Greiner, C. Scheidereit, and B. Dorken, Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest 100, 2961 (1997).PubMedGoogle Scholar
  158. 158.
    158. P. Limtrakul, W. Chearwae, S. Shukla, C. Phisalphong and S. Ambudkar S, Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2)) and multidrug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin. Molecular and Cellular Biochemistry (Sep 8), 2006; Epub ahead of print).Google Scholar
  159. 159.
    159. C. Chearwae, S. Shukla, P. Limtrakul, S. Ambudkar, Modulation of the function of the multidrug resistance linked ATP-binding cassette transporter ABCG2 by cancer chemopreventive agent curcumin. Molecular Cancer Therapeutic 5(8), 1995–2006 (2006).Google Scholar
  160. 160.
    160. R. W. Robey, K. Steadman, O. Polgar, K. Morisaki, M. Blayney, P. Mistry, and S. E. Bates, Pheophorbide a is a specific probe for ABCG2 function and inhibition. Cancer Res 64, 1242 (2004).PubMedGoogle Scholar
  161. 161.
    161. D. Hanahan and R. A. Weinberg, The hallmarks of cancer. Cell 100, 57 (2000).PubMedGoogle Scholar
  162. 162.
    162. N. D. Perkins, The Rel/NF-kappa B family: Friend and foe. Trends Biochem Sci 25,434 (2000).PubMedGoogle Scholar
  163. 163.
    163. C. Y. Wang, J. C. Cusack, Jr., R. Liu, and A. S. Baldwin, Jr., Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med 5, 412 (1999).PubMedGoogle Scholar
  164. 164.
    164. M. Barkett and T. D. Gilmore, Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene 18, 6910 (1999).PubMedGoogle Scholar
  165. 165.
    165. S. Y. Foo and G. P. Nolan, NF-kappaB to the rescue, RELs, apoptosis and cellular transformation. Trends Genet 15, 229 (1999).PubMedGoogle Scholar
  166. 166.
    166. P. A. Baeuerle and D. Baltimore, I kappa B, a specific inhibitor of the NF-kappa B transcription factor. Science 242, 540 (1988).PubMedGoogle Scholar
  167. 167.
    167. S. E. Chuang, P. Y. Yeh, Y. S. Lu, G. M. Lai, C. M. Liao, M. Gao, and A. L. Cheng, Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells. Biochem Pharmacol. 63, 1709 (2002).PubMedGoogle Scholar
  168. 168.
    168. C. Y. Wang, M. W. Mayo, R. G. Korneluk, D. V. Goeddel, and A. S. Baldwin, Jr., NF-kappaB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281, 1680 (1998).PubMedGoogle Scholar
  169. 169.
    169. N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. Munshi, S. P. Treon, and K. C. Anderson, Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: Therapeutic applications. Blood 99, 4079 (2002).PubMedGoogle Scholar
  170. 170.
    170. S. Singh and B. B. Aggarwal, Activation of transcription factor NF-kappaB is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 270, 24,995 (1995).Google Scholar
  171. 171.
    171. S. Aggarwal, H. Ichikawa, Y. Takada, S. K. Sandur, S. Shishodia, and B. B. Aggarwal, Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBα kinase and Akt activation. Mol Pharmacol 69, 195 (2006).PubMedGoogle Scholar
  172. 172.
    172. S. V. Bava, V. T. Puliappadamba, A. Deepti, A. Nair, D. Karunagaran, and R. J. Anto, Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappaB and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem 280, 6301 (2005).PubMedGoogle Scholar

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