Heat Shock Protein 90: The Cancer Chaperone

  • Len Neckers
Part of the Heat Shock Proteins book series (HESP, volume 2)


Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, and/or over-expressed signaling proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple cellular signaling pathways. By inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective toward multiple forms of cancer. Further, because Hsp90 inhibitors also induce Hsf-1-dependent expression of Hsp70, and because certain mutated Hsp90 client proteins are neurotoxic, these drugs display ameliorative properties in several neurodegenerative disease models, suggesting a novel role for Hsp90 inhibitors in treating multiple pathologies involving neurodegeneration


Molecular chaperone Hsp90 cancer protein folding 


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  1. Aghajanian, C., Soignet, S., Dizon, D. S., Pien, C. S., Adams, J., Elliott, P. J., Sabbatini, P., Miller, V., Hensley, M. L., Pezzulli, S., Canales, C., Daud, A. and Spriggs, D. R. (2002) A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res. 8, 2505–2511PubMedGoogle Scholar
  2. Agrawal, N., Pallos, J., Slepko, N., Apostol, B. L., Bodai, L., Chang, L.-W., Chiang, A.-S., Thompson, L. M. and Marsh, J. L. (2005) Identification of combinatorial drug regimens for treatment of Huntington’s disease using Drosophila. Proc Natl Acad Sci U S A. 102, 3777–3781PubMedCrossRefGoogle Scholar
  3. Ali, A., Bharadwaj, S., O’Carroll, R. and Ovsenek, N. (1998) HSP90 interacts with and regulates the activity of heat shock factor 1 in Xenopus oocytes. Mol Cell Biol. 18, 4949–4960PubMedGoogle Scholar
  4. An, W. G., Schulte, T. W. and Neckers, L. M. (2000) The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. Cell Growth Differ. 11, 355–360PubMedGoogle Scholar
  5. Auluck, P. K. and Bonini, N. M. (2002b) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med. 8, 1185–1186CrossRefGoogle Scholar
  6. Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M.-Y. and Bonini, N. M. (2002a) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science. 295, 865–868CrossRefGoogle Scholar
  7. Bagatell, R. and Whitesell, L. (2004) Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther. 3, 1021–1030PubMedCrossRefGoogle Scholar
  8. Bali, P., Pranpat, M., Swaby, R., Fiskus, W., Yamaguchi, H., Balasis, M., Rocha, K., Wang, H. G., Richon, V. and Bhalla, K. (2005) Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplification of her-2. Clin Cancer Res. 11, 6382–6389PubMedCrossRefGoogle Scholar
  9. Banerji, U., O’Donnell, A., Scurr, M., Benson, C., Hanwell, J., Clark, S., Raynaud, F., Turner, A., Walton, M., Workman, P. and Judson, I. (2001) Phase I Trial of the Heat Shock Protein 90 (HSP90) Inhibitor 17-Allylamino 17-Demethoxygeldanamycin 17aag). Pharmacokinetic (PK) Profile and Pharmacodynamic (PD) Endpoints. Proc Am Soc Clin Oncol. 20, abstract 326Google Scholar
  10. Banerji, U., O’Donnell, A., Scurr, M., Benson, C., Stapleton, S., Raynaud, F., Clarke, S., Turner, A., Workman, P. and Judson, I. (2003) A pharmacokinetically (PK) - pharmacodynamically (PD) guided phase I trial of the heat shock protein 90 (HSP90) inhibitor 17-allylamino,17-demethoxygeldanamycin (17AAG). Proc Am Soc Clin Oncol. 22, abstract 797Google Scholar
  11. Banerji, U., O’Donnell, A., Scurr, M., Pacey, S., Stapleton, S., Asad, Y., Simmons, L., Maloney, A., Raynaud, F., Campbell, M., Walton, M., Lakhani, S., Kaye, S., Workman, P. and Judson, I. (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino,17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol. 23, 4152–4161PubMedCrossRefGoogle Scholar
  12. Banerji, U., O’Donnell, A., Scurr, M., Benson, C., Brock, C., Hanwell, J., Stapleton, S., Raynaud, F., Simmons, L., Turner, A., Walton, M., Workman, P. and Judson, I. (2002) A pharmacokinetically (Pk) - pharmacodynamically (Pd) driven phase I trial of the Hsp90 molecular chaperone inhibitor 17-allyamino 17-demethoxygeldanamycin (17AAG). Proc 93rd Annu Meet Am Assoc Cancer Res. 43, Abstract 1352Google Scholar
  13. Basso, A. D., Solit, D. B., Chiosis, G., Giri, B., Tsichlis, P. and Rosen, N. (2002) Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem. 277, 39858–39866PubMedCrossRefGoogle Scholar
  14. Becker, B., Multhoff, G., Farkas, B., Wild, P. J., Landthaler, M., Stolz, W. and Vogt, T. (2004) Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp Dermatol. 13, 27–32PubMedCrossRefGoogle Scholar
  15. Belinsky, M. and Jaiswal, A. K. (1993) NAD(P)H:quinone oxidoreductase1 (DT-diaphorase) expression in normal and tumor tissues. Cancer Metastasis Rev. 12, 103–117PubMedCrossRefGoogle Scholar
  16. Bisht, K. S., Bradbury, C. M., Mattson, D., Kaushal, A., Sowers, A., Markovina, S., Ortiz, K. L., Sieck, L. K., Isaacs, J. S., Brechbiel, M. W., Mitchell, J. B., Neckers, L. M. and Gius, D. (2003) Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity. Cancer Res. 63, 8984–8995PubMedGoogle Scholar
  17. Bonvini, P., Gastaldi, T., Falini, B. and Rosolen, A. (2002) Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Cancer Res. 62, 1559–1566PubMedGoogle Scholar
  18. Bottaro, D. P. and Liotta, L. A. (2003) Out of air is not out of action. Nature. 423, 593–595PubMedCrossRefGoogle Scholar
  19. Burger, A. M., Fiebig, H. H., Newman, D. J., Camalier, R. F. and Sausville, E. A. (1998) Antitumor activity of 17-allylaminogeldanamycin (NSC 330507) in melanoma xenografts is associated with decline in Hsp90 protein expression. 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy. abstract 504Google Scholar
  20. Burger, A. M., Sausville, E. A., Carmalier, R. F., Newman, D. J. and Fiebig, H. H. (2000) Response of human melanomas to 17-AAG is associated with modulation of the molecular chaperone function of Hsp90. Proc Am Assoc Cancer Res. 41, abstract 2844Google Scholar
  21. Cheung, K. M., Matthews, T. P., James, K., Rowlands, M. G., Boxall, K. J., Sharp, S. Y., Maloney, A., Roe, S. M., Prodromou, C., Pearl, L. H., Aherne, G. W., McDonald, E. and Workman, P. (2005) The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors. Bioorg Med Chem Lett. 15, 3338–3343PubMedCrossRefGoogle Scholar
  22. Chiosis, G., Huezo, H., Rosen, N., Mimnaugh, E., Whitesell, L. and Neckers, L. (2003a) 17AAG: Low Target Binding Affinity and Potent Cell Activity-Finding an Explanation. Mol Cancer Ther. 2, 123–129Google Scholar
  23. Chiosis, G., Lucas, B., Huezo, H., Solit, D., Basso, A. and Rosen, N. (2003b) Development of purine-scaffold small molecule inhibitors of Hsp90. Curr Cancer Drug Targets. 3, 371–376CrossRefGoogle Scholar
  24. Chiosis, G., Lucas, B., Shtil, A., Huezo, H. and Rosen, N. (2002) Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinase. Bioorg Med Chem. 10, 3555–3564PubMedCrossRefGoogle Scholar
  25. Chiosis, G., Vilenchik, M., Kim, J. and Solit, D. (2004) Hsp90: the vulnerable chaperone. Drug Discov Today. 9, 881–888PubMedCrossRefGoogle Scholar
  26. Cohen, F. E. (1999) Protein misfolding and prion diseases. J Mol Biol. 293, 313–320PubMedCrossRefGoogle Scholar
  27. Cohen, M. S., Hussain, H. B. and Moley, J. F. (2002) Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery. 132, 960–966; discussion 966–967PubMedCrossRefGoogle Scholar
  28. da Rocha Dias, S., Friedlos, F., Light, Y., Springer, C., Workman, P. and Marais, R. (2005) Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 65, 10686–10691CrossRefGoogle Scholar
  29. DeBoer, C., Meulman, P. A., Wnuk, R. J. and Peterson, D. H. (1970) Geldanamycin, a new antibiotic. J Antibiot (Tokyo). 23, 442–447Google Scholar
  30. Dias, S., Shmelkov, S. V., Lam, G. and Rafii, S. (2002) VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood. 99, 2532–2540PubMedCrossRefGoogle Scholar
  31. Druker, B. J., Tamura, S., Buchdunger, E., Ohno, S., Segal, G. M., Fanning, S., Zimmermann, J. and Lydon, N. B. (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 2, 561–566PubMedCrossRefGoogle Scholar
  32. Dymock, B. W., Barril, X., Brough, P. A., Cansfield, J. E., Massey, A., McDonald, E., Hubbard, R. E., Surgenor, A., Roughley, S. D., Webb, P., Workman, P., Wright, L. and Drysdale, M. J. (2005) Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J Med Chem. 48, 4212–4215PubMedCrossRefGoogle Scholar
  33. Egorin, M. J., Lagattuta, T. F., Hamburger, D. R., Covey, J. M., White, K. D., Musser, S. M. and Eiseman, J. L. (2002) Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol. 49, 7–19PubMedCrossRefGoogle Scholar
  34. Egorin, M. J., Rosen, D. M., Wolff, J. H., Callery, P. S., Musser, S. M. and Eiseman, J. L. (1998) Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res. 58, 2385–2396PubMedGoogle Scholar
  35. Eiseman, J. L., Lan, J., Lagattuta, T. F., Hamburger, D. R., Joseph, E., Covey, J. M. and Egorin, M. J. (2005) Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts. Cancer Chemother Pharmacol. 55, 21–32PubMedCrossRefGoogle Scholar
  36. Eustace, B. K. and Jay, D. G. (2004) Extracellular Roles for the Molecular Chaperone, hsp90. Cell Cycle. 3,Google Scholar
  37. Eustace, B. K., Sakurai, T., Stewart, J. K., Yimlamai, D., Unger, C., Zehetmeier, C., Lain, B., Torella, C., Henning, S. W., Beste, G., Scroggins, B. T., Neckers, L., Ilag, L. L. and Jay, D. G. (2004) Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat Cell Biol. 6, 507–514PubMedCrossRefGoogle Scholar
  38. Feany, M. B. and Bender, W. W. (2000) A Drosophila model of Parkinson’s disease. Nature. 404, 394–398PubMedCrossRefGoogle Scholar
  39. French, B. A., van Leeuwen, F., Riley, N. E., Yuan, Q. X., Bardag-Gorce, F., Gaal, K., Lue, Y. H., Marceau, N. and French, S. W. (2001) Aggresome formation in liver cells in response to different toxic mechanisms: role of the ubiquitin-proteasome pathway and the frameshift mutant of ubiquitin. Exp Mol Pathol. 71, 241–246PubMedCrossRefGoogle Scholar
  40. Fujimoto, J., Shiota, M., Iwahara, T., Seki, N., Satoh, H., Mori, S. and Yamamoto, T. (1996) Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t (2;5). Proc Natl Acad Sci U S A. 93, 4181–4186PubMedCrossRefGoogle Scholar
  41. Fumo, G., Akin, C., Metcalfe, D. D. and Neckers, L. (2004) 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Blood. 103, 1078–1084PubMedCrossRefGoogle Scholar
  42. Georget, V., Terouanne, B., Nicolas, J.-C. and Sultan, C. (2002) Mechanism of antiandrogen action: Key role of Hsp90 in conformational change and transcriptional activity of the androgen receptor. Biochemistry. 41, 11824–11831PubMedCrossRefGoogle Scholar
  43. Giffard, R. G., Xu, L., Zhao, H., Carrico, W., Ouyang, Y. B., Qiao, Y., Sapolsky, R., Steinberg, G., Hu, B. and Yenari, M. A. (2004) Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury. J Exp Biol. 207, 3213–3220PubMedCrossRefGoogle Scholar
  44. Goetz, M. P., Toft, D. O., Ames, M. M. and Erlichman, C. (2003) The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol. 14, 1169–1176PubMedCrossRefGoogle Scholar
  45. Gorre, M. E., Ellwood-Yen, K., Chiosis, G., Rosen, N. and Sawyers, C. L. (2002) BCR-ABL point mutants isolated from patients with STI571-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood. 100, 3041–3044PubMedCrossRefGoogle Scholar
  46. Gradin, K., McGuire, J., Wenger, R. H., Kvietikova, I., fhitelaw, M. L., Toftgard, R., Tora, L., Gassmann, M. and Poellinger, L. (1996) Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor. Mol Cell Biol. 16, 5221–5231PubMedGoogle Scholar
  47. Grbovic, O. M., Basso, A., Sawai, A., Ye, Q., Friedlander, P., Solit, D. and Rosen, N. (2006) V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc. Natl. Acad. Sci. USA. 103, 57–62PubMedCrossRefGoogle Scholar
  48. Guo, W., Reigan, P., Siegel, D., Zirrolli, J., Gustafson, D. and Ross, D. (2005) Formation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Cancer Res. 65, 10006–10015PubMedCrossRefGoogle Scholar
  49. Hahn, W. C. and Weinberg, R. A. (2002) Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2, 331–341PubMedCrossRefGoogle Scholar
  50. Hanahan, D. and Weinberg, R. A. (2000) The hallmarks of cancer. Cell. 100, 57–70PubMedCrossRefGoogle Scholar
  51. Harris, A. L. (2002) Hypoxia- a key regulatory factor in tumor growth. Nat. Rev. Cancer. 2, 38–47PubMedCrossRefGoogle Scholar
  52. Hay, D. G., Sathasivam, K., Tobaben, S., Stahl, B., Marber, M., Mestril, R., Mahal, A., Smith, D. L., Woodman, B. and Bates, G. P. (2004) Progressive decrease in chaperone protein levels in a mouse model of Huntington’s disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet. 13, 1389–1405PubMedCrossRefGoogle Scholar
  53. He, H., Zatorska, D., Kim, J., Aguirre, J., Llauger, L., She, Y., Wu, N., Immormino, R. M., Gewirth, D. T. and Chiosis, G. (2006) Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. J Med Chem. 49, 381–390PubMedCrossRefGoogle Scholar
  54. Hershko, A. and Ciechanover, A. (1998) The ubiquitin system. Annu Rev Biochem. 67, 425–479PubMedCrossRefGoogle Scholar
  55. Hu, B. R., Martone, M. E., Jones, Y. Z. and Liu, C. L. (2000) Protein aggregation after transient cerebral ischemia. J Neurosci. 20, 3191–3199PubMedGoogle Scholar
  56. Hur, E., Kim, H. H., Choi, S. M., Kim, J. H., Yim, S., Kwon, H. J., Choi, Y., Kim, D. K., Lee, M. O. and Park, H. (2002) Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1alpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol. Mol Pharmacol. 62, 975–982PubMedCrossRefGoogle Scholar
  57. Ichihara, M., Murakumo, Y. and Takahashi, M. (2004) RET and neuroendocrine tumors. Cancer Lett. 204, 197–211PubMedCrossRefGoogle Scholar
  58. Isaacs, J. S. (2005) Heat-shock protein 90 inhibitors in antineoplastic therapy: is it all wrapped up? Expert Opin Investig Drugs. 14, 569–589Google Scholar
  59. Isaacs, J. S., Jung, Y. J., Mimnaugh, E. G., Martinez, A., Cuttitta, F. and Neckers, L. M. (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem. 277, 29936–29944PubMedCrossRefGoogle Scholar
  60. Isaacs, J. S., Xu, W. and Neckers, L. (2003) Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell. 3, 213–217PubMedCrossRefGoogle Scholar
  61. Jhiang, S. M. (2000) The RET proto-oncogene in human cancers. Oncogene. 19, 5590–5597PubMedCrossRefGoogle Scholar
  62. Kakizuka, A. (1998) Protein precipitation: a common etiology in neurodegenerative disorders? Trends Genet. 14, 396–402Google Scholar
  63. Kamal, A., Thao, L., Sensintaffar, J., Zhang, L., Boehm, M. F., Fritz, L. C. and Burrows, F. J. (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 425, 407–410PubMedCrossRefGoogle Scholar
  64. Kelland, L. R., Sharp, S. Y., Rogers, P. M., Myers, T. G. and Workman, P. (1999) DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst. 91, 1940–1949.PubMedCrossRefGoogle Scholar
  65. Kim, H. R., Kang, H. S. and Kim, H. D. (1999) Geldanamycin induces heat shock protein expression through activation of HSF1 in K562 erythroleukemic cells. IUBMB Life. 48, 429–433PubMedCrossRefGoogle Scholar
  66. Kitano, H. (2003) Cancer robustness: tumour tactics. Nature. 426, 125PubMedCrossRefGoogle Scholar
  67. Kruger, R. (2004) Genes in familial parkinsonism and their role in sporadic Parkinson’s disease. J Neurol. 251 Suppl 6, VI/2–6Google Scholar
  68. L’Allemain, G. (2002) [Update on \ldots the proteasome inhibitor PS341]. Bull Cancer. 89, 29–30PubMedGoogle Scholar
  69. La Rosee, P., O’Dwyer, M. E. and Druker, B. J. (2002) Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective. Leukemia. 16, 1213–1219PubMedCrossRefGoogle Scholar
  70. Llauger, L., He, H., Kim, J., Aguirre, J., Rosen, N., Peters, U., Davies, P. and Chiosis, G. (2005) Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90. J Med Chem. 48, 2892–2905PubMedCrossRefGoogle Scholar
  71. Lu, A., Ran, R., Parmentier-Batteur, S., Nee, A. and Sharp, F. R. (2002) Geldanamycin induces heat shock proteins in brain and protects against focal cerebral ischemia. J Neurochem. 81, 355–364PubMedCrossRefGoogle Scholar
  72. Mabjeesh, N. J., Post, D. E., Willard, M. T., Kaur, B., Van Meir, E. G., Simons, J. W. and Zhong, H. (2002) Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteasome pathway in prostate cancer cells. Cancer Res. 62, 2478–2482PubMedGoogle Scholar
  73. Machida, H., Matsumoto, Y., Shirai, M. and Kubota, N. (2003) Geldanamycin, an inhibitor of Hsp90, sensitizes human tumour cells to radiation. Int J Radiat Biol. 79, 973–980PubMedCrossRefGoogle Scholar
  74. Maulik, G., Kijima, T., Ma, P. C., Ghosh, S. K., Lin, J., Shapiro, G. I., Schaefer, E., Tibaldi, E., Johnson, B. E. and Salgia, R. (2002) Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res. 8, 620–627PubMedGoogle Scholar
  75. Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R. and Ratcliffe, P. J. (1999) The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 399, 271–275PubMedCrossRefGoogle Scholar
  76. Mimnaugh, E. G., Chavany, C. and Neckers, L. (1996) Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J Biol Chem. 271, 22796–22801PubMedCrossRefGoogle Scholar
  77. Mimnaugh, E. G., Xu, W., Vos, M., Yuan, X., Isaacs, J. S., Bisht, K. S., Gius, D. and Neckers, L. (2004) Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. Mol Cancer Ther. 3, 551–566PubMedGoogle Scholar
  78. Minami, Y., Kiyoi, H., Yamamoto, Y., Yamamoto, K., Ueda, R., Saito, H. and Naoe, T. (2002) Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia. 16, 1535–1540PubMedCrossRefGoogle Scholar
  79. Mitsiades, N., Mitsiades, C. S., Poulaki, V., Chauhan, D., Fanourakis, G., Gu, X., Bailey, C., Joseph, M., Libermann, T. A., Treon, S. P., Munshi, N. C., Richardson, P. G., Hideshima, T. and Anderson, K. C. (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A. 99, 14374–14379PubMedCrossRefGoogle Scholar
  80. Naoe, T., Kiyoe, H., Yamamoto, Y., Minami, Y., Yamamoto, K., Ueda, R. and Saito, H. (2001) FLT3 tyrosine kinase as a target molecule for selective antileukemia therapy. Cancer Chemother Pharmacol. 48, S27–30PubMedCrossRefGoogle Scholar
  81. Nardai, G., Vegh, E. M., Prohaszka, Z. and Csermely, P. (2006) Chaperone-related immune dysfunction: an emergent property of distorted chaperone networks. Trends Immunol. 27, 74–79PubMedCrossRefGoogle Scholar
  82. Neckers, L. (2002) Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med. 8, S55–61Google Scholar
  83. Nimmanapalli, R., O’Bryan, E., Huang, M., Bali, P., Burnette, P. K., Loughran, T., Tepperberg, J., Jove, R. and Bhalla, K. (2002) Molecular characterization and sensitivity of STI-571 (imatinib mesylate, Gleevec)-resistant, Bcr-Abl-positive, human acute leukemia cells to SRC kinase inhibitor PD180970 and 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 62, 5761–5769PubMedGoogle Scholar
  84. Ouyang, Y. B. and Hu, B. R. (2001) Protein ubiquitination in rat brain following hypoglycemic coma. Neurosci Lett. 298, 159–162PubMedCrossRefGoogle Scholar
  85. Page, J., Heath, J., and Fulton, R. (1997) Comparison of geldanamycin (NSC-122750) and 17-allylaminogeldanamycin (NSC-330507D) toxicity in rats. Proc Am Assoc Cancer Res. 38, abstract 2067Google Scholar
  86. Paine-Murrieta, G., Cook, P., Taylor, C. W. and Whitesell, L. (1999) The anti-tumor activity of 17-allylaminogeldanamycin is associated with modulation of target protien levels in vivo. Proc Am Assoc Cancer Res. 40, abstract 119Google Scholar
  87. Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S. and Comoglio, P. M. (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 3, 347–361PubMedCrossRefGoogle Scholar
  88. Plescia, J., Salz, W., Xia, F., Pennati, M., Zaffaroni, N., Daidone, M. G., Meli, M., Dohi, T., Fortugno, P., Nefedova, Y., Gabrilovich, D. I., Colombo, G. and Altieri, D. C. (2005) Rational design of shepherdin, a novel anticancer agent. Cancer Cell. 7, 457–468PubMedCrossRefGoogle Scholar
  89. Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., Stenroos, E. S., Chandrasekharappa, S., Athanassiadou, A., Papapetropoulos, T., Johnson, W. G., Lazzarini, A. M., Duvoisin, R. C., Di Iorio, G., Golbe, L. I. and Nussbaum, R. L. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 276, 2045–2047PubMedCrossRefGoogle Scholar
  90. Prodromou, C. and Pearl, L. H. (2003) Structure and functional relationships of Hsp90. Curr Cancer Drug Targets. 3, 301–323PubMedCrossRefGoogle Scholar
  91. Queitsch, C., Sangster, T. A. and Lindquist, S. (2002) Hsp90 as a capacitor of phenotypic variation. Nature. 417, 618–624PubMedCrossRefGoogle Scholar
  92. Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B. and Velculescu, V. E. (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 418, 934Google Scholar
  93. Rutherford, S. L. and Lindquist, S. (1998) Hsp90 as a capacitor for morphological evolution. Nature. 396, 336–342PubMedCrossRefGoogle Scholar
  94. Santoro, M., Melillo, R. M., Carlomagno, F., Fusco, A. and Vecchio, G. (2002) Molecular mechanisms of RET activation in human cancer. Ann N Y Acad Sci. 963, 116–121PubMedCrossRefGoogle Scholar
  95. Sawyers, C. L., Hochhaus, A., Feldman, E., Goldman, J. M., Miller, C. B., Ottmann, O. G., Schiffer, C. A., Talpaz, M., Guilhot, F., Deininger, M. W., Fischer, T., O’Brien, S. G., Stone, R. M., Gambacorti-Passerini, C. B., Russell, N. H., Reiffers, J. J., Shea, T. C., Chapuis, B., Coutre, S., Tura, S., Morra, E., Larson, R. A., Saven, A., Peschel, C., Gratwohl, A., Mandelli, F., Ben-Am, M., Gathmann, I., Capdeville, R., Paquette, R. L. and Druker, B. J. (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 99, 3530–3539PubMedCrossRefGoogle Scholar
  96. Schneider, C., Sepp-Lorenzino, L., Nimmesgern, E., Ouerfelli, O., Danishefsky, S., Rosen, N. and Hartl, F. U. (1996) Pharmacologic shifting of a balance between protein refolding and degradation mediated by Hsp90. Proc Natl Acad Sci U S A. 93, 14536–14541.PubMedCrossRefGoogle Scholar
  97. Schnur, R. C., Corman, M. L., Gallaschun, R. J., Cooper, B. A., Dee, M. F., Doty, J. L., Muzzi, M. L., DiOrio, C. I., Barbacci, E. G., Miller, P. E. and et al. (1995) erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships. J Med Chem. 38, 3813–3820PubMedCrossRefGoogle Scholar
  98. Schulte, T. W. and Neckers, L. M. (1998) The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol. 42, 273–279PubMedCrossRefGoogle Scholar
  99. Seizinger, B. R., Rouleau, G. A., Ozelius, L. J., Lane, A. H., Farmer, G. E., Lamiell, J. M., Haines, J., Yuen, J. W., Collins, D., Majoor-Krakauer, D. and et al. (1988) Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature. 332, 268–269PubMedCrossRefGoogle Scholar
  100. Shah, N. P., Nicoll, J. M., Nagar, B., Gorre, M. E., Paquette, R. L., Kuriyan, J. and Sawyers, C. L. (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2, 117–125PubMedCrossRefGoogle Scholar
  101. Shimamura, T., Lowell, A. M., Engelman, J. A. and Shapiro, G. I. (2005) Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins. Cancer Res. 65, 6401–6408PubMedCrossRefGoogle Scholar
  102. Shiotsu, Y., Neckers, L. M., Wortman, I., An, W. G., Schulte, T. W., Soga, S., Murakata, C., Tamaoki, T. and Akinaga, S. (2000) Novel oxime derivatives of radicicol induce erythroid differentiation associated with preferential G(1) phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90 complex. Blood. 96, 2284–2291PubMedGoogle Scholar
  103. Siligardi, G., Hu, B., Panaretou, B., Piper, P. W., Pearl, L. H. and Prodromou, C. (2004) Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle. J Biol Chem.Google Scholar
  104. Solit, D., Zheng, F., Drobnjak, M., Munster, P., Higgins, B., Verbel, D., Heller, G., Tong, W., Cordon-Cardo, C., Agus, D., Scher, H. and Rosen, N. (2002) 17-allylamino-17-demthoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res. 986–993Google Scholar
  105. Sreedhar, A. S., Soti, C. and Csermely, P. (2004) Inhibition of Hsp90: a new strategy for inhibiting protein kinases. Biochim Biophys Acta. 1697, 233–242PubMedGoogle Scholar
  106. Stoler, D. L., Chen, N., Basik, M., Kahlenberg, M. S., Rodriguez-Bigas, M. A., Petrelli, N. J. and Anderson, G. R. (1999) The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc Natl Acad Sci U S A. 96, 15121–15126PubMedCrossRefGoogle Scholar
  107. Supko, J. G., Hickman, R. L., Grever, M. R. and Malspeis, L. (1995) Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 36, 305–315PubMedGoogle Scholar
  108. Tacchini, L., Dansi, P., Matteucci, E. and Desiderio, M. A. (2001) Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis. 22, 1363–1371PubMedCrossRefGoogle Scholar
  109. Taylor, J. P., Hardy, J. and Fischbeck, K. H. (2002) Toxic proteins in neurodegenerative disease. Science. 296, 1991–1995PubMedCrossRefGoogle Scholar
  110. Tofaris, G. K. and Spillantini, M. G. (2005) Alpha-synuclein dysfunction in Lewy body diseases. Mov Disord. 20 Suppl 12, S37–44PubMedCrossRefGoogle Scholar
  111. Vanaja, D. K., Mitchell, S. H., Toft, D. O. and Young, C. Y. F. (2002) Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones. 7, 55–64PubMedCrossRefGoogle Scholar
  112. Vilenchik, M., Solit, D., Basso, A., Huezo, H., Lucas, B., He, H., Rosen, N., Spampinato, C., Modrich, P. and Chiosis, G. (2004) Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem Biol. 11, 787–797PubMedCrossRefGoogle Scholar
  113. Waelter, S., Boeddrich, A., Lurz, R., Scherzinger, E., Lueder, G., Lehrach, H. and Wanker, E. E. (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell. 12, 1393–1407PubMedGoogle Scholar
  114. Waza, M., Adachi, H., Katsuno, M., Minamiyama, M., Sang, C., Tanaka, F., Inukai, A., Doyu, M. and Sobue, G. (2005) 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med. 11, 1088–1095PubMedCrossRefGoogle Scholar
  115. Wegele, H., Muller, L. and Buchner, J. (2004) Hsp70 and Hsp90–a relay team for protein folding. Rev Physiol Biochem Pharmacol. 151, 1–44PubMedCrossRefGoogle Scholar
  116. Workman, P. (2004) Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett. 206, 149–157PubMedCrossRefGoogle Scholar
  117. Xu, L., Eiseman, J. L., Egorin, M. J. and D’Argenio, D. Z. (2003) Physiologically-based pharmacokinetics and molecular pharmacodynamics of 17-(allylamino)-17-demethoxygeldanamycin and its active metabolite in tumor-bearing mice. J Pharmacokinet Pharmacodyn. 30, 185–219PubMedCrossRefGoogle Scholar
  118. Yu, X., Guo, Z. S., Marcu, M. G., Neckers, L., Nguyen, D. M., Chen, G. A. and Schrump, D. S. (2002) Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst. 94, 504–513PubMedGoogle Scholar
  119. Zagzag, D., Nomura, M., Friedlander, D. R., Blanco, C., Gagner, J. P., Nomura, N. and Newcomb, E. W. (2003) Geldanamycin inhibits migration of glioma cells in vitro: A potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. J Cell Physiol. 196, 394–402PubMedCrossRefGoogle Scholar
  120. Zhang, H. and Burrows, F. (2004) Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med. 82, 488–499PubMedGoogle Scholar
  121. Zhao, R., Davey, M., Hsu, Y. C., Kaplanek, P., Tong, A., Parsons, A. B., Krogan, N., Cagney, G., Mai, D., Greenblatt, J., Boone, C., Emili, A. and Houry, W. A. (2005) Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Cell. 120, 715–727PubMedCrossRefGoogle Scholar
  122. Zoghbi, H. Y. and Orr, H. T. (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci. 23, 217–247PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Len Neckers
    • 1
  1. 1.Urologic Oncology BranchNational Cancer InstituteBethesdaUSA

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