Journal of Biosciences

, Volume 32, Issue 3, pp 517–530 | Cite as

Heat shock protein 90: The cancer chaperone

  • Len Neckers


Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signalling proteins, as well as multiple mutated, chimeric, and/or over-expressed signalling 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 signalling 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.


Cancer protein folding Hsp90 huntingtin molecular chaperone neurodegeneration 


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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. USA 102 3777–3781PubMedGoogle 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 1185–1186PubMedGoogle 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 295 865–868PubMedGoogle 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 6382–6389PubMedGoogle 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 4152–4161PubMedGoogle 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 39858–39866PubMedGoogle 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 27–32PubMedGoogle 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. 12 103–117PubMedGoogle 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 signalling and cytotoxicity; Cancer Res. 63 8984–8995PubMedGoogle Scholar
  17. Bonvini P, Gastaldi T, Falini B and Rosolen A 2002 Nucleophosminanaplastic 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 (London) 423 593–595Google 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 3338–3343PubMedGoogle Scholar
  22. Chiosis G, Huezo H, Rosen N, Mimnaugh E, Whitesell L and Neckers L 2003 17AAG: Low Target Binding Affinity and Potent Cell Activity-Finding an Explanation; Mol. Cancer Ther. 2 123–129PubMedGoogle Scholar
  23. Chiosis G, Lucas B, Huezo H, Solit D, Basso A and Rosen N 2003 Development of purine-scaffold small molecule inhibitors of Hsp90; Curr. Cancer Drug Targets 3 371–376PubMedGoogle 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 3555–3564PubMedGoogle Scholar
  25. Chiosis G, Vilenchik M, Kim J and Solit D 2004 Hsp90: the vulnerable chaperone; Drug Discov. Today 9 881–888PubMedGoogle Scholar
  26. Cohen F E 1999 Protein misfolding and prion diseases; J. Mol. Biol. 293 313–320PubMedGoogle 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 966–967PubMedGoogle 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 10686–10691PubMedGoogle 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 2532–2540PubMedGoogle 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. 2 561–566PubMedGoogle 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 4212–4215PubMedGoogle 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 7–19PubMedGoogle 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 21–32PubMedGoogle Scholar
  36. Eustace B K and Jay D G 2004 Extracellular Roles for the Molecular Chaperone, hsp90; Cell Cycle 3 1098–1100PubMedGoogle 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. 6 507–514PubMedGoogle Scholar
  38. Feany M B and Bender W W 2000 A Drosophila model of Parkinson’s disease; Nature (London) 404 394–398Google 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. 71 241–246PubMedGoogle 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. USA 93 4181–4186PubMedGoogle 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 1078–1084PubMedGoogle 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 11824–11831PubMedGoogle 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 3213–3220PubMedGoogle 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 1169–1176PubMedGoogle 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 3041–3044PubMedGoogle 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 57–62PubMedGoogle 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 10006–10015PubMedGoogle Scholar
  49. Hahn W C and Weinberg R A 2002 Modelling the molecular circuitry of cancer; Nat. Rev. Cancer 2 331–341PubMedGoogle Scholar
  50. Hanahan D and Weinberg R A 2000 The hallmarks of cancer; Cell 100 57–70PubMedGoogle Scholar
  51. Harris A L 2002 Hypoxia-a key regulatory factor in tumor growth; Nat. Rev. Cancer 2 38–47PubMedGoogle 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 1389–1405PubMedGoogle 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. 49 381–390PubMedGoogle Scholar
  54. Hershko A and Ciechanover A 1998 The ubiquitin system; Annu. Rev. Biochem. 67 425–479PubMedGoogle 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. 62 975–982PubMedGoogle Scholar
  57. Ichihara M, Murakumo Y and Takahashi M 2004 RET and neuroendocrine tumors; Cancer Lett. 204 197–211PubMedGoogle Scholar
  58. Isaacs J S 2005 Heat-shock protein 90 inhibitors in antineoplastic therapy: is it all wrapped up?; Expert. Opin. Investig. Drugs 14 569–589PubMedGoogle 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 29936–29944PubMedGoogle Scholar
  60. Isaacs J S, Xu W and Neckers L 2003 Heat shock protein 90 as a molecular target for cancer therapeutics; Cancer Cell 3 213–217PubMedGoogle Scholar
  61. Jhiang S M 2000 The RET proto-oncogene in human cancers; Oncogene 19 5590–5597PubMedGoogle Scholar
  62. Kakizuka A 1998 Protein precipitation: a common etiology in neurodegenerative disorders?; Trends Genet. 14 396–402PubMedGoogle 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 (London) 425 407–410Google 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 1940–1949PubMedGoogle 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 48 429–433PubMedGoogle Scholar
  66. Kitano H 2003 Cancer robustness: tumour tactics; Nature (London) 426 125Google Scholar
  67. Kruger R 2004 Genes in familial parkinsonism and their role in sporadic Parkinson’s disease; J. Neurol. (Suppl. 6) 251 VI/2–6Google Scholar
  68. L’Allemain G 2002 [Update on … 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 preclinical studies for new combination treatment regimens with the Bcr-Ab1 kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective; Leukemia 16 1213–1219PubMedGoogle 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 2892–2905PubMedGoogle 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. 81 355–364PubMedGoogle 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. 79 973–980PubMedGoogle 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 (London) 399 271–275Google 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 22796–22801PubMedGoogle 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 1535–1540PubMedGoogle 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. USA 99 14374–14379PubMedGoogle 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–S30PubMedGoogle Scholar
  81. Nardai G, Vegh E M, Prohaszka Z and Csermely P 2006 Chaperonerelated immune dysfunction: an emergent property of distorted chaperone networks; Trends Immunol. 27 74–79PubMedGoogle Scholar
  82. Neckers L 2002 Hsp90 inhibitors as novel cancer chemotherapeutic agents; Trends Mol. Med. 8 S55–S61PubMedGoogle 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. 298 159–162PubMedGoogle Scholar
  85. Page J, Heath J, Fulton R et al 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 protein 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 3 347–361PubMedGoogle 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 7 457–468PubMedGoogle Scholar
  89. Polymeropoulos M H, Lavedan C, Leroy E, Ide S E, Dehejia A, Dutra A, Pike B and Root H 1997 Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease; Science 276 2045–2047PubMedGoogle Scholar
  90. Prodromou C and Pearl L H 2003 Structure and functional relationships of Hsp90; Curr. Cancer Drug Targets 3 301–323PubMedGoogle Scholar
  91. Queitsch C, Sangster T A and Lindquist S 2002 Hsp90 as a capacitor of phenotypic variation; Nature (London) 417 618–624Google 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 (London) 418 934Google Scholar
  93. Rutherford S L and Lindquist S 1998 Hsp90 as a capacitor for morphological evolution; Nature (London) 396 336–342Google 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 et al 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 3530–3539PubMedGoogle 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. USA 93 14536–14541PubMedGoogle 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 et al 1995 erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships; J. Med. Chem. 38 3813–3820PubMedGoogle 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. 42 273–279PubMedGoogle 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 et al 1988 Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma; Nature (London) 332 268–269Google 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 2 117–125PubMedGoogle 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 6401–6408PubMedGoogle 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. 279 51989–51998PubMedGoogle 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. USA 96 15121–15126PubMedGoogle 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 1363–1371PubMedGoogle Scholar
  109. Taylor J P, Hardy J and Fischbeck K H 2002 Toxic proteins in neurodegenerative disease; Science 296 1991–1995PubMedGoogle Scholar
  110. Tofaris G K and Spillantini M G 2005 Alpha-synuclein dysfunction in Lewy body diseases; Mov. Disord. (Suppl 12) 20 S37–S44Google 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 55–64PubMedGoogle 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. 11 787–797PubMedGoogle 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 1088–1095PubMedGoogle Scholar
  115. Wegele H, Muller L and Buchner J 2004 Hsp70 and Hsp90-a relay team for protein folding; Rev. Physiol. Biochem. Pharmacol. 151 1–44PubMedGoogle Scholar
  116. Workman P 2004 Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone; Cancer Lett. 206 149–157PubMedGoogle 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. 30 185–219PubMedGoogle 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. 196 394–402PubMedGoogle 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 120 715–727PubMedGoogle Scholar
  122. Zoghbi H Y and Orr H T 2000 Glutamine repeats and neurodegeneration; Annu. Rev. Neurosci. 23 217–247PubMedGoogle Scholar

Copyright information

© Indian Academy of Sciences 2007

Authors and Affiliations

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

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