Targeting chaperones in transformed systems - A focus on Hsp90 and cancer

Expert Opinion on Therapeutic Targets

Volumn 10, Issue 1, 2006, Pages 37-50

  Chiosis, Gabriela ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

Cancer; Hsp90; Transformed system

Indexed keywords

17 ALLYLAMINO 17 DEMETHOXYGELDANAMYCIN; 17 DIMETHYLAMINOETHYLAMINO 17 DEMETHOXYGELDANAMYCIN; 4 [N (2 HYDROXYETHYL) N [2 (3 INDOLYL)ETHYL]AMINOMETHYL]CINNAMOHYDROXAMIC ACID; ADENOSINE TRIPHOSPHATE; ANSAMYCIN DERIVATIVE; BETA ZEARALENOL; CHAPERONE; CISPLATIN; CNF 1010; COUMARIN DERIVATIVE; FR 901228; HEAT SHOCK PROTEIN 90; HEAT SHOCK PROTEIN 90 INHIBITOR; HISTONE DEACETYLASE INHIBITOR; IPI 504; MYCOGRAB; NOVOBIOCIN; OXALIPLATIN; PEPTIDE DERIVATIVE; PROTEIN KINASE B; PURINE DERIVATIVE; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE; RADICICOL; RAF PROTEIN; RECOMBINANT ANTIBODY; SHEPHERDIN; SURVIVIN; TELOMERASE REVERSE TRANSCRIPTASE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANOREXIA; APOPTOSIS; BREAST CANCER; CANCER CELL; CANCER INHIBITION; CANCER THERAPY; CARCINOGENESIS; CELL FUNCTION; CELL SURVIVAL; CELL VIABILITY; CLINICAL TRIAL; DIARRHEA; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG MECHANISM; DRUG SOLUBILITY; DRUG TARGETING; FATIGUE; FEASIBILITY STUDY; GENE MUTATION; HEAT SHOCK RESPONSE; HEMATOLOGIC MALIGNANCY; HUMAN; KIDNEY CANCER; LIVER DYSFUNCTION; LIVER TOXICITY; MALIGNANT TRANSFORMATION; MEDICAL RESEARCH; MELANOMA; MOLECULAR STABILITY; MULTIPLE MYELOMA; MYALGIA; NAUSEA AND VOMITING; NONHUMAN; PANCREATITIS; PROTEIN CONFORMATION; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN PROCESSING; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL TRANSFORMATION, NEOPLASTIC; DRUG DELIVERY SYSTEMS; HSP90 HEAT-SHOCK PROTEINS; HUMANS; MOLECULAR CHAPERONES;

EID: 33244484848     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.10.1.37     Document Type: Review

References (125)

1. DRUKER BJ: Imatinib as a paradigm of targeted therapies. Adv. Cancer Res. (2004) 91:1-30.
2. WILLEMS A, GAUGER K, HENRICHS C, HARBECK N: Antibody therapy for breast cancer. Anti-Cancer Res. (2005) 25:1483-1489.
3. BYRNE BJ, GARST J: Epidermal growth factor receptor inhibitors and their role in non-small-cell lung cancer. Curr. Oncol. Rep. (2005) 7:241-247.
4. REN R: Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat. Rev. Cancer (2005) 5:172-183.
5. WORKMAN P: Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett. (2004) 206:149-157.
6. ZHANG H, BURROWS F: Targeting multiple signal transduction pathways through inhibition of Hsp90. J. Mol. Med. (2004) 82:488-499.
7. CHIOSIS G, VILENCHIK M, KIM J, SOLIT D: Hsp90: the vulnerable chaperone. Drug Discov. Today (2004) 9:881-888.
8. WHITESELL L, LINDQUIST SL: HSP90 and the chaperoning of cancer. Nat. Rev. Cancer (2005) 5:761-772.
9. NECKERS L, NECKERS K: Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics - an update. Expert Opin. Emerg. Drugs (2005) 10:137-149.
10. WEGELE H, MULLER L, BUCHNER J: Hsp70 and Hsp90-a relay team for protein folding. Rev. Physiol. Biochem. Pharmacol. (2004) 151:1-44.
11. PRODROMOU C, PEARL LH: Structure and functional relationships of Hsp90, Curr. Cancer Drug Targets (2003) 3:301-323.
12. PRATT WB, GALIGNIANA MD, MORISHIMA Y. MURPHY PJ: Role of molecular chaperones in steroid receptor action. Essays Biochem. (2004) 40:41-58.
13. CHENE P: ATPases as drug targets: learning from their structure. Nat. Rev. Drug Discov. (2002) 1:665-673.
14. DUTTA R, INOUYE M: GHKL, an emergent ATPase/kinase superfamily. Trends Biochem. Sci. (2000) 25:24-28.
15. NECKERS L, SCHULTE TW, MIMNAUGH E: Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest. New Drugs (1999) 17:361-373.
16. SCHULTE TW, NECKERS LM: The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to Hsp90 and shares important biologic activities with geldanamycin. Cancer Chemother. Pharmacol (1998) 42:273-279.
17. SMITH V, SAUSVILLE EA, CAMALIER RF, FIEBIG HH, BURGER AM: Comparison of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models. Cancer Chemother. Pharmacol. (2005) 56:126-137.
18. SOGA S, SHIOTSU Y, AKINAGA S, SHARMA SV: Development of radicicol analogues. Curr. Cancer Drug Targets (2003) 3:359-369.
19. YAMAMOTO K, GARBACCIO RM, STACHEL SJ et al.: Target oriented total synthesis as a resource in the discovery of potentially valuable agents in oncology: Cycloproparadicicol. Angew. Chemie (2003) 42:1280-1284.
20. MOULIN E, ZOETE V, BARLUENGA S, KARPLUS M, WINSSINGER N: Design, synthesis, and biological evaluation of HSP90 inhibitors based on conformational analysis of radicicol and its analogues. J. Am. Chem. Soc. (2005) 127:6999-7004.
21. CHIOSIS G, LUCAS B, HUEZO H, SOLIT D, BASSO A, ROSEN N: Development of purine-scaffold small molecule inhibitors of Hsp90. Curr. Cancer Drug Targets (2003) 3:363-368.
22. DYMOCK B, BARRIL X, BESWICK M et al.: Adenine derived inhibitors of the molecular chaperone HSP90-SAR explained through multiple X-ray structures. Bioorg. Med. Chem. Lett. (2004) 14:325-328.
23. CHEUNG KM, MATTHEWS TP, JAMES K et al.: 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. (2005) 15:3338-3343.
24. DYMOCK BW, BARRIL X, BROUGH PA et al.: Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J. Med. Chem. (2005) 48:4212-4215.
25. KREUSCH A, HAN S, BRINKER A et al.: Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles. Bioorg. Med. Chem. Lett. (2005) 15:1475-1478.
26. STEBBINS CE, RUSSO AA, SCHNEIDER C, ROSEN N, HARTL U, PAVLETICH NP: Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent. Cell (1997) 89:239-250.
27. ROE SM, PRODROMOU C, O'BRIEN R, LADBURY JE, PIPER PW, PEARL LH: Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J. Med. Chem. (1999) 42:260-266.
28. JEZ JM, CHEN JC, RASTELLI G, STROUD RM, SANTI DV: Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem. Biol. (2003) 10:361-368.
29. WRIGHT L, BARRIL X , DYMOCK B et al.: Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms. Chem. Biol. (2004) 11:775-785.
30. MARCU MG, SCHULTE TW, NECKERS L: Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins. J. Natl. Cancer Inst. (2000) 92:242-248.
31. YU XM, SHEN G, NECKERS L et al.: Hsp90 inhibitors identified from a library of novobiocin analogues. J. Am. Chem. Soc. (2005) 127:12778-12779.
32. MARCU MG, CHADLI A, BOUHOUCHE I, CATELLI M, NECKERS LM: The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J. Biol. Chem. (2000) 275:37181-37186.
33. SOTI C, RACZ A, CSERMELY P: A nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket. J. Biol. Chem. (2002) 277:7066-7075.
34. ITOH H, OGURA M, KOMATSUDA A, WAKUI H, MIURA AB, TASHIMA Y: A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90. Biochem. J. (1999) 343:697-703.
35. ROSENRAGEN MC, SOTI C, SCHMIDT U et al.: The heat shock protein 90-targeting drug cisplatin selectively inhibits steroid receptor activation. Mol. Endocrinol. (2003) 17:1991-2001.
36. MARCU MG, NECKERS LM: The C-terminal half of heat shock protein 90 represents a second site for pharmacologic intervention in chaperone function. Curr. Cancer Drug Targets (2003) 3:343-347.
37. ZHAO YG, GILMORE R, LEONE G, COFFEY MC, WEBER B, LEE PW: Hsp90 phosphorylation is linked to its chaperoning function. Assembly of the reovirus cell attachment protein. J. Biol. Chem. (2001) 276:32822-32827.
38. MIMNAUGH EG, WORLAND PJ, WHITESELL I, NECKERS LM: Possible role for serine/threonine phosphorylation in the regulation of the heteroprotein complex between the hsp90 stress protein and the pp60v-src tyrosine kinase. J. Biol. Chem. (1995) 270:28654-28659.
39. MURPHY PJ, MORISHIMA Y, KOVACS JJ, YAO TP, PRATT WB: Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone. J. Biol. Chem. (2005) 280:33792-33799.
40. BLANK M, MANDEL M, KEISARI Y, MERUELO, D, LAVIE G: Enhanced ubiquitinylation of heat shock protein 90 as a potential mechanism for mitotic cell death in cancer cells induced with hypericin. Cancer Res. (2003) 63:8241-8247.
41. MARTINEZ-RUIZ A, VILLANUEVA L, GONZALEZ DE ORDUNA C et al.: S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc. Natl. Acad. Sci USA (2005) 102:8525-8530.
42. AOYAGI S, ARCHER TK: Modulating molecular chaperone Hsp90 functions through reversible acetylation. Trends Cell Biol. (2005) 15:565-567.
43. YU X, GUO ZS, MARCU MG et al.: Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J. Natl. Cancer Inst. (2002) 94:504-513.
44. NIMMANAPALLI R, FUINO I, BALI P et al.: Historic deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. (2003) 63:5126-5135.
45. GEORGE P, BALI P, ANNAVARAPU S et al.: Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood (2005) 105:1768-1776.
46. RAHMANI M, REESE E, DAI Y et al.: Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to ST1571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change. Mol. Pharmacol. (2005) 67:1166-1176.
47. BALI P, PRANPAT M, SWABY R et al.: Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplification of her-2. Clin. Cancer Res. (2005) 11:6382-6309.
48. BALI P, PRANPAT M, BRADNER J et al.: Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. (2005) 280:26729-26734.
49. PLESCIA J, SALZ W, XIA F et al.: Rational design of shepherdin, a novel anticancer agent. Cancer Cell (2005) 7:457-468.
50. KAMAL A, THAO L, SENSINTAFFAR J et al.: A high affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature (2003) 425:407-410.
51. PANARETOU B, SILIGARDI G, MAYER P et al.: Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Mol. Cell (2002) 10:1307-1318.
52. RIGGS D, COX M, CHEUNG-FLYNN J, PRAPAPANICH V, CARRIGAN P, SMITH D: Functional specificity of cochaperone interactions with Hsp90 client proteins. Crit. Rev. Biochem. Mol. Biol. (2004) 39:279-295.
53. XU Y, LINDQUIST S: Heat-shock protein hsp90 governs the activity of pp60v-src kinase. Proc. Natl. Acad. Sci. USA (1993) 90:7074-7078.
54. WHITESELL, L, MIMNAUGH EG, DE COSTA B, MYERS CE, NECKERS LM: Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc. Natl. Acad. Sci. USA (1994) 91:8324-8328.
55. UEHARA Y. Natural product origins of Hsp90 inhibitors. Curr. Cancer Drug Targets (2003) 3:325-330.
56. XU W, YUAN X, JUNG YJ et al.: The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells. Cancer Res. (2003) 63:7777-7784.
57. MIMNAUGH EG, CHAVANY C, NECKERS L: Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J. Biol. Chem. (1996) 271:22796-22801.
58. SALESSE S, VERFAILLIE CM: BCR/ABL-mediated increased expression of multiple known and novel genes that may contribute to the pathogenesis of chronic myelogenous leukemia. Mol Cancer Ther. (2003) 2:173-182
59. SHIOTSU Y, NECKERS LM, WORTMAN I et al: 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 (2000) 96:2284-2291.
60. BONVINI P, DALLA ROSA H, VIGNES N, ROSOLEN A. Ubiquitination and proteasomal degradation of nucleophosmin-anaplastic lymphoma, kinase induced by 17-allylamino-demethoxygeldanamycin: role of the co-chaperone carboxyl heat shock protein 70-interacting protein. Cancer Res. (2004) 64:3256-3264.
61. GEORGE P, BALI P, COHEN P et al.: Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res. (2004) 64:3645-3652.
62. BELIAKOFF J, BAGATELL R, PAINE-MURRIETA G et al.: Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors. Clin. Cancer Res. (2003) 9:4961-4971.
63. SOLIT DB, ZHENG FF, DROBNJAK M et al.: 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/NEU and inhibits the growth of prostate cancer xenografts. Clin. Cancer Res. (2002) 8:986-993.
64. SHIMAMURA T, LOWELL AM, ENGELMAN JA, SHAPIRO GI: 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. (2005) 65:6401-6408.
65. CASTRO JE, PRADA CE, LORIA O et al.: ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood (2005) 106:2506-2512.
66. VILENCHIK M, SOLIT D, BASSO A et al.: Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem. Biol. (2004) 11:787-797.
67. RUTHERFORD SL, LINDQUIST S: Hsp90 as a capacitor for morphological evolution. Nature (1998) 396:336-342.
68. QUEITSCH C, SANGSTER TA, LINDQUIST S: Hsp90 as a capacitor of phenotypic variation. Nature (2002) 417:618-624.
69. SATO S, FUJITA N, TSURUO T: Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl. Acad. Sci. USA (2000) 97:10832-10837.
70. BASSO AD, SOLIT DB, CHIOSIS G, GIRI B, TSICHLIS P, ROSEN N: Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J. Biol. Chem. (2002) 277:39858-39866.
71. SCHULTE TW, BLAGOSKLONNY MV, INGUI C, NECKERS L: Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association. J. Biol. Chem. (1995) 270:24585-24588.
72. FORTUGNO P, BELTRAMI E, PLESCIA J et al.: Regulation of survivin function by Hsp90. Proc. Natl. Acad. Sci. USA (2003) 100:13791-13796.
73. EUSTACE BK, SAKURAI T, STEWART JK et al.: Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat. Cell Biol. (2004) 6:507-514.
74. STEWART SA: Telomere maintenance and tumorigenesis: an 'ALT' ernative road. Curr. Mol. Med. (2005) 5:253-257.
75. FORSYTHE HL, JARVIS JL, TURNER JW, ELMORE LW, HOLT SE: Stable association of hsp90 and p23, but not hsp70, with active human telomerase. J. Biol. Chem. (2001) 276:15571-15574.
76. AKALIN A, ELMORE LW, FORSYTHE HL et al.: A novel mechanism for chaperone-mediated telomerase regulation during prostate cancer progression. Cancer Res. (2001) 61:4791-4796.
77. BELOZEROV VE, VAN MEIR EG: Hypoxia inducible factor-1: a novel target for cancer therapy. Anti-Cancer Drugs (2005) 16:901-909.
78. ISAACS JS, JUNG YJ, MIMNAUGH EG, MARTINEZ A, CUTTITTA F, NECKERS LM: Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J. Biol. Chem. (2002) 277:29936-29944.
79. LEWIS J, DEVIN A, MILLER A et al.: Disruption of hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappaB activation. J. Biol. Chem. (2000) 275:10519-10526.
80. ZHAO C, WANG E: Heat shock protein 90 suppresses tumor necrosis factor alpha induced apoptosis by preventing the cleavage of Bid in NIH3T3 fibroblasts. Cell Signal, (2004) 16:313-321.
81. PANDEY P, SALEH A, NAKAZAWA A et al.: Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procasapse-9 by heat shock. EMBO J. (2000) 19:4310-4322.
82. LLAUGER L, HE H, KIM J et al.: 8-Arylsulfanyl and 8-arylsulfoxyl adenine derivatives as inhibitors of the heat shock protein 90. J. Med. Chem. (2005) 48:2892-2905.
83. LE BRAZIDEC JY, KAMAL A, BUSCH D et al.: Synthesis and biological evaluation of a new class of geldanamycin derivatives as potent inhibitors of Hsp90. J. Med. Chem. (2004) 47:3865-73.
84. SOGA S, NECKERS LM, SCHULTE TW et al.: KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules. Cancer Res. (1999) 59:2931-2938.
85. EISEMAN JL, LAN J, LAGATTUTA TF et al.: 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. (2005) 55:21-32.
86. BANERJI U, WALTON M, RAYNAUD F et al.: Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models. Clin. Cancer Res. (2005) 11:7023-7032.
87. SYDOR JR, PIEN CS, ZHANG Y et al.: Anti-tumor activity of a novel, water soluble Hsp90 inhibitor IPI-504 in multiple myeloma. Proc. Amer. Assoc. Cancer Res. (2005) 46:Abstract 6160.
88. BANERJI U, O'DONNELL A, SCURR M et al.: Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J. Clin. Oncol. (2005) 23:4152-4161.
89. RAMANATHAN RK, TRUMP DL, EISEMAN JL et al.: Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin. Cancer Res. (2005) 11:3385-3391.
90. GOETZ MP, et al.: Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J. Clin. Oncol. (2005) 23:1078-1087.
91. KOVACS JJ, MURPHY PJM, GAILLARD S et al.: HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell (2005) 18:601-607.
92. XU Y, SINGER MA, LINDQUIST S: Maturation of the tyrosine kinase c-src as a kinase and as a substrate depends on the molecular chaperone Hsp90. Proc. Natl. Acad. Sci. USA (1999) 96:109-114.
93. MALONEY A, CLARKE PA, WORKMAN P: Genes and proteins governing the cellular sensitivity to HSP90 inhibitors: a mechanistic perspective. Curr. Cancer Drug Targets (2003) 3:331-341.
94. ZOU J, GUO Y, GUETTOUCHE T, SMITH DF, VOELLMY R: Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1 Cell (1998) 94:471-480.
95. BHARADWAJ S, ALI A, OVSENEK N: Multiple components of the HSP90 chaperone complex function in regulation of heat shock factor 1 In vivo. Mol. Cell Biol. (1999) 19:8033-8041.
96. SAMALI A, COTTER TG: Heat shock proteins increase resistance to apoptosis. Exp. Cell Res. (1996) 223:163-170.
97. JÄÄTTËLÄ M: Escaping cell death: survival proteins in cancer. Ex. Cell Res. (1999) 248:30-43.
98. REED JC: Mechanisms of apoptosis avoidance in cancer. Curr. Opin. Oncol. (1999) 11:68-75.
99. MOSSER DD, MORIMOTO RI: Molecular chaperones and the stress of oncogenesis. Oncogene (2004) 23:2907-2918.
100. LI CY, LEE JS, KO YG, KIM JI, SEO JS: Heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation. J. Biol. Chem. (2000) 275:25665-25671.
101. SALEH A, SRINIVASULA SM, BALKIR I, ROBBINS PD, ALNEMRI ES: Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat. Cell Biol. (2000) 2:476-483.
102. BEERE HM, WOLF BB, CAIN K et al.: Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat. Cell Biol. (2000) 8:469-475.
103. JAATTELA M, WISSING D, KOKHOLM K, KALLUNKI T, EGEBLAD M: Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J. (1998) 17:6124-6134.
104. KOMAROVA EY, AFANASYEVA EA, BULATOVA MM et al.: Downstream caspases are novel targets for the antiapoptotic activity of the molecular chaperone hsp70. Cell Stress Chaperones (2004) 9:265-275.
105. STANKIEWICZ AR, LACHAPELLE G, FOO CP, RADICIONI SM, MOSSER DD: Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J. Biol. Chem. (2005) 280:38729-38739.
106. RAVAGNAN L, GURBUXANI S, SUSIN SA et al.: Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat. Cell Biol. (2001) 9:839-843.
107. GABAI VL, MERIIN AB, YAGLOM JA, MOSSER DD, SHERMAN MY: Heat shock protein 70 protects from caspase-independent programmed cell death via suppression of stress kinase jnk. Scientific World Journal (2001) 1:36.
108. BAGATELL R, PAINE-MURRIETA GD, TAYLOR CW et al.: Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of hsp90-binding agents. Clin. Cancer Res. (2000) 6:3312-3318.
109. GABAI VL, BUDAGOVA KR, SHERMAN MY. Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents. Oncogene (2005) 24:3328-3338.
110. BURGER AM, FIEBIG HH, STINSON SP, SAUSVILLE EA. 17-(Allylamino)-17-demethoxygeldanamycin activity in human melanoma models. Anti-Cancer Drugs (2004) 15:377-387.
111. MALONEY A, CLARKE PA, WORKMAN P: Genes and proteins governing the cellular sensitivity to HSP90 inhibitors: a mechanistic perspective. Curr. Cancer Drug Targets (2003) 3:331-341.
112. GUO F, SIGUA C, BALI P et al.: Abrogation of hsp70 induction: A strategy to enhance the antileukemia effects of hsp90 inhibitor 17-allylamino-demethoxy geldanamycin (17-AAG). Proc. Amer. Assoc. Cancer Res. (2005) Abstract 3275.
113. ZHANG H, YANG Y-C, LE D et al.: The two faces of Hsp90: Dissecting the Cytotoxic and cytoprotective responses with selective Hsp90 modulators. Proc. Amer. Assoc. Cancer Res. (2005):Abstract 1527.
114. BAGATELL R, BELIAKOFF J, DAVID CL, MARRON MT, WHITESELL L: Hsp90 inhibitors deplete key anti-apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin. Int. J. Cancer (2005) 113:179-188.
115. MCCOLLUM A, TOFT D, ERLICHMAN C: Proc. Amer. Assoc. Cancer Res. (2004)-Abstract 3748.
116. NARDAI G, SASS B, EBER J, OROSZ G, CSERMELY P: Reactive cysteines of the 90-kDa heat shock protein, Hsp90. Arch. Biochem. Biophys. (2000) 384(1):59-67.
117. MADDEN T-A, PUMFORD S, BARROW D et al.: Development of acquired resistance to 17(Allylamino)-17-demethoxygeldanamycin (17-AAG) in hormone refractory breast cancers in vitro. Proc. Amer. Assoc. Cancer Res. (2005):Abstract LB-267.
118. MIMNAUGH EG, XU W, VOS M et al.: Simultaneous inhibition of hsp90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. Mol. Cancer Ther. (2004) 3(5):551-566.
119. ENMON R, YANG WH, BALLANGRUD AM et al.: Combination treatment with 17-N-allylamino-17-demethoxy geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids. Cancer Res. (2003) 63:8393-8399.
120. BISHT KS, BRADBURY CM, MATTSON D et al.: 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. (2003) 63:8984-8995.
121. MCCOLLUM A, TOFF DO, ERLICHMAN C. Geldanamycin enhances cisplatin cytotoxicity through loss of Akt activation in A549 cells. Clin. Cancer Res. (2003) 9:6178.
122. MUNSTER PN, BASSO A, SOLIT D, NORTON L, ROSEN N: Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. Clin. Cancer Res. (2001) 7:2228-2236.
123. SMITH-JONES PM, SOLIT DB, AKHURST T, AFROZE F, ROSEN N, LARSON M: The pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors can be imaged in animals with 68Ga labeled F(ab')2 fragments of Herceptin. Nature Biotech. (2004) 22:701-706.
124. COWEN LE, LINDQUIST S: Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science (2005) 309:2185-2189.
125. DEVANEY E, O'NEILL K, HARNETT W, WHITESELL L, KINNAIRD JH: Hsp90 is essential in the filarial nematode Brugia pahangi. Int. J. Parasitol. (2005) 35:627-636.