Evaluating Dual Hsp90 and Hsp70 Inhibition as a Cancer Therapy

Part of the Topics in Medicinal Chemistry book series (TMC, volume 19)


The heat shock proteins (Hsps) are a family of highly conserved proteins involved in the regulation of numerous cellular processes including those associated with cancer. Inhibiting the function of these Hsps, specifically Hsp70 and Hsp90, is a major strategy used in the development of new cancer therapies. Numerous Hsp90 inhibitors have been evaluated in the clinic, and while some have experienced success, many have produced disappointing results. One reason explaining their failure is that they induce a cytoprotective response that protects cancer cells from the negative effects of Hsp90 inhibition. In order to maximise the therapeutic outcomes, dual inhibition of Hsp70 and Hsp90 can be employed to overcome cell rescue mechanisms induced by monotherapies. In this chapter, we discuss dual inhibition of Hsp70 and Hsp90 using small molecules and evaluate the potential of this strategy for the development of cancer therapeutics.


Dual inhibitors Heat shock proteins Heat shock response Hsp70 Hsp90 


  1. 1.
    Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475(7356):324–332CrossRefGoogle Scholar
  2. 2.
    Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C (2007) Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol 81(1):15–27CrossRefGoogle Scholar
  3. 3.
    Young JC, Agashe VR, Siegers K, Hartl FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5(10):781–791CrossRefGoogle Scholar
  4. 4.
    Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover KD, Karras GI, Lindquist S (2012) Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150(5):987–1001CrossRefGoogle Scholar
  5. 5.
    Whitesell L, Mimnaugh EG, De Costa B, Meyers CE, Neckers LM (1994) 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 U S A 91(18):8324–8328CrossRefGoogle Scholar
  6. 6.
    Jhaveri K, Modi S (2012) HSP90 inhibitors for cancer therapy and overcoming drug resistance. Adv Pharmacol 65:471–517CrossRefGoogle Scholar
  7. 7.
    Jhaveri K, Taldone T, Modi S, Chiosis G (2012) Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 1823(3):742–755CrossRefGoogle Scholar
  8. 8.
    Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A, Arkenau HT, Moreno-Farre J, Banerji U, Roels B, Peachey H, Aherne W, de Bono JS, Raynaud F, Workman P, Judson I (2011) A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin Cancer Res 17(6):1561–1570CrossRefGoogle Scholar
  9. 9.
    Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, D’Andrea G, Dickler M, Moynahan ME, Sugarman S, Ma W, Patil S, Norton L, Hannah AL, Hudis C (2011) HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 17(15):5132–5139CrossRefGoogle Scholar
  10. 10.
    Sequist LV, Gettinger S, Senzer NN, Martins RG, Janne PA, Lilenbaum R, Gray JE, Iafrate AJ, Katayama R, Hafeez N, Sweeney J, Walker JR, Fritz C, Ross RW, Grayzel D, Engelman JA, Borger DR, Paez G, Natale R (2010) Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 28(33):4953–4960CrossRefGoogle Scholar
  11. 11.
    Lancet JE, Gojo I, Burton M, Quinn M, Tighe SM, Kersey K, Zhong Z, Albitar MX, Bhalla K, Hannah AL, Baer MR (2010) Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia 24:699–705CrossRefGoogle Scholar
  12. 12.
    Rajan A, Kelly RJ, Trepel JB, Kim YS, Alarcon SV, Kummar S, Gutierrez M, Crandon S, Zein WM, Jain L, Mannargudi B, Figg WD, Houk BE, Shnaidman M, Brega N, Giaccone G (2011) A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin Cancer Res 17(21):6831–6839CrossRefGoogle Scholar
  13. 13.
    Sydor JR, Normant E, Pien CS, Porter JR, Ge J, Grenier L, Pak RH, Ali JA, Dembski MS, Hudak J, Patterson J, Penders C, Pink M, Read MA, Sang J, Woodward C, Zhang Y, Grayzel DS, Wright J, Barrett JA, Palombella VJ, Adams J, Tong JK (2006) Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A 103(46):17408–17413CrossRefGoogle Scholar
  14. 14.
    Prodromou C, Roe SM, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1997) Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90(1):65–75CrossRefGoogle Scholar
  15. 15.
    Chavany C, Mimnaugh E, Miller P, Bitton R, Nguyen P, Trepel J, Whitesell L, Schnur R, Moyer J, Neckers L (1996) p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2. J Biol Chem 271:4974–4977CrossRefGoogle Scholar
  16. 16.
    Johnson RD, Haber A, Rinehart KLJ (1974) Geldanamycin biosynthesis and carbon magnetic resonance. J Am Chem Soc 96:3316–3317CrossRefGoogle Scholar
  17. 17.
    Li YH, Lu QN, Wang HQ, Tao PZ, Jiang JD (2012) Geldanamycin, a ligand of heat shock protein 90, inhibits herpes simplex virus type 2 replication both in vitro and in vivo. J Antibiot (Tokyo) 65:509–512CrossRefGoogle Scholar
  18. 18.
    Rinehart KL, Sasaki K, Slomp G, Grostic MF, Olson EC (1970) Geldanamycin. I. Structure assignment. J Am Chem Soc 92:7591–7593CrossRefGoogle Scholar
  19. 19.
    Schnur RC, Corman ML, Gallaschun RJ, Cooper BA, Dee MF, Doty JL, Muzzi ML, DiOrio CI, Barbacci EG, Miller PE, Pollack VA, Savage DM, Sloan DE, Pustilnik LR, Moyer JD, Moyer MP (1995) erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships. J Med Chem 38:3813–3820CrossRefGoogle Scholar
  20. 20.
    Wang Y, McAlpine SR (2015) C-terminal heat shock protein 90 modulators produce desirable oncogenic properties. Org Biomol Chem 13:4627–4631CrossRefGoogle Scholar
  21. 21.
    Wang Y, McAlpine SR (2015) Combining an Hsp70 inhibitor with either an N-terminal and C-terminal hsp90 inhibitor produces mechanistically distinct phenotypes. Org Biomol Chem 13:3691–3698CrossRefGoogle Scholar
  22. 22.
    Wang Y, McAlpine SR (2015) Heat shock protein 90 inhibitors: will they ever succeed as chemotherapeutics? Future Med Chem 7(2):87–90CrossRefGoogle Scholar
  23. 23.
    Wang Y, Mcalpine SR (2015) N-terminal and C-terminal modulation of Hsp90 produce dissimilar phenotypes. Chem Commun 51:1410–1413CrossRefGoogle Scholar
  24. 24.
    Wang Y, McAlpine SR (2015) Regulating the cytoprotective response in cancer cells using simultaneous inhibition of Hsp90 and Hsp70. Org Biomol Chem 13:2108–2116CrossRefGoogle Scholar
  25. 25.
    Yamaki H, Suzuki H, Choi EC, Tanaka N (1982) Inhibition of DNA synthesis in murine tumor cells by geldanamycin, an antibiotic of the benzoquinoid ansamycin group. J Antibiot (Tokyo) 35:886–892CrossRefGoogle Scholar
  26. 26.
    Morimoto RI (1998) Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 12:3788–3796CrossRefGoogle Scholar
  27. 27.
    Anckar J, Sistonen L (2011) Regulation of HSF1 in the heat stress response: implications in aging and disease. Annu Rev Biochem 80:1089–1115CrossRefGoogle Scholar
  28. 28.
    Chiosis G, JHuezo H, Rosen N, Mimgaugh E, Whitesell L, Neckers L (2003) Binding affinity and potent cell activity-finding an explanation. Mol Cancer Ther 2:123–129Google Scholar
  29. 29.
    Mahalingam D, Swords R, Carew JS, Nawrocki ST, Bhalla K, Giles FJ (2009) Targeting HSP90 for cancer therapy. Br J Cancer 100:1523–1529CrossRefGoogle Scholar
  30. 30.
    Ali A, Bharadwaj S, O’Carroll R, Ovsenek N (1998) Hsp90 interacts with and regulates the activity of heat shock factor 1 in Xenopus oocytes. Mol Cell Biol 18:4949–4960CrossRefGoogle Scholar
  31. 31.
    Bharadwaj S, Ali A, Ovsenek N (1999) Multiple components of the HSP90 chaperone complex function in regulation of heat shock factor 1 in vivo. Mol Cell Biol 19:8033–8041CrossRefGoogle Scholar
  32. 32.
    Guo Y, Guettouche T, Fenna M, Boellmann F, Pratt WB (2001) Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex. J Biol Chem 276:45791–45799CrossRefGoogle Scholar
  33. 33.
    Morimoto RI (2002) Dynamic remodelling of transcription complexes by molecular chaperones. Cell 110:281–284CrossRefGoogle Scholar
  34. 34.
    Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R (1998) Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP complex) that forms a stress-sensitive complex with HSF1. Cell 94:471–480CrossRefGoogle Scholar
  35. 35.
    Vujanac M, Fenaroli A, Zimarino V (2005) Constitutive nuclear import and stress-regulated nucleocytoplasmic shuttling of mammalian heat-shock factor 1. Traffic 6:214–229CrossRefGoogle Scholar
  36. 36.
    Kline MP, Morimoto RI (1997) Repression of the heat shock factor 1 transcriptional activation domain is modulated by constitutive phosphorylation. Mol Cell Biol 17:2107–2115CrossRefGoogle Scholar
  37. 37.
    Sandqvist A, Bjork JK, Akerfelt M, Chitikova Z, Grichine A (2009) Heterotrimerization of heat shock factors 1 and 2 provides a transcriptional switch in response to distinct stimuli. Mol Biol Cell 20:1340–1347CrossRefGoogle Scholar
  38. 38.
    Xiao H, Perisic O, Lis JT (1991) Cooperative binding of Drosophila heat shock factor to arrays of conserved 5 bp unit. Cell 64:585–593CrossRefGoogle Scholar
  39. 39.
    Core LJ, Lis JT (2008) Transcription regulation through promoter-proximal pausing of RNA polymerase II. Science 319:1791–1792CrossRefGoogle Scholar
  40. 40.
    Rougvie AE, Lis JT (1988) The RNA polymerase II molecule at the 5′ end of the uninduced hsp70 gene of D. melanogaster is transcriptionally engaged. Cell 54:795–804CrossRefGoogle Scholar
  41. 41.
    Morimoto RI, Tissieres A, Georgopoulos C (1990) The stress response, function of the proteins and perspectives. In: Morimoto RI, Tissieres A, Georgopoulos C (eds) Stress protein in biology and medicinal. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 1–36CrossRefGoogle Scholar
  42. 42.
    Day JEH, Sharp SY, Rowlands MG, Aherne W, Hayes A, Raynaud FI, Lewis W, Roe SM, Prodromou C, Pearl LH, Workman P, Moody CJ (2011) Targeting the Hsp90 molecular chaperone with novel macrolactams. Synthesis, structural, binding, and cellular studies. ACS Chem Biol 6(12):1339–1347CrossRefGoogle Scholar
  43. 43.
    Powers MV, Valenti M, Miranda S, Maloney A, Eccles SA, Thomas G, Clarke PA, Workman P (2013) Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic bax. Oncotarget 4(11):1963–1975CrossRefGoogle Scholar
  44. 44.
    Workman P, Al-Lazikani B (2013) Drugging cancer genomes. Nat Rev Drug Discov 12(12):889–890CrossRefGoogle Scholar
  45. 45.
    Powers MV, Jones K, Barillari C, Westwood I, van Montfort RL, Workman P (2010) Targeting HSP70: the second potentially druggable heat shock protein and molecular chaperone? Cell Cycle 9:1542–1550CrossRefGoogle Scholar
  46. 46.
    Beere HM (2004) “The stress of dying”: the role of heat shock proteins in the regulation of apoptosis. J Cell Sci 117:2641–2651CrossRefGoogle Scholar
  47. 47.
    Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM, Green DR (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475CrossRefGoogle Scholar
  48. 48.
    Guo F, Sigua C, Bali P, George P, Fiskus W, Scuto A, Annavarapu S, Mouttaki A, Sondarva G, Wei S, Wu J, Djeu J, Bhalla K (2005) Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 105:1246–1255CrossRefGoogle Scholar
  49. 49.
    Nylandsted J, Gyrd-Hansen M, Danielewicz A, Fehrenbacher N, Lademann U, Høyer-Hansen M, Weber E, Multhoff G, Rohde M, Jäättelä M (2004) Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 200:425–435CrossRefGoogle Scholar
  50. 50.
    Ardi VC, Alexander LD, Johnson VA, McAlpine SR (2011) Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins. ACS Chem Biol 6:1357–1367CrossRefGoogle Scholar
  51. 51.
    Eskew JD, Sadikot T, Morales P, Duren A, Dunwiddie I, Swink M, Zhang X, Hembruff S, Donnelly A, Rajewski RA, Blagg B, Manjarrez JR, Matts RL, Holzbeierlein JM, Vielhauer GA (2011) Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells. BMC Cancer 11:468CrossRefGoogle Scholar
  52. 52.
    Koay YC, McConnell JR, Wang Y, Kim SJ, McAlpine SR (2014) Chemically accessible Hsp90 inhibitor that does not induce a heat shock response. ACS Med Chem Lett 5:771–776CrossRefGoogle Scholar
  53. 53.
    Kunicki JB, Petersen MN, Alexander LD, Ardi VC, McConnell JR, McAlpine SR (2011) Synthesis and evaluation of biotinylated sansalvamide A analogs and their modulation of Hsp90. Bioorg Med Chem Lett 21:4716–4719CrossRefGoogle Scholar
  54. 54.
    McConnell JM, Alexander LD, McAlpine SR (2014) A heat shock protein inhibitor that modulates immunophilins and regulates hormone receptors. Bioorg Med Chem Lett 24:661–666CrossRefGoogle Scholar
  55. 55.
    Shelton SNS, Matthews ME, Lu SB, Donnelly Y, Szabla AC, Tanol K, Vielhauer M, Rajewski GA, Matts RA, Blagg RL, Robertson BS (2009) KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kDa heat shock protein, exerts potent antiproliferative effects in human leukemic cells. Mol Pharmacol 76:1314–1322CrossRefGoogle Scholar
  56. 56.
    Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858CrossRefGoogle Scholar
  57. 57.
    Horibe T, Kohno M, Haramoto M, Ohara K, Kawakami K (2011) Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent. J Transl Med 9:8CrossRefGoogle Scholar
  58. 58.
    Neckers L, Mimnaugh E, Schulte TW (1999) Hsp90 as an anti-cancer target. Drug Resist Updat 2:165–172CrossRefGoogle Scholar
  59. 59.
    Scott MD, Frydman J (2003) Aberrant protein folding as the molecular basis of cancer. Methods Mol Biol 232:67–76Google Scholar
  60. 60.
    Workman P, Burrows F, Neckers L, Rosend N (2007) Drugging the cancer chaperone Hsp90: combinational therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci 1113:202–216CrossRefGoogle Scholar
  61. 61.
    Yi F, Regan L (2008) A novel class of small molecule inhibitors of Hsp90. ACS Chem Biol 3:645–654CrossRefGoogle Scholar
  62. 62.
    Falsone SF, Gesslbauer B, Tirk F, Piccinini AM, Kungl AJ (2005) A proteomic snapshot of the human heat shock protein 90 interactome. FEBS Lett 579:6350–6354CrossRefGoogle Scholar
  63. 63.
    Horibe T, Torisawa A, Kohno M, Kawakami K (2012) Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells. Mol Cancer 11:59CrossRefGoogle Scholar
  64. 64.
    Kamal A, Boehm MF, Burrows FJ (2004) Therapeutic and diagnostic implications of Hsp90 activation. Trends Mol Med 10:283–290CrossRefGoogle Scholar
  65. 65.
    McClellan AJ, Xia Y, Deutschbauer AM, Davis RW, Gerstein M, Frydman J (2007) Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approach. Cell 131:121–135CrossRefGoogle Scholar
  66. 66.
    Welch WJ (1991) The role of heat-shock proteins as molecular chaperones. Curr Opin Cell Biol 3:1033–1038CrossRefGoogle Scholar
  67. 67.
    Westerheide SD, Morimoto RI (2005) Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem 280:33097–33100CrossRefGoogle Scholar
  68. 68.
    Pearl LH, Prodromou C (2000) Structure and in vivo function of Hsp90. Curr Opin Struct Biol 10:46–51CrossRefGoogle Scholar
  69. 69.
    Young JC, Moarefi I, Hartl FU (2001) Hsp90: a specialized but essential protein-folding tool. J Cell Biol 154:267–273CrossRefGoogle Scholar
  70. 70.
    Horibe T, Kawamoto M, Kohno M, Kawakami K (2012) Cytotoxic activity to acute myeloid leukemia cells by Antp-TPR hybrid peptide targeting Hsp90. J Biosci Bioeng 114:96–103CrossRefGoogle Scholar
  71. 71.
    Isaacs JS, Xu W, Neckers L (2003) Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3:213–217CrossRefGoogle Scholar
  72. 72.
    Biamonte MA, Van de Water R, Arndt JW, Scannevin RH, Perret D, Lee WC (2010) Heat shock protein 90: inhibitors in clinical trials. J Med Chem 53:3–17CrossRefGoogle Scholar
  73. 73.
    Janin YL (2010) ATPase inhibitors of heat-shock protein 90, second season. Drug Discov Today 15:342–353CrossRefGoogle Scholar
  74. 74.
    Powers MV, Clarke PA, Workman P (2009) Death by chaperone: HSP90, HSP70 or both? Cell Cycle 8:518–526CrossRefGoogle Scholar
  75. 75.
    Butcher EC (2005) Can cell systems biology rescue drug discovery? Nat Rev Drug Discov 4:461–467CrossRefGoogle Scholar
  76. 76.
    Drysdale MJ, Brough PA, Massey A, Jensen MR, Schoepfer J (2006) Targeting Hsp90 for the treatment of cancer. Curr Opin Drug Discov Devel 9:483–495Google Scholar
  77. 77.
    Alexander LD, Partridge JR, Agard DA, McAlpine SR (2011) A small molecule that preferentially binds the closed Hsp90 conformation. Bioorg Med Chem Lett 21:7068–7071CrossRefGoogle Scholar
  78. 78.
    Kusuma BR, Peterson LB, Zhao H, Vielhauer G, Holzberlein J, Blagg BS (2011) Targeting the heat shock protein 90 dimer with dimeric inhibitors. J Med Chem 54:6234–6253CrossRefGoogle Scholar
  79. 79.
    Vasko RC, Rodriguez RA, Cunningham CN, Ardi VC, Agard DA, McAlpine SR (2010) Mechanistic studies of Sansalvamide A-amide: an allosteric modulator of Hsp90. ACS Med Chem Lett 1:4–8CrossRefGoogle Scholar
  80. 80.
    Yu XM, Shen G, Cronk B, Marcu M, Holzberlein J, Neckers LM, Blagg BSJ (2005) Hsp90 inhibitors identified from a library of novobiocin analogues. J Am Chem Soc 127:12778–12779CrossRefGoogle Scholar
  81. 81.
    Gandhi N, Wild AT, Chettiar ST, Aziz K, Kato Y, Gajula RP, Williams RD, Cades JA, Annadanam A, Song D, Zhang Y, Hales RK, Herman JM, Armour E, DeWeese TL, Schaeffer EM, Tran PT (2013) Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells. Cancer Biol Ther 14:347–356CrossRefGoogle Scholar
  82. 82.
    Goldman JW, Raju RN, Gordon GA, El-Hariry I, Teofilivici F, Vukovic VM, Bradley R, Karol MD, Chen Y, Guo W, Inoue T, Rosen LS (2013) A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies. BMC Cancer 13:152–161CrossRefGoogle Scholar
  83. 83.
    Graham B, Curry J, Smyth T, Fazal L, Feltell R, Harada I, Coyle J, Williams B, Reule M, Angove H, Cross DM, Lyons J, Wallis NG, Thompson NT (2012) The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer. Cancer Sci 103:522–527CrossRefGoogle Scholar
  84. 84.
    Modi S, Saura C, Henderson C, Lin NU, Mahtani R, Goddard J, Rodenas E, Hudis C, O’Shaughnessy J, Baselga J (2013) A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer. Breast Cancer Res Treat 139:107–113CrossRefGoogle Scholar
  85. 85.
    Song D, Chaerkady R, Tan AC, García-García E, Nalli A, Suárez-Gauthier A, López-Ríos F, Zhang XF, Solomon A, Tong J, Read M, Fritz C, Jimeno A, Pandey A, Hidalgo M (2008) Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer. Mol Cancer Ther 7:3275–3284CrossRefGoogle Scholar
  86. 86.
    Zhang H, Chung D, Yang YC, Neely L, Tsurumoto S, Fan J, Zhang L, Biamonte M, Brekken J, Lundgren K, Burrows F (2006) Identification of new biomarkers for clinical trials of Hsp90 inhibitors. Mol Cancer Ther 5:1256–1264CrossRefGoogle Scholar
  87. 87.
    Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci U S A 106:8368–8373CrossRefGoogle Scholar
  88. 88.
    Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31:164–172CrossRefGoogle Scholar
  89. 89.
    Chatterjee M, Andrulis M, Stühmer T, Müller E, Hofmann C, Steinbrunn T, Heimberger T, Schraud H, Kressmann S, Einsele H, Bargou RC (2013) The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma. Haematologica 98:1132–1141CrossRefGoogle Scholar
  90. 90.
    Davenport EL, Zeisig A, Aronson LI, Moore HE, Hockley S, Gonzalez D, Smith EM, Powers MV, Sharp SY, Workman P, Morgan GJ, Davies FE (2010) Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma. Leukemia 24(10):1804–1807CrossRefGoogle Scholar
  91. 91.
    Gaspar N, Sharp SY, Eccles SA, Gowan S, Popov S, Jones C, Pearson A, Vassal G, Workman P (2010) Mechanistic evaluation of the novel HSP90 inhibitor NVP-AUY922 in adult and pediatric glioblastoma. Mol Cancer Ther 9:1219–1233CrossRefGoogle Scholar
  92. 92.
    Maloney A, Clarke PA, Naaby-Hansen S, Stein R, Koopman J-O, Akpan A, Yang A, Zvelebil M, Cramer R, Stimson L, Aherne W, Banerji U, Judson I, Sharp S, Powers M, deBilly E, Salmons J, Walton M, Burlingame A, Waterfield M, Workman P (2007) Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res 67:3239–3253CrossRefGoogle Scholar
  93. 93.
    McCollum AK, TenEyck CJ, Sauer BM, Toft DO, Erlichman C (2006) Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Cancer Res 66:10967–10975CrossRefGoogle Scholar
  94. 94.
    Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918CrossRefGoogle Scholar
  95. 95.
    Powers MV, Clarke PA, Workman P (2008) Dual targeting of Hsc70 and Hsp72 inhibits Hsp90 function and induces tumor-specific apoptosis. Cancer Cell 14:250–262CrossRefGoogle Scholar
  96. 96.
    Stühmer T, Chatterjee M, Grella E, Seggewiss R, Langer C, Müller S, Schoepfer J, Garcia-Echeverria C, Quadt C, Jensen MR, Einsele H, Bargou RC (2009) Anti-myeloma activity of the novel 2-aminothienopyrimidine Hsp90 inhibitor NVP-BEP800. Br J Haematol 47:319–327CrossRefGoogle Scholar
  97. 97.
    Stühmer T, Zöllinger A, Siegmund D, Chatterjee M, Grella E, Knop S, Kortüm M, Unzicker C, Jensen MR, Quadt C, Chène P, Schoepfer J, García-Echeverría C, Einsele H, Wajant H, Bargou RC (2008) Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma. Leukemia 22:1604–1612CrossRefGoogle Scholar
  98. 98.
    Wahyudi H, Wang Y, McAlpine SR (2014) Utilizing a Dimerization strategy to inhibit the dimer protein Hsp90: synthesis and biological activity of a sansalvamide A dimer. Org Biomol Chem 12:765–773CrossRefGoogle Scholar
  99. 99.
    Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124CrossRefGoogle Scholar
  100. 100.
    Whitesell L, Santagata S, Lin NU (2012) Inhibiting HSP90 to treat cancer: a strategy in evolution. Curr Mol Med 12:1108–1124CrossRefGoogle Scholar
  101. 101.
    Creagh EM, Sheehan D, Cotter TG (2000) Heat shock proteins--modulators of apoptosis in tumour cells. Leukemia 14:1161–1173CrossRefGoogle Scholar
  102. 102.
    Jäättelä M, Wissing D, Kokholm K, Kallunki T, Egeblad M (1998) Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J 17:6124–6134CrossRefGoogle Scholar
  103. 103.
    Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–483CrossRefGoogle Scholar
  104. 104.
    Takayama S, Reed JC, Homma S (2003) Heat-shock proteins as regulators of apoptosis. Oncogene 22:9041–9047CrossRefGoogle Scholar
  105. 105.
    Gurbuxani S, Schmitt E, Cande C, Parcellier A, Hammann A, Daugas E, Kouranti I, Spahr C, Pance A, Kroemer G, Garrido C (2003) Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22:6669–6678CrossRefGoogle Scholar
  106. 106.
    Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843CrossRefGoogle Scholar
  107. 107.
    Nylandsted J, Rohde M, Brand K, Bastholm L, Elling F, Jäättelä M (2000) Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci U S A 97:7871–7876CrossRefGoogle Scholar
  108. 108.
    Nylandsted J, Wick W, Hirt UA, Brand K, Rohde M, Leist M, Weller M, Jäättelä M (2002) Eradication of glioblastoma, and breast and colon carcinoma xenografts by Hsp70 depletion. Cancer Res 62:7139–7142Google Scholar
  109. 109.
    Ishii T, Udono H, Yamano T, Ohta H, Uenaka A, Ono T, Hizuta A, Tanaka N, Srivastava PK, Nakayama E (1999) Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. J Immunol 162:1303–1309Google Scholar
  110. 110.
    Multhoff G (2002) Activation of natural killer cells by heat shock protein 70. Int J Hyperthermia 18:576–585CrossRefGoogle Scholar
  111. 111.
    Rérole AL, Gobbo J, De Thonel A, Schmitt E, Pais de Barros JP, Hammann A, Lanneau D, Fourmaux E, Deminov O, Micheau O, Lagrost L, Colas P, Kroemer G, Garrido C (2011) Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy. Cancer Res 71(2):484–495CrossRefGoogle Scholar
  112. 112.
    Srivastava PK (2008) New jobs for ancient chaperones. Sci Am 299:50–55CrossRefGoogle Scholar
  113. 113.
    Stangl S, Gehrmann M, Riegger J, Kuhs K, Riederer I, Sievert W, Hube K, Mocikat R, Dressel R, Kremmer E, Pockley AG, Friedrich L, Vigh L, Skerra A, Multhoff G (2011) Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody. Proc Natl Acad Sci U S A 108(2):733–738CrossRefGoogle Scholar
  114. 114.
    Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem 53:4585–4602CrossRefGoogle Scholar
  115. 115.
    Kaiser M, Kühnl A, Reins J, Fischer S, Ortiz-Tanchez J, Schlee C, Mochmann LH, Heesch S, Benlasfer O, Hofmann WK, Thiel E, Baldus CD (2011) Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia. Blood Cancer J 1(7):e28. doi: 10.1038/bcj.2011.28 CrossRefGoogle Scholar
  116. 116.
    Massey AJ, Williamson DS, Browne H, Murray JB, Dokurno P, Shaw T, Macias AT, Daniels Z, Geoffroy S, Dopson M, Lavan P, Matassova N, Francis GL, Graham CJ, Parsons R, Wang Y, Padfield A, Comer M, Drysdale MJ, Wood M (2010) A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 66(3):535–545CrossRefGoogle Scholar
  117. 117.
    Reikvam H, Nepstad I, Sulen A, Gjertsen BT, Hatfield KJ, Bruserud Ø (2013) Increased antileukemic effects in human acute myeloid leukemia by combining HSP70 and HSP90 inhibitors. Expert Opin Investig Drugs 22:551–563CrossRefGoogle Scholar
  118. 118.
    Williamson DS, Borgognoni J, Clay A, Daniels Z, Dokurno P, Drysdale MJ, Foloppe N, Francis GL, Graham CJ, Howes R, Macias AT, Murray JB, Parsons R, Shaw T, Surgenor AE, Terry L, Wang Y, Wood M, Massey AJ (2009) Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J Med Chem 52:1510–1513CrossRefGoogle Scholar
  119. 119.
    Leu JI, Pimkina J, Frank A, Murphy ME, George DL (2009) A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 36(1):15–27CrossRefGoogle Scholar
  120. 120.
    Fewell SW, Smith CM, Lyon MA, Dumitrescu TP, Wipf P, Day BW, Brodsky JL (2004) Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. J Biol Chem 279(49):51131–51140CrossRefGoogle Scholar
  121. 121.
    Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC, Kang Y, She Y, Wu N, Felts S, Wipf P, Massague J, Jiang X, Brodsky JL, Krystal GW, Chiosis G (2007) Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol 3:498–507CrossRefGoogle Scholar
  122. 122.
    Estey EH (2012) Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 87:89–99CrossRefGoogle Scholar
  123. 123.
    Kaufmann SH, Karp JE, Litzow MR, Mesa RA, Hogan W, Steensma DP, Flatten KS, Loegering DA, Schneider PA, Peterson KL, Maurer MJ, Smith BD, Greer J, Chen Y, Reid JM, Ivy SP, Ames MM, Adjei AA, Erlichman C, Karnitz LM (2011) Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia. Haematologica 96:1619–1626CrossRefGoogle Scholar
  124. 124.
    Reikvam H, Ersvaer E, Bruserud O (2009) Heat shock protein 90 - a potential target in the treatment of human acute myelogenous leukemia. Curr Cancer Drug Targets 9:761–776CrossRefGoogle Scholar
  125. 125.
    Wisen S, Bertelsen EB, Thompson AD, Patury S, Ung P, Chang L, Evans CG, Walter GM, Wipf P, Carlson HA, Brodsky JL, Zuiderweg ER, Gestwicki JE (2010) Binding of a small molecule at a protein-protein interface regulates the chaperone activity of hsp70-hsp40. ACS Chem Biol 5(6):611–622CrossRefGoogle Scholar
  126. 126.
    Braunstein MJ, Scott SS, Scott CM, Behrman S, Walter P, Wipf P, Coplan JD, Chrico W, Joseph D, Brodsky JL, Batuman O (2011) Antimyeloma effects of the heat shock protein 70 molecular chaperone inhibitor MAL3-101. J Oncol 2011:232037CrossRefGoogle Scholar
  127. 127.
    Schmitt E, Maingret L, Puig PE, Rerole AL, Ghiringhelli F, Hammann A, Solary E, Kroemer G, Garrido C (2006) Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma. Cancer Res 66:4191–4197CrossRefGoogle Scholar
  128. 128.
    Schmitt E, Parcellier A, Gurbuxani S, Cande C, Hammann A, Morales MC, Hunt CR, Dix DJ, Kroemer RT, Giordanetto F, Jäättelä M, Penninger JM, Pance A, Kroemer G, Garrido C (2003) Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant. Cancer Res 63(23):8233–8240Google Scholar
  129. 129.
    Matsumori Y, Hong SM, Aoyama K, Fan Y, Kayama T, Sheldon RA, Vexler ZS, Ferriero DM, Weinstein PR, Liu J (2005) Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. J Cereb Blood Flow Metab 25:899–910CrossRefGoogle Scholar
  130. 130.
    Daugaard M, Rohde M, Jäättelä M (2007) The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett 581:3702–3710CrossRefGoogle Scholar
  131. 131.
    Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5:2592–2601CrossRefGoogle Scholar
  132. 132.
    Sherman M, Multhoff G (2007) Heat shock proteins in cancer. Ann N Y Acad Sci 1113:192–201CrossRefGoogle Scholar
  133. 133.
    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, Judson I (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23:4152–4161CrossRefGoogle Scholar
  134. 134.
    Banerji U, Walton M, Raynaud F, Grimshaw R, Kelland L, Valenti M, Judson I, Workman P (2005) 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 11:7023–7032CrossRefGoogle Scholar
  135. 135.
    Goetz MP, Toft D, Reid J, Ames M, Stensgard B, Safgren S, Adjei AA, Sloan J, Atherton P, Vasile V, Salazaar S, Adjei A, Croghan G, Erlichman C (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23:1078–1087CrossRefGoogle Scholar
  136. 136.
    Hostein I, Robertson D, DiStefano F, Workman P, Clarke PA (2001) Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res 61:4003–4009Google Scholar
  137. 137.
    Gabai VL, Budagova KR, Sherman MY (2005) 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 24:3328–3338CrossRefGoogle Scholar
  138. 138.
    Yoon YJ, Kim JA, Shin KD, Shin DS, Han YM, Lee YJ, Lee JS, Kwon BM, Han DC (2011) KRIBB11 inhibits HSP70 synthesis through inhibition of heat shock factor 1 function by impairing the recruitment of positive transcription elongation factor b to the hsp70 promoter. J Biol Chem 286(3):1737–1747CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Faculty of Science, School of ChemistryUniversity of New South WalesSydneyAustralia

Personalised recommendations