Skip to main content

Advertisement

Log in

Advances in HSP27 and HSP90-targeting strategies for glioblastoma

  • Topic Review
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. There is a critical need for novel strategies to abolish the molecular mechanisms that support GBM growth, invasion and treatment resistance. The heat shock proteins, HSP27 and HSP90, serve these pivotal roles in tumor cells and have been identified as effective targets for developing therapeutics. Natural and synthetic inhibitors have been evaluated in clinical trials for several forms of systemic cancer but none as yet for GBM. This topic review summarizes the current preclinical evidence and rationale to define the potential of HSP27 and HSP90 inhibitors in GBM management.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, Villano JL (2014) Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomark Prev 23:1985–1996. doi:10.1158/1055-9965.EPI-14-0275

    Article  CAS  Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Eng J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  3. Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Powers MV, Workman P (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581:3758–3769. doi:10.1016/j.febslet.2007.05.040

    Article  CAS  PubMed  Google Scholar 

  5. Ampie L, Choy W, Lamano JB, Fakurnejad S, Bloch O, Parsa AT (2015) Heat shock protein vaccines against glioblastoma: from bench to bedside. J Neurooncol 123:441–448. doi:10.1007/s11060-015-1837-7

    Article  CAS  PubMed  Google Scholar 

  6. Belkacemi L, Hebb MO (2014) HSP27 knockdown produces synergistic induction of apoptosis by HSP90 and kinase inhibitors in glioblastoma multiforme. Anticancer Res 34:4915–4927

    CAS  PubMed  Google Scholar 

  7. Wachsberger PR, Lawrence YR, Liu Y, Rice B, Feo N, Leiby B, Dicker AP (2014) Hsp90 inhibition enhances PI-3 kinase inhibition and radiosensitivity in glioblastoma. J Cancer Res Clin Oncol 140:573–582. doi:10.1007/s00432-014-1594-6

    Article  CAS  PubMed  Google Scholar 

  8. Dungey FA, Caldecott KW, Chalmers AJ (2009) Enhanced radiosensitization of human glioma cells by combining inhibition of poly(ADP-ribose) polymerase with inhibition of heat shock protein 90. Mol Cancer Ther 8:2243–2254. doi:10.1158/1535-7163.MCT-09-0201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772. doi:10.1038/nrc1716

    Article  CAS  PubMed  Google Scholar 

  10. Zoubeidi A, Gleave M (2012) Small heat shock proteins in cancer therapy and prognosis. Int J Biochem Cell Biol 44:1646–1656. doi:10.1016/j.biocel.2012.04.010

    Article  CAS  PubMed  Google Scholar 

  11. Akerfelt M, Morimoto RI, Sistonen L (2010) Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11:545–555. doi:10.1038/nrm2938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nomura N, Nomura M, Sugiyama K, Hamada J (2007) Phorbol 12-myristate 13-acetate (PMA)-induced migration of glioblastoma cells is mediated via p38MAPK/Hsp27 pathway. Biochem Pharmacol 74:690–701. doi:10.1016/j.bcp.2007.06.018

    Article  CAS  PubMed  Google Scholar 

  13. Golembieski WA, Thomas SL, Schultz CR, Yunker CK, McClung HM, Lemke N, Cazacu S, Barker T, Sage EH, Brodie C, Rempel SA (2008) HSP27 mediates SPARC-induced changes in glioma morphology, migration, and invasion. Glia 56:1061–1075. doi:10.1002/glia.20679

    Article  PubMed  Google Scholar 

  14. Aloy MT, Hadchity E, Bionda C, Diaz-Latoud C, Claude L, Rousson R, Arrigo AP, Rodriguez-Lafrasse C (2008) Protective role of Hsp27 protein against gamma radiation-induced apoptosis and radiosensitization effects of Hsp27 gene silencing in different human tumor cells. Int J Radiat Oncol Biol Phys 70:543–553. doi:10.1016/j.ijrobp.2007.08.061

    Article  CAS  PubMed  Google Scholar 

  15. Wang X, Chen M, Zhou J, Zhang X (2014) HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (review). Int J Oncol 45:18–30. doi:10.3892/ijo.2014.2399

    PubMed  Google Scholar 

  16. Jakubowicz-Gil J, Langner E, Badziul D, Wertel I, Rzeski W (2013) Silencing of Hsp27 and Hsp72 in glioma cells as a tool for programmed cell death induction upon temozolomide and quercetin treatment. Toxicol Appl Pharmacol 273:580–589. doi:10.1016/j.taap.2013.10.003

    Article  CAS  PubMed  Google Scholar 

  17. Kamada M, So A, Muramaki M, Rocchi P, Beraldi E, Gleave M (2007) Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells. Mol Cancer Ther 6:299–308. doi:10.1158/1535-7163.MCT-06-0417

    Article  CAS  PubMed  Google Scholar 

  18. Gibert B, Simon S, Dimitrova V, Diaz-Latoud C, Arrigo AP (2013) Peptide aptamers: tools to negatively or positively modulate HSPB1(27) function. Philos Trans R Soc Lond B 368:20120075. doi:10.1098/rstb.2012.0075

    Article  Google Scholar 

  19. Gibert B, Hadchity E, Czekalla A, Aloy MT, Colas P, Rodriguez-Lafrasse C, Arrigo AP, Diaz-Latoud C (2011) Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers. Oncogene 30:3672–3681. doi:10.1038/onc.2011.73

    Article  CAS  PubMed  Google Scholar 

  20. Kim EJ, Choi CH, Park JY, Kang SK, Kim YK (2008) Underlying mechanism of quercetin-induced cell death in human glioma cells. Neurochem Res 33:971–979. doi:10.1007/s11064-007-9416-8

    Article  CAS  PubMed  Google Scholar 

  21. Jakubowicz-Gil J, Langner E, Badziul D, Wertel I, Rzeski W (2014) Quercetin and sorafenib as a novel and effective couple in programmed cell death induction in human gliomas. Neurotox Res 26:64–77. doi:10.1007/s12640-013-9452-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sang DP, Li RJ, Lan Q (2014) Quercetin sensitizes human glioblastoma cells to temozolomide in vitro via inhibition of Hsp27. Acta Pharmacol Sin 35:832–838. doi:10.1038/aps.2014.22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zamin LL, Filippi-Chiela EC, Vargas J, Demartini DR, Meurer L, Souza AP, Bonorino C, Salbego C, Lenz G (2014) Quercetin promotes glioma growth in a rat model. Food Chem Toxicol 63:205–211. doi:10.1016/j.fct.2013.11.002

    Article  CAS  PubMed  Google Scholar 

  24. Sreedhar AS, Kalmar E, Csermely P, Shen YF (2004) Hsp90 isoforms: functions, expression and clinical importance. FEBS Lett 562:11–15

    Article  PubMed  Google Scholar 

  25. Neckers L, Workman P (2012) Hsp90 molecular chaperone inhibitors: are we there yet. Clin Cancer Res 18:64–76. doi:10.1158/1078-0432.CCR-11-1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sato S, Fujita N, Tsuruo T (2000) Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA 97:10832–10837. doi:10.1073/pnas.170276797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Siegelin MD, Plescia J, Raskett CM, Gilbert CA, Ross AH, Altieri DC (2010) Global targeting of subcellular heat shock protein—90 networks for therapy of glioblastoma. Mol Cancer Ther 9:1638–1646. doi:10.1158/1535-7163.MCT-10-0097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kang BH, Plescia J, Dohi T, Rosa J, Doxsey SJ, Altieri DC (2007) Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131:257–270. doi:10.1016/j.cell.2007.08.028

    Article  CAS  PubMed  Google Scholar 

  29. Zagzag D, Nomura M, Friedlander DR, Blanco CY, Gagner JP, Nomura N, Newcomb EW (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 196:394–402. doi:10.1002/jcp.10306

    Article  CAS  PubMed  Google Scholar 

  30. Miekus K, Kijowski J, Sekula M, Majka M (2012) 17AEP-GA, an HSP90 antagonist, is a potent inhibitor of glioblastoma cell proliferation, survival, migration and invasion. Oncol Rep 28:1903–1909. doi:10.3892/or.2012.1996

    CAS  PubMed  Google Scholar 

  31. Garcia-Morales P, Carrasco-Garcia E, Ruiz-Rico P, Martinez-Mira R, Menendez-Gutierrez MP, Ferragut JA, Saceda M, Martinez-Lacaci I (2007) Inhibition of Hsp90 function by ansamycins causes downregulation of cdc2 and cdc25c and G(2)/M arrest in glioblastoma cell lines. Oncogene 26:7185–7193. doi:10.1038/sj.onc.1210534

    Article  CAS  PubMed  Google Scholar 

  32. Sauvageot CM, Weatherbee JL, Kesari S, Winters SE, Barnes J, Dellagatta J, Ramakrishna NR, Stiles CD, Kung AL, Kieran MW, Wen PY (2009) Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro Oncol 11:109–121. doi:10.1215/15228517-2008-060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Newcomb EW, Lukyanov Y, Schnee T, Esencay M, Fischer I, Hong D, Shao Y, Zagzag D (2007) The geldanamycin analogue 17-allylamino-17-demethoxygeldanamycin inhibits the growth of GL261 glioma cells in vitro and in vivo. Anticancer Drugs 18:875–882. doi:10.1097/CAD.0b013e3281430df8

    CAS  PubMed  Google Scholar 

  34. Premkumar DR, Arnold B, Jane EP, Pollack IF (2006) Synergistic interaction between 17-AAG and phosphatidylinositol 3-kinase inhibition in human malignant glioma cells. Mol Carcinog 45:47–59. doi:10.1002/mc.20152

    Article  CAS  PubMed  Google Scholar 

  35. Premkumar DR, Arnold B, Pollack IF (2006) Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growth. Mol Carcinog 45:288–301. doi:10.1002/mc.20141

    Article  CAS  PubMed  Google Scholar 

  36. Jane EP, Pollack IF (2008) The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells. Cancer Lett 268:46–55. doi:10.1016/j.canlet.2008.03.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Boridy S, Le PU, Petrecca K, Maysinger D (2014) Celastrol targets proteostasis and acts synergistically with a heat-shock protein 90 inhibitor to kill human glioblastoma cells. Cell Death Dis 5:e1216. doi:10.1038/cddis.2014.182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Garcia-Carbonero R, Carnero A, Paz-Ares L (2013) Inhibition of HSP90 molecular chaperones: moving into the clinic. Lancet Oncol 14:e358–369. doi:10.1016/S1470-2045(13)70169-4

    Article  CAS  PubMed  Google Scholar 

  39. Egorin MJ, Lagattuta TF, Hamburger DR, Covey JM, White KD, Musser SM, Eiseman JL (2002) Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol 49:7–19

    Article  CAS  PubMed  Google Scholar 

  40. Bull EE, Dote H, Brady K, Burgan WE, Carter DJ, Cerra MA, Oswald KA, Hollingshead MG, Camphausen K, Tofilon PJ (2004) Enhanced tumor cell radiosensitivity and abrogation of G2 and S phase arrest by the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin. Clin Cancer Res 10:8077–8084. doi:10.1158/1078-0432.CCR-04-1212

    Article  CAS  PubMed  Google Scholar 

  41. Massey AJ, Schoepfer J, Brough PA, Brueggen J, Chene P, Drysdale MJ, Pfaar U, Radimerski T, Ruetz S, Schweitzer A, Wood M, Garcia-Echeverria C, Jensen MR (2010) Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor NVP-BEP800. Mol Cancer Ther 9:906–919. doi:10.1158/1535-7163.MCT-10-0055

    Article  CAS  PubMed  Google Scholar 

  42. Hartmann S, Gunther N, Biehl M, Katzer A, Kuger S, Worschech E, Sukhorukov VL, Krohne G, Zimmermann H, Flentje M, Djuzenova CS (2013) Hsp90 inhibition by NVP-AUY922 and NVP-BEP800 decreases migration and invasion of irradiated normoxic and hypoxic tumor cell lines. Cancer Lett 331:200–210. doi:10.1016/j.canlet.2012.12.027

    Article  CAS  PubMed  Google Scholar 

  43. Stingl L, Stuhmer T, Chatterjee M, Jensen MR, Flentje M, Djuzenova CS (2010) Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction. Br J Cancer 102:1578–1591. doi:10.1038/sj.bjc.6605683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wu J, Wang W, Shao Q, Xiao G, Cheng J, Yuan Y, Zhang M (2014) Irradiation facilitates the inhibitory effect of the heat shock protein 90 inhibitor NVP-BEP800 on the proliferation of malignant glioblastoma cells through attenuation of the upregulation of heat shock protein 70. Exp Ther Med 8:893–898. doi:10.3892/etm.2014.1800

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B, Atoyan R, Wang J, Samson M, Forrester J, DellaRocca S, Xu GX, Tao X, Zhai HX, Cai X, Qian C (2009) CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res 15:4046–4057. doi:10.1158/1078-0432.CCR-09-0152

    Article  CAS  PubMed  Google Scholar 

  46. Yin X, Zhang H, Lundgren K, Wilson L, Burrows F, Shores CG (2010) BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy. Int J Cancer 126:1216–1225. doi:10.1002/ijc.24815

    CAS  PubMed  Google Scholar 

  47. Lundgren K, Zhang H, Brekken J, Huser N, Powell RE, Timple N, Busch DJ, Neely L, Sensintaffar JL, Yang YC, McKenzie A, Friedman J, Scannevin R, Kamal A, Hong K, Kasibhatla SR, Boehm MF, Burrows FJ (2009) BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol Cancer Ther 8:921–929. doi:10.1158/1535-7163.MCT-08-0758

    Article  CAS  PubMed  Google Scholar 

  48. Azoitei N, Diepold K, Brunner C, Rouhi A, Genze F, Becher A, Kestler H, van Lint J, Chiosis G, Koren J 3rd, Frohling S, Scholl C, Seufferlein T (2014) HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization. Cancer Res 74:7125–7136. doi:10.1158/0008-5472.CAN-14-1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Beckner ME, Fellows-Mayle W, Zhang Z, Agostino NR, Kant JA, Day BW, Pollack IF (2010) Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int J Cancer 126:2282–2295. doi:10.1002/ijc.24918

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhu H, Woolfenden S, Bronson RT, Jaffer ZM, Barluenga S, Winssinger N, Rubenstein AE, Chen R, Charest A (2010) The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme. Mol Cancer Ther 9:2618–2626. doi:10.1158/1535-7163.MCT-10-0248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lock RB, Carol H, Maris JM, Kang MH, Reynolds CP, Kolb EA, Gorlick R, Keir ST, Billups CA, Kurmasheva RT, Houghton PJ, Smith MA (2013) Initial testing (stage 1) of ganetespib, an Hsp90 inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 60:E42–45. doi:10.1002/pbc.24451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Eccles SA, Massey A, Raynaud FI, Sharp SY, Box G, Valenti M, Patterson L, de Haven Brandon A, Gowan S, Boxall F, Aherne W, Rowlands M, Hayes A, Martins V, Urban F, Boxall K, Prodromou C, Pearl L, James K, Matthews TP, Cheung KM, Kalusa A, Jones K, McDonald E, Barril X, Brough PA, Cansfield JE, Dymock B, Drysdale MJ, Finch H, Howes R, Hubbard RE, Surgenor A, Webb P, Wood M, Wright L, Workman P (2008) NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 68:2850–2860. doi:10.1158/0008-5472.CAN-07-5256

    Article  CAS  PubMed  Google Scholar 

  53. 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 9:1219–1233. doi:10.1158/1535-7163.MCT-09-0683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sessa C, Shapiro GI, Bhalla KN, Britten C, Jacks KS, Mita M, Papadimitrakopoulou V, Pluard T, Samuel TA, Akimov M, Quadt C, Fernandez-Ibarra C, Lu H, Bailey S, Chica S, Banerji U (2013) First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res 19:3671–3680. doi:10.1158/1078-0432.CCR-12-3404

    Article  CAS  PubMed  Google Scholar 

  55. Kang MH, Reynolds CP, Houghton PJ, Alexander D, Morton CL, Kolb EA, Gorlick R, Keir ST, Carol H, Lock R, Maris JM, Wozniak A, Smith MA (2012) Initial testing (stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program. Pediatr Blood Cancer 59:185–188. doi:10.1002/pbc.23154

    Article  PubMed  PubMed Central  Google Scholar 

  56. Canella A, Xu J, Yoo JY, Kaur B, Nagarajan P, Kesanakurti D, Puduvalli VK (2015) Characterization of the activity of AT13387, a novel second generation HSP90 inhibitor against gliomas. Neuro Oncol 17:1. doi:10.1093/neuonc/nov204.05

    Article  Google Scholar 

  57. Spiegelberg D, Dascalu A, Mortensen AC, Abramenkovs A, Kuku G, Nestor M, Stenerlow B (2015) The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells. Oncotarget 6:35652–35666. doi:10.18632/oncotarget.5363

    PubMed  Google Scholar 

  58. Spreafico A, Delord JP, De Mattos-Arruda L, Berge Y, Rodon J, Cottura E, Bedard PL, Akimov M, Lu H, Pain S, Kaag A, Siu LL, Cortes J (2015) A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies. Br J Cancer 112:650–659. doi:10.1038/bjc.2014.653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Altieri DC, Stein GS, Lian JB, Languino LR (2012) TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta 1823:767–773. doi:10.1016/j.bbamcr.2011.08.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Shen Y, Li J, Nitta M, Futalan D, Steed T, Treiber JM, Taich Z, Stevens D, Wykosky J, Chen HZ, Carter BS, Becher OJ, Kennedy R, Esashi F, Sarkaria JN, Furnari FB, Cavenee WK, Desai A, Chen CC (2015) Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition. Oncotarget 6:11751–11767. doi:10.18632/oncotarget.3996

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthew O. Hebb.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van Ommeren, R., Staudt, M.D., Xu, H. et al. Advances in HSP27 and HSP90-targeting strategies for glioblastoma. J Neurooncol 127, 209–219 (2016). https://doi.org/10.1007/s11060-016-2070-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-016-2070-8

Keywords

Navigation