Skip to main content
SpringerLink
Log in

Hsp90 inhibitors as promising agents for radiotherapy

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The 90-kD heat shock protein (Hsp90) is an abundant molecular chaperone catalyzing maturation and activation of client proteins. A number of the Hsp90 client proteins are components of cancer cell-associated signaling pathways that ensure unlimited growth of tumors and their resistance to chemotherapy and radiotherapy. Upon inhibition of the Hsp90 chaperone function, such client proteins are destabilized and degraded which disrupts multiple pathways essential for tumor cell survival; hence, pharmacological Hsp90 inhibitors could be applied in anticancer therapy. Several Hsp90-inhibiting compounds are currently tested in preclinical or phase I–III clinical trials as single anticancer agents or in combination with conventional drugs and radiation. The present review summarizes the data characterizing Hsp90 inhibitors as agents that sensitize human tumors to irradiation which may improve the outcome of radiotherapy. We also discuss molecular mechanisms of the Hsp90 inhibition-induced radiosensitization and its selectivity toward cancer cells.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Stravopodis DJ, Margaritis LH, Voutsinas GE (2007) Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr Med Chem 14:3122–3138

    Article  CAS  PubMed  Google Scholar 

  2. Hwang M, Moretti L, Lu B (2009) Hsp90 inhibitors: multi-target antitumor effects and novel combinatorial therapeutic approaches in cancer therapy. Curr Med Chem 16:3081–3092

    Article  CAS  PubMed  Google Scholar 

  3. Kamal A, Thao L, Sensintaffar J, Boehm ZL, MF FLC, Burrows FJ (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410

    Article  CAS  PubMed  Google Scholar 

  4. Zaidi SH, Huddart RA, Harrington KJ (2009) Novel targeted radiosensitisers in cancer treatment. Curr Drug Discov Technol 6:103–34

    Article  CAS  PubMed  Google Scholar 

  5. Russel JS, Burgan W, Oswald KA, Camphausen K, Tofilon PJ (2003) Enhanced cell killing induced by the combination of radiation and the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin: a multitarget approach to radiosensitization. Clin Cancer Res 9:3749–3755

    Google Scholar 

  6. Enmon R, Yang W-H, Ballangrud AM, Solit DB, Heller G, Rosen N, Scher HI, Sgouros G (2003) Combination treatment with 17-N-Allylamino-17-Demethoxy Geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids. Cancer Res 63:8393–8399

    CAS  PubMed  Google Scholar 

  7. Ochel HJ, Gademan G (2006) In vitro combined modality treatment of prostate carcinoma cells with 17-(allylamino)-17-demethoxygeldanamycin and ionizing radiation. Anticancer Res 26:2085–2091

    CAS  PubMed  Google Scholar 

  8. Noguchi M, Yu D, Hirayama R, Ninomiya Y, Sekine E, Kubota N, Ando K, Okayasu R (2006) Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxy- geldanamycin. Biochem Biophys Res Commun 351:658–663

    Article  CAS  PubMed  Google Scholar 

  9. Bull EE, Dote H, Brady KJ, 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

    Article  CAS  PubMed  Google Scholar 

  10. Dote H, Cerna D, Burgan W, Camphausen K, Tofilon PJ (2005) ErbB3 expression predicts tumor cell radiosensitization induced by Hsp90 inhibition. Cancer Res 65:6967–6975

    Article  CAS  PubMed  Google Scholar 

  11. Harashima K, Akimoto T, Nonaka T, Tsuzuki K, Mitsuhashi N, Nakano T (2009) Heat shock protein 90 (Hsp90) chaperone complex inhibitor, radicicol, potentiated radiation-induced cell death in a hormone-sensitive prostate cancer cell line trough degradation of the androgen receptor. Int J Radiat Biol 81:63–76

    Article  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. Bisht KS, Bradbury CM, Mattson D, Kaushal A, Sowers A, Markovina S, Ortiz KL, Sieck LK, Isaacs JS, Brechbiel MW, Mitchell JB, Neckers LM, Gius D (2003) Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity. Cancer Res 63:8984–8995

    CAS  PubMed  Google Scholar 

  14. Dote H, Burgan WE, Camphausen K, Tofilon J (2006) Inhibition of Hsp90 compromises the DNA damage response to radiation. Cancer Res 66:9211–9220

    Article  CAS  PubMed  Google Scholar 

  15. Machida H, Matsumoto Y, Shirai M, Kubota N (2003) Geldanamycin, an inhibitor of Hsp90, sensitizes human tumour cells to radiation. Int J Radiat Biol 79:973–980

    Article  CAS  PubMed  Google Scholar 

  16. Kim WY, Oh SH, Woo JK, Hong WK, Lee HY (2009) Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1α. Cancer Res 69:1624–1632

    Article  CAS  PubMed  Google Scholar 

  17. Koll TT, Feis SS, Wright MH, Teniola MM, Richardson MM, Robles AI, Bradsher J, Capala J, Varticovski L (2008) HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair. Mol Cancer Ther 7:1985–1992

    Article  CAS  PubMed  Google Scholar 

  18. Matsumoto Y, Machida H, Kubota N (2005) Preferential sensitization of tumor cells to radiation by heat shock protein 90 inhibitor geldanamycin. J Radiat Res (Tokyo) 46:215–221

    Article  CAS  Google Scholar 

  19. Kobayashi S, Nantz R, Kitamura T, Higashikubo R, Horikoshi N (2005) Combined inhibition of extracellular signal-regulated kinases and HSP90 sensitizes human colon carcinoma cells to ionizing radiation. Oncogene 24:3011–3019

    Article  CAS  PubMed  Google Scholar 

  20. Mashida H, Nakajima S, Shikano N, Nishio J, Okada S, Asayama M, Shira M, Kubota N (2005) Heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis. Cancer Sci 96:911–917

    Article  Google Scholar 

  21. Shintani S, Zhang T, Aslam A, Sebastian K, Yoshimura T, Hamakawa H (2006) P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines. Int J Oncol 29:1111–1115

    CAS  PubMed  Google Scholar 

  22. Kim IA, No M, Lee JM, Shin JH, Oh JS, Choi EJ, Kim IH, Atadja P, Bernhard EJ (2009) Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: potential role of histone deacetylase 6. Radiother Oncol 92:125–132

    Article  CAS  PubMed  Google Scholar 

  23. Yin X, Zhang H, Lundgren K, Wilson L, Burrows F, Shores CG (2009) BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy. Int J Cancer (in press)

  24. Yi T, Li H, Wang X, Wu Z (2008) Enhancement radiosensitization of breast cancer cells by deguelin. Cancer Biother Radiopharm 23:355–362

    Article  CAS  PubMed  Google Scholar 

  25. Wu X, Wanders A, Wardega P, Tinge B, Gedda L, Bergstrom S, Sooman L, Gullbo J, Bergqvist M, Hesselius P, Lennartsson J, Ekman S (2009) Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin. Br J Cancer 100:334–343

    Article  CAS  PubMed  Google Scholar 

  26. Bagatell R, Paine-Murrieta GD, Taylor CW, Pulcini EJ, Akinaga S, Benjamin IJ, Whitesell L (2000) Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of hsp90-binding agents. Clin Cancer Res 6:3312–3318

    CAS  PubMed  Google Scholar 

  27. O’Callaghan-Sunol C, Gabai VL (2007) Involvement of heat shock proteins in protection of tumor cells from genotoxic stresses. In: Calderwood S, Sherman MY, Ciocca DR (eds) Heat shock proteins in cancer, Springer, pp. 169–190

  28. Kabakov A (2007) Heat shock proteins against radiation-induced apoptosis: facts, hypotheses, prospects. In: Corvin A (ed) New developments in cell apoptosis research. Nova Science Publishers, NY, pp. 121–158

    Google Scholar 

  29. Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, Fuks Z, Kolesnick R (2003) Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:1155–1159

    Article  CAS  PubMed  Google Scholar 

  30. Kabakov AE, Makarova YM, Malyutina YV (2008) Radiosensitization of human endothelial cells through Hsp90 inhibition with 17-N-allilamino-17-demethoxygeldanamycin. Int J Radiat Oncol Biol Phys 71:858–865

    CAS  PubMed  Google Scholar 

  31. Daozhen C, Lu L, Min Y, Xinyu J, Ying H (2007) Synthesis of (131)I-labeled-[(131)I]iodo-17-allylamino-17-demethoxy geldanamycin ([(131)I]iodo-17-AAG) and its biodistribution in mice. Cancer Biother Radiopharm 22:607–612

    Article  PubMed  Google Scholar 

  32. Wenyong T, Lu L, Daozhen C, Weidong Y, Ying H (2009) An experimental study on the antitumor effect of 131I–17-AAG in vitro and in vivo. Ann Nucl Med 23:113–122

    Article  CAS  PubMed  Google Scholar 

  33. Bertram J, Palfner K, Hiddemann W, Kneba M (1996) Increase of P-glycoprotein-mediated drug resistance by hsp90 beta. Anticancer Drugs 7:838–845

    Article  CAS  PubMed  Google Scholar 

  34. Radujkovic A, Schad M, Topaly J, Veldwijk MR, Laufs S, Schultheis BS, Jauch A, Melo JV, Fruehauf S, Zeller WJ (2005) Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL – inhibition of P-glycoprotein function by 17-AAG. Leukemia 19:1198–1206

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest statement

The authors declare that they have no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Radiation Biochemistry, Medical Radiology Research Center, Obninsk, 249036, Russia

    Alexander E. Kabakov & Vladimir A. Kudryavtsev

  2. Department of Biochemistry, Boston University Medical School, Boston, MA, 02118, USA

    Vladimir L. Gabai

  3. Department of Radiation Biochemistry, Medical Radiology Research Center, 4 Korolev Street, Obninsk, 249036, Russia

    Alexander E. Kabakov

Authors
  1. Alexander E. Kabakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vladimir A. Kudryavtsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vladimir L. Gabai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander E. Kabakov.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kabakov, A.E., Kudryavtsev, V.A. & Gabai, V.L. Hsp90 inhibitors as promising agents for radiotherapy. J Mol Med 88, 241–247 (2010). https://doi.org/10.1007/s00109-009-0562-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-009-0562-0

Keywords

Search

Navigation