Skip to main content
SpringerLink
Log in

Organelle-specific Hsp90 inhibitors

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that is involved in the folding, activation, and stabilization of numerous oncogenic proteins. It has become an attractive therapeutic target, especially for eradicating malignant cancers and overcoming chemotherapy resistance. The Hsp90 family in mammalian cells is composed of four major homologs: Hsp90α, Hsp90β, 94-kDa glucose-regulated protein (Grp94), and TNF receptor-associated protein 1 (Trap1). Hsp90α and Hsp90β are mainly localized in the cytoplasm, while Grp94 and Trap1 reside in the endoplasmic reticulum and the mitochondria, respectively. Additionally, some Hsp90 s are secreted from the cytoplasm, commonly called extracellular Hsp90. Interestingly, each Hsp90 isoform is localized in a particular organelle, possesses a unique biological function, and participates in various physiological and pathological processes. To inhibit the organelle-specific Hsp90 chaperone function, there have been significant efforts to accumulate Hsp90 inhibitors in particular cellular compartments. This review introduces current studies regarding the delivery of Hsp90 inhibitors to subcellular organelles, particularly to the extracellular matrix and the mitochondria, and discusses their biological insights and therapeutic implications.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Aggarwal, S. 2010. Targeted cancer therapies. Nature Reviews Drug Discovery 9: 427–428.

    Article  CAS  PubMed  Google Scholar 

  • Allan, R.K., D. Mok, B.K. Ward, and T. Ratajczak. 2006. Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90: Evidence that coumarin antibiotics disrupt Hsp90 dimerization. Journal of Biological Chemistry 281: 7161–7171.

    Article  CAS  PubMed  Google Scholar 

  • Baines, C.P., R.A. Kaiser, N.H. Purcell, N.S. Blair, H. Osinska, M.A. Hambleton, E.W. Brunskill, M.R. Sayen, R.A. Gottlieb, G.W. Dorn, J. Robbins, and J.D. Molkentin. 2005. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658–662.

    Article  CAS  PubMed  Google Scholar 

  • Basso, E., L. Fante, J. Fowlkes, V. Petronilli, M.A. Forte, and P. Bernardi. 2005. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. Journal of Biological Chemistry 280: 18558–18561.

    Article  CAS  PubMed  Google Scholar 

  • Becker, B., G. Multhoff, B. Farkas, P.J. Wild, M. Landthaler, W. Stolz, and T. Vogt. 2004. Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Experimental Dermatology 13: 27–32.

    Article  CAS  PubMed  Google Scholar 

  • Bohonowych, J.E., M.W. Hance, K.D. Nolan, M. Defee, C.H. Parsons, and J.S. Isaacs. 2014. Extracellular Hsp90 mediates an NF-kappaB dependent inflammatory stromal program: Implications for the prostate tumor microenvironment. Prostate 74: 395–407.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Boran, A.D., and R. Iyengar. 2010. Systems approaches to polypharmacology and drug discovery. Current Opinion in Drug Discovery & Development 13: 297–309.

    CAS  Google Scholar 

  • Brough, P.A., W. Aherne, X. Barril, J. Borgognoni, K. Boxall, J.E. Cansfield, K.M. Cheung, I. Collins, N.G. Davies, M.J. Drysdale, B. Dymock, S.A. Eccles, H. Finch, A. Fink, A. Hayes, R. Howes, R.E. Hubbard, K. James, A.M. Jordan, A. Lockie, V. Martins, A. Massey, T.P. Matthews, E. McDonald, C.J. Northfield, L.H. Pearl, C. Prodromou, S. Ray, F.I. Raynaud, S.D. Roughley, S.Y. Sharp, A. Surgenor, D.L. Walmsley, P. Webb, M. Wood, P. Workman, and L. Wright. 2008. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: Potential therapeutic agents for the treatment of cancer. Journal of Medicinal Chemistry 51: 196–218.

    Article  CAS  PubMed  Google Scholar 

  • Burgess, E.F., A.J. Ham, D.L. Tabb, D. Billheimer, B.J. Roth, S.S. Chang, M.S. Cookson, T.J. Hinton, K.L. Cheek, S. Hill, and J.A. Pietenpol. 2008. Prostate cancer serum biomarker discovery through proteomic analysis of alpha-2 macroglobulin protein complexes. Proteomics Clinical Applications 2: 1223.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chaffer, C.L., and R.A. Weinberg. 2011. A perspective on cancer cell metastasis. Science 331: 1559–1564.

    Article  CAS  PubMed  Google Scholar 

  • Chen, B., W.H. Piel, L. Gui, E. Bruford, and A. Monteiro. 2005. The HSP90 family of genes in the human genome: Insights into their divergence and evolution. Genomics 86: 627–637.

    Article  CAS  PubMed  Google Scholar 

  • Chen, C.F., Y. Chen, K. Dai, P.L. Chen, D.J. Riley, and W.H. Lee. 1996. A new member of the hsp90 family of molecular chaperones interacts with the retinoblastoma protein during mitosis and after heat shock. Molecular and Cellular Biology 16: 4691–4699.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen, J.S., Y.M. Hsu, C.C. Chen, L.L. Chen, C.C. Lee, and T.S. Huang. 2010. Secreted heat shock protein 90alpha induces colorectal cancer cell invasion through CD91/LRP-1 and NF-kappaB-mediated integrin alphaV expression. Journal of Biological Chemistry 285: 25458–25466.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Costantino, E., F. Maddalena, S. Calise, A. Piscazzi, V. Tirino, A. Fersini, A. Ambrosi, V. Neri, F. Esposito, and M. Landriscina. 2009. TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptotis in human colorectal carcinoma cells. Cancer Letters 279: 39–46.

    Article  CAS  PubMed  Google Scholar 

  • Eustace, B.K., T. Sakurai, J.K. Stewart, D. Yimlamai, C. Unger, C. Zehetmeier, B. Lain, C. Torella, S.W. Henning, G. Beste, B.T. Scroggins, L. Neckers, L.L. Ilag, and D.G. Jay. 2004. Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nature Cell Biology 6: 507–514.

    Article  CAS  PubMed  Google Scholar 

  • Fang, W., X. Li, Q. Jiang, Z. Liu, H. Yang, S. Wang, S. Xie, Q. Liu, T. Liu, J. Huang, W. Xie, Z. Li, Y. Zhao, E. Wang, F.M. Marincola, and K. Yao. 2008. Transcriptional patterns, biomarkers and pathways characterizing nasopharyngeal carcinoma of Southern China. Journal of Translational Medicine 6: 32.

    Article  PubMed Central  PubMed  Google Scholar 

  • Felts, S.J., B.A. Owen, P. Nguyen, J. Trepel, D.B. Donner, and D.O. Toft. 2000. The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. Journal of Biological Chemistry 275: 3305–3312.

    Article  CAS  PubMed  Google Scholar 

  • Hance, M.W., K. Dole, U. Gopal, J.E. Bohonowych, A. Jezierska-Drutel, C.A. Neumann, H. Liu, I.P. Garraway, and J.S. Isaacs. 2012. Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. Journal of Biological Chemistry 287: 37732–37744.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jeong, C.H., H.B. Park, W.J. Jang, S.H. Jung, and Y.H. Seo. 2014. Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC). Bioorganic & Medicinal Chemistry Letters 24: 224–227.

    Article  CAS  Google Scholar 

  • Kang, B.H., and D.C. Altieri. 2009. Compartmentalized cancer drug discovery targeting mitochondrial Hsp90 chaperones. Oncogene 28: 3681–3688.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kang, B.H., J. Plescia, T. Dohi, J. Rosa, S.J. Doxsey, and D.C. Altieri. 2007. Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131: 257–270.

    Article  CAS  PubMed  Google Scholar 

  • Kang, B.H., J. Plescia, H.Y. Song, M. Meli, G. Colombo, K. Beebe, B. Scroggins, L. Neckers, and D.C. Altieri. 2009. Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. Journal of Clinical Investigation 119: 454–464.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Karagiannis, E.D., and A.S. Popel. 2006. Distinct modes of collagen type I proteolysis by matrix metalloproteinase (MMP) 2 and membrane type I MMP during the migration of a tip endothelial cell: Insights from a computational model. Journal of Theoretical Biology 238: 124–145.

    Article  CAS  PubMed  Google Scholar 

  • Kusuma, B.R., A. Khandelwal, W. Gu, D. Brown, W. Liu, G. Vielhauer, J. Holzbeierlein, and B.S. Blagg. 2014. Synthesis and biological evaluation of coumarin replacements of novobiocin as Hsp90 inhibitors. Bioorganic & Medicinal Chemistry 22: 1441–1449.

    Article  CAS  Google Scholar 

  • Landriscina, M., M.R. Amoroso, A. Piscazzi, and F. Esposito. 2010. Heat shock proteins, cell survival and drug resistance: The mitochondrial chaperone TRAP1, a potential novel target for ovarian cancer therapy. Gynecologic Oncology 117: 177–182.

    Article  CAS  PubMed  Google Scholar 

  • Leav, I., J. Plescia, H.L. Goel, J. Li, Z. Jiang, R.J. Cohen, L.R. Languino, and D.C. Altieri. 2010. Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. American Journal of Pathology 176: 393–401.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee, T., and Y.H. Seo. 2013. Targeting the hydrophobic region of Hsp90’s ATP binding pocket with novel 1,3,5-triazines. Bioorganic & Medicinal Chemistry Letters 23: 6427–6431.

    Article  CAS  Google Scholar 

  • Leskovar, A., H. Wegele, N.D. Werbeck, J. Buchner, and J. Reinstein. 2008. The ATPase cycle of the mitochondrial Hsp90 analog Trap1. Journal of Biological Chemistry 283: 11677–11688.

    Article  CAS  PubMed  Google Scholar 

  • Li, W., D. Sahu, and F. Tsen. 2012a. Secreted heat shock protein-90 (Hsp90) in wound healing and cancer. Biochimica et Biophysica Acta 1823: 730–741.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li, Y., G.E. Karagoz, Y.H. Seo, T. Zhang, Y. Jiang, Y. Yu, A.M. Duarte, S.J. Schwartz, R. Boelens, K. Carroll, S.G. Rudiger, and D. Sun. 2012b. Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50(Cdc37) complex and direct interactions with amino acids residues of Hsp90. Journal of Nutritional Biochemistry 23: 1617–1626.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mahalingam, D., R. Swords, J.S. Carew, S.T. Nawrocki, K. Bhalla, and F.J. Giles. 2009. Targeting HSP90 for cancer therapy. British Journal of Cancer 100: 1523–1529.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Marcu, M.G., T.W. Schulte, and L. Neckers. 2000. Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins. Journal of the National Cancer Institute 92: 242–248.

    Article  CAS  PubMed  Google Scholar 

  • Masuda, Y., G. Shima, T. Aiuchi, M. Horie, K. Hori, S. Nakajo, S. Kajimoto, T. Shibayama-Imazu, and K. Nakaya. 2004. Involvement of tumor necrosis factor receptor-associated protein 1 (TRAP1) in apoptosis induced by beta-hydroxyisovalerylshikonin. Journal of Biological Chemistry 279: 42503–42515.

    Article  CAS  PubMed  Google Scholar 

  • McCready, J., J.D. Sims, D. Chan, and D.G. Jay. 2010. Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: A role for plasminogen activation. BMC Cancer 10: 294.

    Article  PubMed Central  PubMed  Google Scholar 

  • McCready, J., D.S. Wong, J.A. Burlison, W. Ying, and D.G. Jay. 2014. An Impermeant Ganetespib Analog Inhibits Extracellular Hsp90-Mediated Cancer Cell Migration that Involves Lysyl Oxidase 2-like Protein. Cancers (Basel) 6: 1031–1046.

    Article  Google Scholar 

  • Milane, L., M. Trivedi, A. Singh, M. Talekar, and M. Amiji. 2015. Mitochondrial biology, targets, and drug delivery. Journal of Controlled Release 207: 40–58.

    Article  CAS  PubMed  Google Scholar 

  • Montesano Gesualdi, N., G. Chirico, G. Pirozzi, E. Costantino, M. Landriscina, and F. Esposito. 2007. Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. Stress 10: 342–350.

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa, T., S. Shimizu, T. Watanabe, O. Yamaguchi, K. Otsu, H. Yamagata, H. Inohara, T. Kubo, and Y. Tsujimoto. 2005. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434: 652–658.

    Article  CAS  PubMed  Google Scholar 

  • Patten, D.A., M. Germain, M.A. Kelly, and R.S. Slack. 2010. Reactive oxygen species: Stuck in the middle of neurodegeneration. Journal of Alzheimer’s Disease 20(Suppl 2): S357–S367.

    PubMed  Google Scholar 

  • Petrelli, A., and S. Giordano. 2008. From single- to multi-target drugs in cancer therapy: When aspecificity becomes an advantage. Current Medicinal Chemistry 15: 422–432.

    Article  CAS  PubMed  Google Scholar 

  • Pimienta, G., K.M. Herbert, and L. Regan. 2011. A compound that inhibits the HOP-Hsp90 complex formation and has unique killing effects in breast cancer cell lines. Molecular Pharmaceutics 8: 2252–2261.

    Article  CAS  PubMed  Google Scholar 

  • Proia, D.A., and R.C. Bates. 2014. Ganetespib and HSP90: Translating preclinical hypotheses into clinical promise. Cancer Research 74: 1294–1300.

    Article  CAS  PubMed  Google Scholar 

  • Rajendran, L., V. Udayar, and Z.V. Goodger. 2012. Lipid-anchored drugs for delivery into subcellular compartments. Trends in Pharmacological Sciences 33: 215–222.

    Article  CAS  PubMed  Google Scholar 

  • Schleiff, E., and T. Becker. 2011. Common ground for protein translocation: Access control for mitochondria and chloroplasts. Nature Reviews Molecular Cell Biology 12: 48–59.

    Article  CAS  PubMed  Google Scholar 

  • Segarra, M., C. Vilardell, K. Matsumoto, J. Esparza, E. Lozano, C. Serra-Pages, A. Urbano-Marquez, K.M. Yamada, and M.C. Cid. 2005. Dual function of focal adhesion kinase in regulating integrin-induced MMP-2 and MMP-9 release by human T lymphoid cells. FASEB Journal 19: 1875–1877.

    Article  PubMed  Google Scholar 

  • Seo, Y.H. 2013. Discovery of licochalcone A as a natural product inhibitor of Hsp90 and its effect on gefitinib resistance in non-small cell lung cancer (NSCLC). Bulletin of the Korean Chemical Society 34: 1917–1920.

    Article  CAS  Google Scholar 

  • Seo, Y.H. 2015. Small molecule inhibitors to disrupt protein-protein interactions of heat shock protein 90 chaperone machinery. Journal of Cancer Prevention 20: 5–11.

    Article  PubMed Central  PubMed  Google Scholar 

  • Seo, Y.H., and S.Y. Park. 2014. Synthesis of flavokawain analogues and their anti-neoplastic effects on drug-resistant cancer cells through Hsp90 inhibition. Bullein of Korean Chemical Society 35: 1154–1158.

    Article  CAS  Google Scholar 

  • Shimamura, T., S.A. Perera, K.P. Foley, J. Sang, S.J. Rodig, T. Inoue, L. Chen, D. Li, J. Carretero, Y.C. Li, P. Sinha, C.D. Carey, C.L. Borgman, J.P. Jimenez, M. Meyerson, W. Ying, J. Barsoum, K.K. Wong, and G.I. Shapiro. 2012. Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer. Clinical Cancer Research 18: 4973–4985.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sidera, K., M. Gaitanou, D. Stellas, R. Matsas, and E. Patsavoudi. 2008. A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2. Journal of Biological Chemistry 283: 2031–2041.

    Article  CAS  PubMed  Google Scholar 

  • Sidera, K., and E. Patsavoudi. 2014. HSP90 inhibitors: Current development and potential in cancer therapy. Recent Patents on Anticancer Drug Discovery 9: 1–20.

    CAS  Google Scholar 

  • Song, H.Y., J.D. Dunbar, Y.X. Zhang, D. Guo, and D.B. Donner. 1995. Identification of a protein with homology to hsp90 that binds the type 1 tumor necrosis factor receptor. Journal of Biological Chemistry 270: 3574–3581.

    Article  CAS  PubMed  Google Scholar 

  • Sotgia, F., U.E. Martinez-Outschoorn, and M.P. Lisanti. 2011. Mitochondrial oxidative stress drives tumor progression and metastasis: Should we use antioxidants as a key component of cancer treatment and prevention? BMC Medicine 9: 62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sreedhar, A.S., E. Kalmar, P. Csermely, and Y.F. Shen. 2004. Hsp90 isoforms: Functions, expression and clinical importance. FEBS Letters 562: 11–15.

    Article  PubMed  Google Scholar 

  • Stellas, D., A. El Hamidieh, and E. Patsavoudi. 2010. Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits. BMC Cell Biology 11: 51.

    Article  PubMed Central  PubMed  Google Scholar 

  • Taipale, M., D.F. Jarosz, and S. Lindquist. 2010. HSP90 at the hub of protein homeostasis: Emerging mechanistic insights. Nature Reviews Molecular Cell Biology 11: 515–528.

    Article  CAS  PubMed  Google Scholar 

  • Thuringer, D., A. Hammann, N. Benikhlef, E. Fourmaux, A. Bouchot, G. Wettstein, E. Solary, and C. Garrido. 2011. Transactivation of the epidermal growth factor receptor by heat shock protein 90 via Toll-like receptor 4 contributes to the migration of glioblastoma cells. Journal of Biological Chemistry 286: 3418–3428.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tsutsumi, S., and L. Neckers. 2007. Extracellular heat shock protein 90: A role for a molecular chaperone in cell motility and cancer metastasis. Cancer Science 98: 1536–1539.

    Article  CAS  PubMed  Google Scholar 

  • Tsutsumi, S., B. Scroggins, F. Koga, M.J. Lee, J. Trepel, S. Felts, C. Carreras, and L. Neckers. 2008. A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion. Oncogene 27: 2478–2487.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang, X., X. Song, W. Zhuo, Y. Fu, H. Shi, Y. Liang, M. Tong, G. Chang, and Y. Luo. 2009. The regulatory mechanism of Hsp90alpha secretion and its function in tumor malignancy. Proceedings of the National Academy of Sciences USA 106: 21288–21293.

    Article  CAS  Google Scholar 

  • Whitesell, L., and S.L. Lindquist. 2005. HSP90 and the chaperoning of cancer. Nature Reviews Cancer 5: 761–772.

    Article  CAS  PubMed  Google Scholar 

  • Woodley, D.T., J. Fan, C.F. Cheng, Y. Li, M. Chen, G. Bu, and W. Li. 2009. Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90alpha autocrine signaling to promote keratinocyte migration. Journal of Cell Science 122: 1495–1498.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wright, L., X. Barril, B. Dymock, L. Sheridan, A. Surgenor, M. Beswick, M. Drysdale, A. Collier, A. Massey, N. Davies, A. Fink, C. Fromont, W. Aherne, K. Boxall, S. Sharp, P. Workman, and R.E. Hubbard. 2004. Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms. Chemistry & Biology 11: 775–785.

    Article  CAS  Google Scholar 

  • Yi, F., and L. Regan. 2008. A novel class of small molecule inhibitors of Hsp90. ACS Chemical Biology 3: 645–654.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang, T., A. Hamza, X. Cao, B. Wang, S. Yu, C.G. Zhan, and D. Sun. 2008. A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Molecular Cancer Therapeutics 7: 162–170.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2011-0023605).

Author information

Authors and Affiliations

  1. College of Pharmacy, Keimyung University, Daegu, 704-701, Korea

    Young Ho Seo

Authors
  1. Young Ho Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young Ho Seo.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest with any person or any organization.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seo, Y.H. Organelle-specific Hsp90 inhibitors. Arch. Pharm. Res. 38, 1582–1590 (2015). https://doi.org/10.1007/s12272-015-0636-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-015-0636-1

Keywords

Search

Navigation