Annals of Oncology 14:1169-1176, 2003
© 2003 European Society for Medical Oncology
Review Article |
The Hsp90 chaperone complex as a novel target for cancer therapy
Division Medical Oncology, Department of Biochemistry and Molecular Biology, Division of Developmental Oncology Research and Mayo Graduate School, Rochester, MN 55905, USA
Received 12 February 2003; accepted 11 March 2003
Abstract
Background:
Heat shock protein 90 (Hsp90) is responsible for chaperoning proteins involved in cell signaling, proliferation and survival. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an anticancer agent currently in phase I trials in the USA and UK. It represents a class of drugs, the benzoquinone ansamycin antibiotics, capable of binding and disrupting the function of Hsp90, leading to the depletion of multiple oncogenic client proteins.
Materials and methods:
Studies were identified through a PubMed search, review of bibliographies of relevant articles and review of abstracts from national meetings.
Results:
Preclinical studies have demonstrated that disruption of many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. Following an overview of the mechanism of action of ansamycin antibiotics and the pathways they disrupt, we review the current clinical status of 17-AAG, and discuss future directions for combinations of traditional antineoplastics with 17-AAG.
Conclusions:
17-AAG represents a class of drugs capable of affecting multiple targets in the signal transduction pathway involved in tumor cell proliferation and survival. Early results from phase I studies indicate that 17-AAG administration results in an acceptable toxicity profile while achieving in vivo disruption of client proteins.
Key words: 17-AAG, heat shock protein, Hsp90
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. J. Myung, J.-H. Yoon, B. H. Kim, J.-H. Lee, E. U. Jung, and H.-S. Lee Heat Shock Protein 90 Inhibitor Induces Apoptosis and Attenuates Activation of Hepatic Stellate Cells J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 276 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Y. Zhong, J.-H. Ding, J. A. Adams, G. Ghosh, and X.-D. Fu Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones Genes & Dev., February 15, 2009; 23(4): 482 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. McCollum, K. B. Lukasiewicz, C. J. TenEyck, W. L. Lingle, D. O. Toft, and C. Erlichman Cisplatin abrogates the geldanamycin-induced heat shock response Mol. Cancer Ther., October 1, 2008; 7(10): 3256 - 3264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. McCollum, C. J. TenEyck, B. Stensgard, B. W. Morlan, K. V. Ballman, R. B. Jenkins, D. O. Toft, and C. Erlichman P-Glycoprotein-Mediated Resistance to Hsp90-Directed Therapy Is Eclipsed by the Heat Shock Response Cancer Res., September 15, 2008; 68(18): 7419 - 7427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Pedersen, I. H. Madshus, C. Haslekas, and E. Stang Geldanamycin-Induced Down-Regulation of ErbB2 from the Plasma Membrane Is Clathrin Dependent but Proteasomal Activity Independent Mol. Cancer Res., March 1, 2008; 6(3): 491 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Poulaki, E. Iliaki, N. Mitsiades, C. S. Mitsiades, Y. N. Paulus, D. V. Bula, E. S. Gragoudas, and J. W. Miller Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis FASEB J, July 1, 2007; 21(9): 2113 - 2123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bae, C. Mitsiades, Y.-T. Tai, R. Bertheau, M. Shammas, R. B. Batchu, C. Li, L. Catley, R. Prabhala, K. C. Anderson, et al. Phenotypic and Functional Effects of Heat Shock Protein 90 Inhibition on Dendritic Cell J. Immunol., June 15, 2007; 178(12): 7730 - 7737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Mizuno, S. Khurts, T. Seki, Y. Hirota, S. Kaneko, and S. Murakami Human Telomerase Exists in Two Distinct Active Complexes In Vivo J. Biochem., May 1, 2007; 141(5): 641 - 652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xu and L. Neckers Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells Clin. Cancer Res., March 15, 2007; 13(6): 1625 - 1629. [Full Text] [PDF]
|
|
|
|
|
|
R. K. Ramanathan, M. J. Egorin, J. L. Eiseman, S. Ramalingam, D. Friedland, S. S. Agarwala, S. P. Ivy, D. M. Potter, G. Chatta, E. G. Zuhowski, et al. Phase I and Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin in Adult Patients with Refractory Advanced Cancers Clin. Cancer Res., March 15, 2007; 13(6): 1769 - 1774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Stellas, A. Karameris, and E. Patsavoudi Monoclonal Antibody 4C5 Immunostains Human Melanomas and Inhibits Melanoma Cell Invasion and Metastasis Clin. Cancer Res., March 15, 2007; 13(6): 1831 - 1838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Tiligada Chemotherapy: induction of stress responses Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S115 - S124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Sydor, E. Normant, C. S. Pien, J. R. Porter, J. Ge, L. Grenier, R. H. Pak, J. A. Ali, M. S. Dembski, J. Hudak, et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90 PNAS, November 14, 2006; 103(46): 17408 - 17413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Nowakowski, A. K. McCollum, M. M. Ames, S. J. Mandrekar, J. M. Reid, A. A. Adjei, D. O. Toft, S. L. Safgren, and C. Erlichman A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer. Clin. Cancer Res., October 15, 2006; 12(20): 6087 - 6093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Guo, P. Reigan, D. Siegel, J. Zirrolli, D. Gustafson, and D. Ross The Bioreduction of a Series of Benzoquinone Ansamycins by NAD(P)H:Quinone Oxidoreductase 1 to More Potent Heat Shock Protein 90 Inhibitors, the Hydroquinone Ansamycins Mol. Pharmacol., October 1, 2006; 70(4): 1194 - 1203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. Barker, A. V. McNamara, S. A. Rackstraw, D. E. Nelson, M. R. White, A. J. M. Watson, and J. R. Jenkins Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage Nucleic Acids Res., February 16, 2006; 34(4): 1148 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Compton, L. W. Elmore, K. Haydu, C. K. Jackson-Cook, and S. E. Holt Induction of Nitric Oxide Synthase-Dependent Telomere Shortening after Functional Inhibition of Hsp90 in Human Tumor Cells Mol. Cell. Biol., February 15, 2006; 26(4): 1452 - 1462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Wan, M. S. Albom, L. Lu, M. R. Quail, N. C. Becknell, L. R. Weinberg, D. R. Reddy, B. P. Holskin, T. S. Angeles, T. L. Underiner, et al. Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells Blood, February 15, 2006; 107(4): 1617 - 1623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. H. Arlander, S. J. Felts, J. M. Wagner, B. Stensgard, D. O. Toft, and L. M. Karnitz Chaperoning Checkpoint Kinase 1 (Chk1), an Hsp90 Client, with Purified Chaperones J. Biol. Chem., February 3, 2006; 281(5): 2989 - 2998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. V. Georgakis, Y. Li, G. Z. Rassidakis, H. Martinez-Valdez, L. J. Medeiros, and A. Younes Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal-Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death Clin. Cancer Res., January 15, 2006; 12(2): 584 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Ohji, S. Hidayat, A. Nakashima, C. Tokunaga, N. Oshiro, K.-i. Yoshino, K. Yokono, U. Kikkawa, and K. Yonezawa Suppression of the mTOR-Raptor Signaling Pathway by the Inhibitor of Heat Shock Protein 90 Geldanamycin J. Biochem., January 1, 2006; 139(1): 129 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ma, V. Lakshmikanthan, R. W. Lewis, and M. V. Kumar Sensitization of TRAIL-resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin Mol. Cancer Ther., January 1, 2006; 5(1): 170 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. O. Ibrahim, T. Hahn, C. Franke, D. P. Stiehl, R. Wirthner, R. H. Wenger, and D. M. Katschinski Induction of the Hypoxia-Inducible Factor System by Low Levels of Heat Shock Protein 90 Inhibitors Cancer Res., December 1, 2005; 65(23): 11094 - 11100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Chung, S. Lee, E. A. Sausville, Q. Ryan, J. E. Karp, I. Gojo, W. G. Telford, M.-J. Lee, H. S. Kong, and J. B. Trepel Histone Deacetylase Inhibitor Pharmacodynamic Analysis by Multiparameter Flow Cytometry Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 397 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cortes and H. Kantarjian New Targeted Approaches in Chronic Myeloid Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6316 - 6324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Mesa, D. Loegering, H. L. Powell, K. Flatten, S. J. H. Arlander, N. T. Dai, M. P. Heldebrant, B. T. Vroman, B. D. Smith, J. E. Karp, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine Blood, July 1, 2005; 106(1): 318 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yin, H. Zhang, F. Burrows, L. Zhang, and C. G. Shores Potent Activity of a Novel Dimeric Heat Shock Protein 90 Inhibitor against Head and Neck Squamous Cell Carcinoma In vitro and In vivo Clin. Cancer Res., May 15, 2005; 11(10): 3889 - 3896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Ramanathan, D. L. Trump, J. L. Eiseman, C. P. Belani, S. S. Agarwala, E. G. Zuhowski, J. Lan, D. M. Potter, S. P. Ivy, S. Ramalingam, 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., May 1, 2005; 11(9): 3385 - 3391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Kim, S.-M. Park, M. R. Kang, S.-Y. Oh, T. H. Lee, M. T. Muller, and I. K. Chung Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT Genes & Dev., April 1, 2005; 19(7): 776 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Goetz, D. Toft, J. Reid, M. Ames, B. Stensgard, S. Safgren, A. A. Adjei, J. Sloan, P. Atherton, V. Vasile, et al. Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients With Advanced Cancer J. Clin. Oncol., February 20, 2005; 23(6): 1078 - 1087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]
|
|
|
|
|
|
D. K. Marsee, A. Venkateswaran, H. Tao, D. Vadysirisack, Z. Zhang, D. D. Vandre, and S. M. Jhiang Inhibition of Heat Shock Protein 90, a Novel RET/PTC1-associated Protein, Increases Radioiodide Accumulation in Thyroid Cells J. Biol. Chem., October 15, 2004; 279(42): 43990 - 43997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bagatell and L. Whitesell Altered Hsp90 function in cancer: A unique therapeutic opportunity Mol. Cancer Ther., August 1, 2004; 3(8): 1021 - 1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cortes, D. Thomas, C. Koller, F. Giles, E. Estey, S. Faderl, G. Garcia-Manero, D. McConkey, G. Patel, R. Guerciolini, et al. Phase I Study of Bortezomib in Refractory or Relapsed Acute Leukemias Clin. Cancer Res., May 15, 2004; 10(10): 3371 - 3376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. G. Mimnaugh, W. Xu, M. Vos, X. Yuan, J. S. Isaacs, K. S. Bisht, D. Gius, and L. Neckers Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity Mol. Cancer Ther., May 1, 2004; 3(5): 551 - 566. [Abstract] [Full Text] [PDF]
|
|
E-letters:
Read all E-letters
- Hsp90 isoforms
- Chris S
- Annals of Oncology, 18 Sep 2008 [Full text]