| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
Departments of Medicine and Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
17-allyl-aminogeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a highly conserved pocket in the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of certain signaling proteins. 17-AAG has antitumor activity in cell culture and animal xenograft models and is currently in clinical trial. It causes an RB-dependent G1 arrest, differentiation, and apoptosis. RB-negative cells arrest in mitosis and undergo apoptosis. Hsp90 plays an important role in the cellular response to environmental stress. Therefore, we tested whether the regulation of Hsp90 function by 17-AAG could sensitize cells to cytotoxic agents. 17-AAG sensitized tumor cells to Taxol and doxorubicin. Taxanes cause growth arrest in mitosis and apoptosis. The addition of 17-AAG to cells after exposure to Taxol significantly increased both the activation of caspases 9 and 3 and apoptosis. In cells with intact RB, exposure to 17-AAG before Taxol resulted in G1 arrest and abrogated apoptosis. Schedule dependence was not seen in cells with mutated RB, because both agents blocked cells in mitosis. Schedule- or RB-dependence was also not observed when cells were treated with 17-AAG and doxorubicin, a DNA-intercalating agent that acts on different phases of the cell cycle. These findings suggest that inhibition of Hsp90 function by 17-AAG enhances the apoptotic effects of cytotoxic agents. The sequence of drug administration and the RB status significantly influence efficacy.
Commentary
Clin. Cancer Res. 2001 7: 2155-2158.
This article has been cited by other articles:
|
|
 |
|
  J. K. Woo, D. S. Choi, H. T. Tran, B. E. Gilbert, W. K. Hong, and H.-Y. Lee Liposomal Encapsulation of Deguelin: Evidence for Enhanced Antitumor Activity in Tobacco Carcinogen-Induced and Oncogenic K-ras-Induced Lung Tumorigenesis Cancer Prevention Research, April 1, 2009; 2(4): 361 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Banerji Heat Shock Protein 90 as a Drug Target: Some Like It Hot Clin. Cancer Res., January 1, 2009; 15(1): 9 - 14. [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]
|
|
|
|
|
|
S. S. Ramalingam, M. J. Egorin, R. K. Ramanathan, S. C. Remick, R. P. Sikorski, T. F. Lagattuta, G. S. Chatta, D. M. Friedland, R. G. Stoller, D. M. Potter, et al. A Phase I Study of 17-Allylamino-17-Demethoxygeldanamycin Combined with Paclitaxel in Patients with Advanced Solid Malignancies Clin. Cancer Res., June 1, 2008; 14(11): 3456 - 3461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Cao, M. Bloomston, T. Zhang, W. L. Frankel, G. Jia, B. Wang, N. C. Hall, R. M. Koch, H. Cheng, M. V. Knopp, et al. Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor Clin. Cancer Res., March 15, 2008; 14(6): 1831 - 1839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ocana and A. Pandiella Identifying Breast Cancer Druggable Oncogenic Alterations: Lessons Learned and Future Targeted Options Clin. Cancer Res., February 15, 2008; 14(4): 961 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sawai, S. Chandarlapaty, H. Greulich, M. Gonen, Q. Ye, C. L. Arteaga, W. Sellers, N. Rosen, and D. B. Solit Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel Cancer Res., January 15, 2008; 68(2): 589 - 596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Solit, S. P. Ivy, C. Kopil, R. Sikorski, M. J. Morris, S. F. Slovin, W. K. Kelly, A. DeLaCruz, T. Curley, G. Heller, et al. Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer Clin. Cancer Res., March 15, 2007; 13(6): 1775 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Sharp, K. Boxall, M. Rowlands, C. Prodromou, S. M. Roe, A. Maloney, M. Powers, P. A. Clarke, G. Box, S. Sanderson, et al. In vitro Biological Characterization of a Novel, Synthetic Diaryl Pyrazole Resorcinol Class of Heat Shock Protein 90 Inhibitors Cancer Res., March 1, 2007; 67(5): 2206 - 2216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. Robles, M. H. Wright, B. Gandhi, S. S. Feis, C. L. Hanigan, A. Wiestner, and L. Varticovski Schedule-Dependent Synergy between the Heat Shock Protein 90 Inhibitor 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin and Doxorubicin Restores Apoptosis to p53-Mutant Lymphoma Cell Lines. Clin. Cancer Res., November 1, 2006; 12(21): 6547 - 6556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bauer, L. K. Yu, G. D. Demetri, and J. A. Fletcher Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res., September 15, 2006; 66(18): 9153 - 9161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sain, B. Krishnan, M. G. Ormerod, A. De Rienzo, W. M. Liu, S. B. Kaye, P. Workman, and A. L. Jackman Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT Mol. Cancer Ther., May 1, 2006; 5(5): 1197 - 1208. [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]
|
|
|
|
|
|
T. Shimamura, A. M. Lowell, J. A. Engelman, and G. I. Shapiro Epidermal Growth Factor Receptors Harboring Kinase Domain Mutations Associate with the Heat Shock Protein 90 Chaperone and Are Destabilized following Exposure to Geldanamycins Cancer Res., July 15, 2005; 65(14): 6401 - 6408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Banerji, A. O'Donnell, M. Scurr, S. Pacey, S. Stapleton, Y. Asad, L. Simmons, A. Maloney, F. Raynaud, M. Campbell, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced Malignancies J. Clin. Oncol., June 20, 2005; 23(18): 4152 - 4161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Solit, Y. She, J. Lobo, M. G. Kris, H. I. Scher, N. Rosen, and F. M. Sirotnak Pulsatile Administration of the Epidermal Growth Factor Receptor Inhibitor Gefitinib Is Significantly More Effective than Continuous Dosing for Sensitizing Tumors to Paclitaxel Clin. Cancer Res., March 1, 2005; 11(5): 1983 - 1989. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 I. A. Vasilevskaya, T. V. Rakitina, and P. J. O'Dwyer Quantitative Effects on c-Jun N-Terminal Protein Kinase Signaling Determine Synergistic Interaction of Cisplatin and 17-Allylamino-17-Demethoxygeldanamycin in Colon Cancer Cell Lines Mol. Pharmacol., January 1, 2004; 65(1): 235 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Schmitt, A. Parcellier, S. Gurbuxani, C. Cande, A. Hammann, M. C. Morales, C. R. Hunt, D. J. Dix, R. T. Kroemer, F. Giordanetto, et al. Chemosensitization by a Non-apoptogenic Heat Shock Protein 70-Binding Apoptosis-Inducing Factor Mutant Cancer Res., December 1, 2003; 63(23): 8233 - 8240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Enmon, W.-H. Yang, A. M. Ballangrud, D. B. Solit, G. Heller, N. Rosen, H. I. Scher, and G. Sgouros Combination Treatment with 17-N-Allylamino-17-Demethoxy Geldanamycin and Acute Irradiation Produces Supra-Additive Growth Suppression in Human Prostate Carcinoma Spheroids Cancer Res., December 1, 2003; 63(23): 8393 - 8399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rahmani, C. Yu, Y. Dai, E. Reese, W. Ahmed, P. Dent, and S. Grant Coadministration of the Heat Shock Protein 90 Antagonist 17-Allylamino- 17-demethoxygeldanamycin with Suberoylanilide Hydroxamic Acid or Sodium Butyrate Synergistically Induces Apoptosis in Human Leukemia Cells Cancer Res., December 1, 2003; 63(23): 8420 - 8427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Jia, C. Yu, M. Rahmani, G. Krystal, E. A. Sausville, P. Dent, and S. Grant Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways Blood, September 1, 2003; 102(5): 1824 - 1832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Goetz, D. O. Toft, M. M. Ames, and C. Erlichman The Hsp90 chaperone complex as a novel target for cancer therapy Ann. Onc., August 1, 2003; 14(8): 1169 - 1176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. Vasilevskaya, T. V. Rakitina, and P. J. O'Dwyer Geldanamycin and its 17-Allylamino-17-Demethoxy Analogue Antagonize the Action of Cisplatin in Human Colon Adenocarcinoma Cells: Differential Caspase Activation as a Basis for Interaction Cancer Res., June 15, 2003; 63(12): 3241 - 3246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Villa, M. Folini, C. D. Porta, A. Valentini, M. Pennati, M. G. Daidone, and N. Zaffaroni Inhibition of telomerase activity by geldanamycin and 17-allylamino, 17-demethoxygeldanamycin in human melanoma cells Carcinogenesis, May 1, 2003; 24(5): 851 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Workman Auditing the Pharmacological Accounts for Hsp90 Molecular Chaperone Inhibitors: Unfolding the Relationship between Pharmacokinetics and Pharmacodynamics Mol. Cancer Ther., February 1, 2003; 2(2): 131 - 138. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, G. Fanourakis, X. Gu, C. Bailey, M. Joseph, T. A. Libermann, S. P. Treon, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells PNAS, October 29, 2002; 99(22): 14374 - 14379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Basso, D. B. Solit, G. Chiosis, B. Giri, P. Tsichlis, and N. Rosen Akt Forms an Intracellular Complex with Heat Shock Protein 90 (Hsp90) and Cdc37 and Is Destabilized by Inhibitors of Hsp90 Function J. Biol. Chem., October 11, 2002; 277(42): 39858 - 39866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Mabjeesh, D. E. Post, M. T. Willard, B. Kaur, E. G. Van Meir, J. W. Simons, and H. Zhong Geldanamycin Induces Degradation of Hypoxia-inducible Factor 1{alpha} Protein via the Proteosome Pathway in Prostate Cancer Cells Cancer Res., May 1, 2002; 62(9): 2478 - 2482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Sausville Combining Cytotoxics and 17-Allylamino, 17-Demethoxygeldanamycin: Sequence and Tumor Biology Matters : Commentary re: P. Munster et al., Modulation of Hsp90 Function by Ansamycins Sensitizes Breast Cancer Cells to Chemotherapy-induced Apoptosis in an RB- and Schedule-dependent Manner. Clin. Cancer Res., 7: 2228-2236, 2001. Clin. Cancer Res., August 1, 2001; 7(8): 2155 - 2158. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
