© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 22, 1940-1949,
November 17, 1999
© 1999 Oxford University Press
DT-Diaphorase Expression and Tumor Cell Sensitivity to 17-Allylamino,17-demethoxygeldanamycin, an Inhibitor of Heat Shock Protein 90
Affiliations of authors: L. R. Kelland, S. Y. Sharp, P. M. Rogers, P. Workman, Cancer Research Campaign Centre for Cancer Therapeutics, The Institute of Cancer Research, Surrey, U.K.; T. G. Myers, Developmental Therapeutics Program, Information Technology Branch, National Cancer Institute, Bethesda, MD.
Correspondence to: Paul Workman, Ph.D., Cancer Research Campaign Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd., Sutton, Surrey SM2 5NG, U.K. (e-mail-paulw{at}icr.ac.uk).
BACKGROUND: To our knowledge, 17-allylamino,17-demethoxygeldanamycin (17AAG) is the first inhibitor of heat shock protein 90 (Hsp90) to enter a phase I clinical trial in cancer. Inhibition of Hsp90, a chaperone protein (a protein that helps other proteins avoid misfolding pathways that produce inactive or aggregated states), leads to depletion of important oncogenic proteins, including Raf-1 and mutant p53 (also known as TP53). Given its ansamycin benzoquinone structure, we questioned whether the antitumor activity of 17AAG was affected by expression of the NQO1 gene, which encodes the quinone-metabolizing enzyme DT-diaphorase. METHODS: The antitumor activity of 17AAG and other Hsp90 inhibitors was determined by use of a sulforhodamine B-based cell growth inhibition assay in culture and by the arrest of xenograft tumor growth in nude mice. DT-diaphorase activity was determined by use of a spectrophotometric assay, and protein expression was determined by means of western immunoblotting. RESULTS: In two independent in vitro human tumor cell panels, we observed a positive relationship between DT-diaphorase expression level and growth inhibition by 17AAG. Stable, high-level expression of the active NQO1 gene transfected into the DT-diaphorase-deficient (by NQO1 mutation) BE human colon carcinoma cell line resulted in a 32-fold increase in 17AAG growth-inhibition activity. Increased sensitivity to 17AAG in the transfected cell line was also confirmed in xenografts. The extent of depletion of Raf-1 and mutant p53 protein confirmed that the Hsp90 inhibition mechanism was maintained in cells with high and low levels of DT-diaphorase. 17AAG was shown to be a substrate for purified human DT-diaphorase. CONCLUSION: These results suggest that the antitumor activity and possibly the toxicologic properties of 17AAG in humans may be influenced by the expression of DT-diaphorase. Careful monitoring for NQO1 polymorphism and the level of tumor DT-diaphorase activity is therefore recommended in clinical trials with 17AAG.
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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]
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R. Bagatell, O. Khan, G. Paine-Murrieta, C. W. Taylor, S. Akinaga, and L. Whitesell Destabilization of Steroid Receptors by Heat Shock Protein 90-binding Drugs: A Ligand-independent Approach to Hormonal Therapy of Breast Cancer Clin. Cancer Res., July 1, 2001; 7(7): 2076 - 2084. [Abstract] [Full Text] [PDF]
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 A. Sittler, R. Lurz, G. Lueder, J. Priller, M. K. Hayer-Hartl, F. U. Hartl, H. Lehrach, and E. E. Wanker Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease Hum. Mol. Genet., June 1, 2001; 10(12): 1307 - 1315. [Abstract] [Full Text] [PDF]
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I. Hostein, D. Robertson, F. DiStefano, P. Workman, and P. Andrew Clarke Inhibition of Signal Transduction by the Hsp90 Inhibitor 17-Allylamino-17-demethoxygeldanamycin Results in Cytostasis and Apoptosis Cancer Res., May 1, 2001; 61(10): 4003 - 4009. [Abstract] [Full Text]
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J. Yang, J.-M. Yang, M. Iannone, W. J. Shih, Y. Lin, and W. N. Hait Disruption of the EF-2 Kinase/Hsp90 Protein Complex: A Possible Mechanism to Inhibit Glioblastoma by Geldanamycin Cancer Res., May 1, 2001; 61(10): 4010 - 4016. [Abstract] [Full Text]
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S. E. Dunn, J. V. Torres, J. S. Oh, D. M. Cykert, and J. C. Barrett Up-Regulation of Urokinase-Type Plasminogen Activator by Insulin-like Growth Factor-I Depends upon Phosphatidylinositol-3 Kinase and Mitogen-activated Protein Kinase Kinase Cancer Res., February 1, 2001; 61(4): 1367 - 1374. [Abstract] [Full Text]
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S. Y. Sharp, L. R. Kelland, M. R. Valenti, L. A. Brunton, S. Hobbs, and P. Workman Establishment of an Isogenic Human Colon Tumor Model for NQO1 Gene Expression: Application to Investigate the Role of DT-Diaphorase in Bioreductive Drug Activation In Vitro and In Vivo Mol. Pharmacol., November 1, 2000; 58(5): 1146 - 1155. [Abstract] [Full Text]
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