HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 2, 1107-1118, January 13, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/2/1107    most recent M511607200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fernández, Y. Articles by Soengas, M. S. Search for Related Content PubMed PubMed Citation Articles by Fernández, Y. Articles by Soengas, M. S. Social Bookmarking                      What's this?

Chemical Blockage of the Proteasome Inhibitory Function of Bortezomib

IMPACT ON TUMOR CELL DEATH^*

Yolanda Fernández1, Thomas P. Miller, Christophe Denoyelle, Jose A. Esteban¶, Wen-Hua Tang, Audrey L. Bengston, and María S. Soengas2

From the Comprehensive Cancer Center and the Departments of Dermatology and ^¶Pharmacology, University of Michigan, Ann Arbor, Michigan 48109

The proteasome inhibitor bortezomib is emerging as a potent anti-cancer agent. Still, recent clinical trials have revealed a significant secondary toxicity of bortezomib. Consequently, there is much interest in dissecting the mechanism of action of this compound to rationally improve its therapeutic index. The cytotoxic effect of bortezomib is frequently characterized by interfering with downstream events derived from the accumulation of proteasomal targets. Here we identify the first chemical agent able to act upstream of the proteasome to prevent cell killing by bortezomib. Specifically, we show that the polyhydroxyl compound Tiron can function as a competitive inhibitor of bortezomib. This effect of Tiron was surprising, since it is a classical radical spin trap and was expected to scavenge reactive oxygen species produced as a consequence of bortezomib action. The inhibitory effect of Tiron against bortezomib was selective, since it was not shared by other antioxidants, such as vitamin E, MnTBAP, L-N-acetyl-cysteine, and FK-506. Comparative analyses with nonboronated proteasome inhibitors (i.e. MG132) revealed a specificity of Tiron for bortezomib. We exploited this novel feature of Tiron to define the "point of no return" of proteasome inhibition in melanoma cells and to block cell death in a three-dimensional model of human skin. Cells from T-cell lymphoma, breast carcinoma, and non-small cell lung cancer were also responsive to Tiron, suggesting a broad impact of this agent as a bortezomib blocker. These results may have important implications for the analysis of bortezomib in vivo and for the design of drug mixtures containing proteasome inhibitors.

Received for publication, October 26, 2005

^* This work was supported by a Dermatology Foundation Career Development Award and National Institutes of Health Grant R01 CA107237 (to M. S. S). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a postdoctoral fellowship from the Spanish Ministry of Education and Science.

² A V Foundation for Cancer Research Scholar. To whom correspondence should be addressed: Melanoma Program and Dept. of Dermatology, University of Michigan Comprehensive Cancer Center (4217 CCGC), 1500 E. Medical Center Dr., Ann Arbor, MI 48109. Tel.: 734-936-5643; Fax: 734-647-9654; E-mail: soengas{at}umich.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. A. Nikiforov, M. Riblett, W.-H. Tang, V. Gratchouck, D. Zhuang, Y. Fernandez, M. Verhaegen, S. Varambally, A. M. Chinnaiyan, A. J. Jakubowiak, et al. Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition PNAS, December 4, 2007; 104(49): 19488 - 19493. [Abstract] [Full Text] [PDF]

				M. H. Ossipov, I. Bazov, L. R. Gardell, J. Kowal, T. Yakovleva, I. Usynin, T. J. Ekstrom, F. Porreca, and G. Bakalkin Control of Chronic Pain by the Ubiquitin Proteasome System in the Spinal Cord J. Neurosci., August 1, 2007; 27(31): 8226 - 8237. [Abstract] [Full Text] [PDF]

				W.-X. Ding, H.-M. Ni, X. Chen, J. Yu, L. Zhang, and X.-M. Yin A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells Mol. Cancer Ther., March 1, 2007; 6(3): 1062 - 1069. [Abstract] [Full Text] [PDF]

				M. Verhaegen, J. A. Bauer, C. Martin de la Vega, G. Wang, K. G. Wolter, J. C. Brenner, Z. Nikolovska-Coleska, A. Bengtson, R. Nair, J. T. Elder, et al. A Novel BH3 Mimetic Reveals a Mitogen-Activated Protein Kinase-Dependent Mechanism of Melanoma Cell Death Controlled by p53 and Reactive Oxygen Species Cancer Res., December 1, 2006; 66(23): 11348 - 11359. [Abstract] [Full Text] [PDF]

				J.-Z. Qin, H. Xin, L. A. Sitailo, M. F. Denning, and B. J. Nickoloff Enhanced Killing of Melanoma Cells by Simultaneously Targeting Mcl-1 and NOXA Cancer Res., October 1, 2006; 66(19): 9636 - 9645. [Abstract] [Full Text] [PDF]