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Research Articles: Therapeutics, Targets, and Development

Gene expression analysis of gallium-resistant and gallium-sensitive lymphoma cells reveals a role for metal-responsive transcription factor-1, metallothionein-2A, and zinc transporter-1 in modulating the antineoplastic activity of gallium nitrate

¹ Division of Neoplastic Diseases, Department of Medicine and ² Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin

Requests for reprints: Christopher R. Chitambar, Division of Neoplastic Diseases, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226. Phone: 414-805-4600; Fax: 414-806-4606. E-mail: chitambr{at}mcw.edu

Abstract

Several clinical trials have shown gallium nitrate to be an active agent in the treatment of lymphoma. Whereas gallium is known to target cellular iron homeostasis, the basis for lymphoma cell resistance to gallium is not known. Understanding mechanisms of resistance may suggest strategies to enhance the clinical efficacy of gallium. In the present study, we used a focused DNA microarray to compare the expression of genes related to metal metabolism in gallium-resistant and gallium-sensitive lymphoma cell lines developed by us. Gallium-resistant cells were found to display a marked increase in gene expression for metallothionein-2A and the zinc transporter ZnT-1. Cells exposed to gallium nitrate displayed an increase in the binding of metal-responsive transcription factor-1 to metal response element sequences involved in the transcriptional regulation of metallothionein and ZnT-1 genes. Gallium nitrate induced metallothionein-2A and ZnT-1 expression in cells. A role for metallothionein in modulating the antineoplastic activity of gallium was confirmed by showing that the induction of metallothionein expression by zinc provided partial protection against the cytotoxicity of gallium and by showing that the level of endogenous metallothionein in lymphoma cell lines correlated with their sensitivity to gallium nitrate. Immunohistochemical staining of lymphomatous tissues revealed metallothionein protein to be variably expressed in different lymphomas. Our studies show for the first time that gallium acts on pathways related to zinc metabolism and that metal-responsive transcription factor-1 activity and metallothionein expression contribute to the development of gallium drug resistance. Furthermore, the endogenous level of metallothionein in lymphoma may be an important determinant of clinical response to gallium nitrate. [Mol Cancer Ther 2007;6(2):633–43]

Grant support: United States Public Health Service RO1 CA109518 (C.R. Chitambar).

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.

Conflict of interest statement: C.R. Chitambar has served previously as a consultant for Genta, Inc., the manufacturer of gallium nitrate.

³ http://www.superarray.com

Received 9/11/06; revised 11/ 1/06; accepted 12/15/06.

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				C. R. Chitambar, D. P. Purpi, J. Woodliff, M. Yang, and J. P. Wereley Development of Gallium Compounds for Treatment of Lymphoma: Gallium Maltolate, a Novel Hydroxypyrone Gallium Compound, Induces Apoptosis and Circumvents Lymphoma Cell Resistance to Gallium Nitrate J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1228 - 1236. [Abstract] [Full Text] [PDF]