17-DMAG targets the NF-kappa B family of proteins to induce apoptosis in CLL: clinical implications of HSP90 inhibition

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Blood First Edition Paper, prepublished online March 29, 2010; DOI

10.1182/blood-2010-01-263756.

17-DMAG targets the NF-kappa B family of proteins to induce apoptosis in CLL:

clinical implications of HSP90 inhibition

Hertlein1, Amy J. Wagner1, 1, S. Lin1, Kami J.

Maddocks1, H. Towns, III1, Virginia M. Goettl1, Xiaoli Zhang2,

Jarjoura2, Chelsey A. 1, A. West1, Carlo M. Croce3, C. Byrd1

and Amy J. 1,*

1 Department of Internal Medicine, Division of Hematology and Oncology,

Comprehensive Cancer Center at The Ohio State University, Columbus, OH, United

States; 2 Center for Biostatistics, The Ohio State University, Columbus, OH,

United States; 3 Human Cancer Genetics Program and Department of Molecular

Virology, Immunology and Medical Genetics, OSU School of Medicine, Ohio State

University, Columbus, OH, United States

* Corresponding author; email: amy.johnson@...

Abstract

The HSP90 client: chaperone interaction stabilizes several important enzymes and

anti-apoptotic proteins, and pharmacologic inhibition of HSP90 results in rapid

client protein degradation. Therefore HSP90 inhibition is an attractive

therapeutic approach when this protein is active, a phenotype commonly observed

in transformed but not normal cells. In chronic lymphocytic leukemia (CLL)

cells, it has been previously shown that HSP90 is in the activated form.

However, pre-clinical studies with HSP90 inhibitors such as 17-AAG demonstrated

depletion of only a subset of client proteins and very modest tumor

cytotoxicity. Herein, we describe another HSP90 inhibitor, 17-DMAG, that is

cytotoxic to CLL but not normal lymphocytes. Treatment with 17-DMAG leads to

depletion of the HSP90 client protein IKK, resulting in diminished NF-kappa B

p50/p65 DNA binding, decreased NF-kappa B target gene transcription, and caspase

dependent apoptosis. The ability of 17-DMAG to function as an NF-kappa B

inhibitor is of great interest clinically, as few currently available CLL drugs

target this transcription factor. Therefore, in order to determine the in vivo

effect of 17-DMAG treatment in CLL, we used a TCL1-SCID transplant mouse model.

Treatment with 17-DMAG significantly decreased the white blood cell count and

prolonged the survival of these mice. Based on these results, we conclude that

17-DMAG antagonizes NF-kappa B signaling pathways, leads to the decrease in

several survival proteins in CLL, and therefore represents a novel therapy

warranting further clinical pursuit in this and other B cell lymphoproliferative

disorders.

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