The Histone Deacetylase Inhibitor MGCD0103 Induces Apoptosis in B-Cell Chronic Lymphocytic Leukemia Cells through a Mitochondria-Mediated Caspase Activation Cascade

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BlankThe Histone Deacetylase Inhibitor MGCD0103 Induces Apoptosis in B-Cell

Chronic Lymphocytic Leukemia Cells through a Mitochondria-Mediated Caspase

Activation Cascade

1.. El-Khoury1,

2.. Etienne Moussay1,

3.. Bassam Janji1,

4.. Valérie Palissot1,

5.. Nasséra Aouali1,

6.. Nicolaas H.C. Brons1,

7.. Kris Van Moer1,

8.. Sandrine Pierson1,

9.. Van Dyck1 and

10.. Guy Berchem1,2

+ Author Affiliations

1.. Authors' Affiliations:1Laboratory of Experimental Hemato-Oncology, Public

Research Center for Health (CRP-Santé) and 2Centre Hospitalier de Luxembourg,

Luxembourg, Luxembourg

1.. Corresponding Authors:

El-Khoury, Laboratory of Experimental Hemato-Oncology, Public

Research Center for Health (CRP-Santé), 84 Val Fleuri, L-1526 Luxembourg,

Luxembourg. Phone: 352-26970-232; Fax: 352-26970-390. E-mail:

victoria.elkhoury@... or Guy Berchem, Centre Hospitalier de Luxembourg,

4 rue Barblé, L-1210 Luxembourg, Luxembourg. Phone: 352-4411-2084/8315; Fax:

352-441215. E-mail: berchem.guy@...

Abstract

Clinical trials have shown activity of the isotype-selective histone deacetylase

(HDAC) inhibitor MGCD0103 in different hematologic malignancies. There are data

to support the use of HDAC inhibitors in association with other cancer

therapies. To propose a rational combination therapy, it is necessary to depict

the molecular basis behind the cytotoxic effect of MGCD0103. In this study, we

found that MGCD0103 was substantially more toxic in neoplastic B cells relative

to normal cells, and we described the death pathways activated by MGCD0103 in

B-cell chronic lymphocytic leukemia (CLL) cells from 32 patients. MGCD0103

decreased the expression of Mcl-1 and induced translocation of Bax to the

mitochondria, mitochondrial depolarization, and release of cytochrome c in the

cytosol. Caspase processing in the presence of the caspase inhibitor Q-VD-OPh

and time course experiments showed that caspase-9 was the apical caspase. Thus,

MGCD0103 induced the intrinsic pathway of apoptosis in CLL cells. Moreover,

MGCD0103 treatment resulted in the activation of a caspase cascade downstream of

caspase-9, caspase-dependent amplification of mitochondrial depolarization,

activation of calpain, and Bax cleavage. We propose a model whereby the

intrinsic pathway of apoptosis triggered by MGCD0103 in CLL is associated with a

mitochondrial death amplification loop. Mol Cancer Ther; 9(5); OF1–12. ©2010

AACR.

Footnotes

a.. Note: Supplementary material for this article is available at Molecular

Cancer Therapeutics Online (http://mct.aacrjournals.org/).

b.. Authorship: Contribution: V. El-Khoury designed the study, did

experiments, analyzed data, and wrote the article. E. Moussay, B. Janji, V.

Palissot, N. Aouali, and E. Van Dyck discussed experiments and revised the

article. N.H.C. Brons analyzed data. K. Van Moer and S. Pierson carried out

experiments. G. Berchem supervised the project, recruited and obtained written

consents from patients and healthy donors, collected clinical data, and revised

the article.

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