The histone deacetylase inhibitor MGCD0103 induces apoptosis in B-cell chronic lymphocytic leukemia cells through a mitochondria-mediated caspase activation cascade

Victoria El-Khoury*, Etienne Moussay, Bassam Janji, Valérie Palissot, Nasséra Aouali, Nicolaas H.C. Brons, Kris Van Moer, Sandrine Pierson, Eric Van Dyck, Guy Berchem

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1349-1360
Number of pages12
JournalMolecular Cancer Therapeutics
Volume9
Issue number5
DOIs
Publication statusPublished - May 2010

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