Characterization of the apoptotic and therapeutic activities of the histone deacetylase inhibitors LAQ824 and LBH589 using a mouse model of B cell lymphoma

Ellis, L., Lindemann, R., Newbold, A., Whitecross, K., Cluse, L., Pelligrini, M., Wei, A., Scott, C., Atadja, P., Lowe, S. W., Johnstone, R. W. (December 2007) Characterization of the apoptotic and therapeutic activities of the histone deacetylase inhibitors LAQ824 and LBH589 using a mouse model of B cell lymphoma. Molecular Cancer Therapeutics, 6 (11). 3475S-3476S. ISSN 1535-7163

URL: http://mct.aacrjournals.org/content/6/11_Supplemen...

Abstract

Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival including inhibition of tumor cell cycle progression, induction of tumor cell-selective apoptosis, suppression of angiogenesis and modulation of immune responses and show promising activity against hematological malignancies in clinical trials. Using the Eµ-myc model of B-cell lymphoma and the HDACi LBH589 and LAQ824 we demonstrated a direct correlation between induction of tumor cell death in vivo and therapeutic efficacy. Neither HDACi required p53 activity or a functional death receptor pathway, but mediated lymphoma cell death via the intrinsic apoptotic pathway as demonstrated by decreased apoptosis and therapeutic activity of LBH589 and LAQ825 against Eµ-myc/Bcl-2 and Eµ-myc/Bcl-XL cells. Interestingly, both LBH589 and LAQ824 effectively killed Eµ-myc/caspase-9-/- and Eµ-myc/Apaf-1-/- lymphomas, which lack a functional apoptosome and thus have a defective apoptotic program downstream of the mitochondria. These cells did not display classic morphological or biological features of apoptosis following treatment with LBH589 and LAQ824 however their clonogenic capacity was significantly reduced and interestingly electron microscopy analysis indicated that these HDACi-treated cells underwent autophagy. Importantly, both Eµ-myc/caspase-9-/- and Eµ-myc/Apaf-1-/- responded to LBH589 and LAQ824 in vivo indicating that in the absence of an effective apoptotic program downstream of mitochondrial membrane perturbation, tumor cells can undergo autophagy and this is sufficient to mediate therapeutic efficacy. Our studies provide important information regarding the mechanisms of action of LBH589 and LAQ824 that may have broader implications regarding future stratification of patients receiving therapy with these agents and the use of these compounds in combination with other anti-cancer agents.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > B cell lymphoma
therapies
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > histone deacetylase
Publication Type > Meeting Abstract
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: CSHL Librarian
Date: December 2007
Date Deposited: 15 Nov 2011 17:04
Last Modified: 23 Mar 2018 16:32
URI: http://repository.cshl.edu/id/eprint/23010

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