Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma

Lindemann, R. K., Newbold, A., Whitecross, K. F., Cluse, L. A., Frew, A. J., Ellis, L., Williams, S., Wiegmans, A. P., Dear, A. E., Scott, C. L., Pellegrini, M., Wei, A., Richon, V. M., Marks, P. A., Lowe, S. W., Smyth, M. J., Johnstone, R. W. (May 2007) Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. Proc Natl Acad Sci U S A, 104 (19). pp. 8071-6. ISSN 0027-8424

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Abstract

Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition of 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 Emu-myc model of B cell lymphoma, we screened tumors with defined genetic alterations in apoptotic pathways for therapeutic responsiveness to the HDACi vorinostat. We demonstrated a direct correlation between induction of tumor cell apoptosis in vivo and therapeutic efficacy. Vorinostat did not require p53 activity or a functional death receptor pathway to kill Emu-myc lymphomas and mediate a therapeutic response but depended on activation of the intrinsic apoptotic pathway with the proapoptotic BH3-only proteins Bid and Bim playing an important role. Our studies provide important information regarding the mechanisms of action of HDACi that have broad implications regarding stratification of patients receiving HDACi therapy alone or in combination with other anticancer agents.

Item Type:	Paper
Uncontrolled Keywords:	BH3-only proteins Bid Bim vorinostat
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types > B cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > B cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > B cells diseases & disorders > cancer diseases & disorders > cancer > angiogenesis 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 diseases & disorders > cancer > cancer types > lymphoma
CSHL Authors:	Lowe, Scott W. Scott, Clare L.
Communities:	CSHL labs > Lowe lab
Depositing User:	CSHL Librarian
Date:	8 May 2007
Date Deposited:	11 Nov 2011 15:06
Last Modified:	09 Nov 2017 15:54
PMCID:	PMC1876573
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/23082

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