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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-11-3514.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 4055-4062
NEOPLASIA
Molecular sequelae of histone deacetylase inhibition in human
malignant B cells
Nicholas Mitsiades,
Constantine S. Mitsiades,
Paul
G. Richardson,
Ciaran McMullan,
Vassiliki Poulaki,
Galinos Fanourakis,
Robert Schlossman,
Dharminder Chauhan,
Nikhil C. Munshi,
Teru Hideshima,
Victoria M. Richon,
Paul A. Marks, and
Kenneth C. Anderson
From the Jerome Lipper Multiple Myeloma Center,
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA; Department of Medicine, Harvard Medical
School, Boston, MA; Massachusetts Eye and Ear Infirmary, Harvard
Medical School, Boston, MA; Aton Pharma, Tarrytown, NY; and Memorial
Sloan-Kettering Cancer Center, New York, NY.
Histone acetylation modulates gene expression, cellular
differentiation, and survival and is regulated by the opposing
activities of histone acetyltransferases (HATs) and histone
deacetylases (HDACs). HDAC inhibition results in accumulation of
acetylated nucleosomal histones and induces differentiation and/or
apoptosis in transformed cells. In this study, we characterized the
effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and
patient cells from B-cell malignancies, including multiple myeloma (MM)
and related disorders. SAHA induced apoptosis in all tumor cells
tested, with increased p21 and p53 protein levels and dephosphorylation
of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2
family members in regulation of SAHA-induced cell death.
Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated
SAHA-induced apoptosis, confirming its protective role. SAHA did not
induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early
phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not
protect against SAHA. Conversely, poly(ADP)ribose polymerase
(PARP) was cleaved in a pattern indicative of calpain activation, and
the calpain inhibitor calpeptin abrogated SAHA-induced cell death.
Importantly, SAHA sensitized MM.1S cells to death receptor-mediated
apoptosis and inhibited the secretion of interleukin 6 (IL-6)
induced in bone marrow stromal cells (BMSCs) by binding of MM cells,
suggesting that it can overcome cell adhesion-mediated drug
resistance. Our studies delineate the mechanisms whereby HDAC
inhibitors mediate anti-MM activity and overcome drug resistance in the
BM milieu and provide the framework for clinical evaluation of SAHA,
which is bioavailable, well tolerated, and bioactive after oral
administration, to improve patient outcome.
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