T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance

被引:166
作者
Piekarz, RL [1 ]
Robey, RW [1 ]
Zhan, ZR [1 ]
Kayastha, G [1 ]
Sayah, A [1 ]
Abdeldaim, AH [1 ]
Torrico, S [1 ]
Bates, SE [1 ]
机构
[1] NCI, Canc Therapeut Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1182/blood-2003-09-3068
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Depsipeptide (FK228) is a novel histone deacetylase inhibitor currently in clinical trials and the first to demonstrate clinical activity in patients. Responses have been observed in patients with T-cell lymphomas, despite prior treatment with multiple chemotherapeutic agents. To better understand the effects of histone deacetylase inhibitors on T-cell lymphoma, the human T-cell lymphoma cell line HUT78 was tested for sensitivity and molecular response to depsipeptide. Treatment with depsipeptide, as well as other histone deacetylase inhibitors, caused induction of histone acetylation, induction of p21 expression, and substantial apoptosis without significant cell cycle arrest. Treatment with the caspase inhibitor z-VAD-fmk significantly inhibited depsipeptide-induced apoptosis, enabling detection of cell cycle arrest. Treatment with depsipeptide increased expression of the interleukin-2 (IL-2) receptor, and combination with the IL-2 toxin conjugate denileukin diftitox resulted in more than additive toxicity. Cells selected for resistance to depsipeptide overexpressed the multidrug resistance pump, P-glycoprotein (Pgp). However, cells selected for resistance to depsipeptide in the presence of a Pgp inhibitor had a Pgp-independent mechanism of resistance. These studies confirm the activity of depsipeptide in a T-cell lymphoma model and suggest a general sensitivity of T-cell lymphoma to histone deacetylase inhibitors, an emerging new class of anticancer agents. (C) 2004 by The American Society of Hematology.
引用
收藏
页码:4636 / 4643
页数:8
相关论文
共 62 条
[1]   Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17) [J].
Amin, HM ;
Saeed, S ;
Alkan, S .
BRITISH JOURNAL OF HAEMATOLOGY, 2001, 115 (02) :287-297
[2]   p21WAF1 is required for butyrate-mediated growth inhibition of human colon cancer cells [J].
Archer, SY ;
Meng, SF ;
Shei, A ;
Hodin, RA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (12) :6791-6796
[3]   EXPRESSION OF A DRUG-RESISTANCE GENE IN HUMAN NEURO-BLASTOMA CELL-LINES - MODULATION BY RETINOIC ACID-INDUCED DIFFERENTIATION [J].
BATES, SE ;
MICKLEY, LA ;
CHEN, YN ;
RICHERT, N ;
RUDICK, J ;
BIEDLER, JL ;
FOJO, AT .
MOLECULAR AND CELLULAR BIOLOGY, 1989, 9 (10) :4337-4344
[4]   DECREASED MUTATION-RATE FOR CELLULAR-RESISTANCE TO DOXORUBICIN AND SUPPRESSION OF MDR1 GENE ACTIVATION BY THE CYCLOSPORINE PSC-833 [J].
BEKETICORESKOVIC, L ;
DURAN, GE ;
CHEN, G ;
DUMONTET, C ;
SIKIC, BI .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1995, 87 (21) :1593-1602
[5]   Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts [J].
Bernhard, D ;
Ausserlechner, MJ ;
Tonko, M ;
Löffler, M ;
Hartmann, BL ;
Csordas, A ;
Kofler, R .
FASEB JOURNAL, 1999, 13 (14) :1991-2001
[6]  
Bernstein ZP, 2001, BLOOD, V98, p238B
[7]   n-butyrate downregulates the stimulatory function of peripheral blood-derived antigen-presenting cells: a potential mechanism for modulating T-cell responses by short-chain fatty acids [J].
Bohmig, GA ;
Krieger, PM ;
Saemann, MD ;
Wenhardt, C ;
Pohanka, E ;
Zlabinger, GJ .
IMMUNOLOGY, 1997, 92 (02) :234-243
[8]  
Bunn PA, 1996, J CELL BIOCHEM, P12
[9]  
Burgess AJ, 2001, MOL PHARMACOL, V60, P828
[10]   Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer [J].
Cameron, EE ;
Bachman, KE ;
Myöhänen, S ;
Herman, JG ;
Baylin, SB .
NATURE GENETICS, 1999, 21 (01) :103-107