Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells

被引:75
作者
Dai, Yun [1 ]
Chen, Shuang [1 ]
Kramer, Lora B. [1 ]
Funk, Vanessa L. [1 ]
Dent, Paul [2 ]
Grant, Steven [1 ,2 ,3 ]
机构
[1] Virginia Commonwealth Univ, Div Hematol Oncol, Massey Canc Ctr, Dept Med, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Biochem, Richmond, VA 23298 USA
[3] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Pharmacol, Richmond, VA 23298 USA
关键词
D O I
10.1158/1078-0432.CCR-07-1934
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The goal of this study was to characterize interactions between the proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors (HDACI) romidepsin or belinostat in chronic lymphocytic leukemia (CLL) cells. Experimental Design: Primary and cultured (JVM-3 and MEC-2) CLL cells were exposed to agents alone or in combination, after which cell death was determined by 7-aminoactinomycin D staining/flow cytometry. Acetylation of target proteins, activation of caspase cascades, and expression of apoptosis-regulatory proteins were monitored by Western blot analysis. Nuclear factor-kappa B (NF-kappa B) activity was determined by luciferase reporter assay. Cells were transiently transfected with wild-type and acetylation site-mutated (inactive) ReIA(p65) (e.g., K221R, K310R, or K281/221/310R) and assessed for HDACI sensitivity. Results: Combined exposure to very low concentrations of romidepsin or belinostat (i.e., low nanomolar and submicromolar, respectively) in combination with low nanomolar concentrations of bortezomib synergistically induced cell death in primary and cultured CLL cells. These events were likely associated with prevention of HDACI-mediated RelA acetylation and NF-kappa B activation by bortezomib, down-regulation of antiapoptotic proteins (i.e., Bcl-xL, Mcl-1, and XIAP), as well as up-regulation of the proapoptotic protein Bim, resulting in activation of caspase cascade. Finally, CLL cells transfected with inactive ReIA displayed a significant increase in HDACI lethality. Conclusions: Coadministration of the clinically relevant HDACls romidepsin or belinostat with bortezomib synergistically induces cell death in CLL cells, likely through mechanisms involving, among other factors, NF-kappa B inactivation and perturbation in the expression of proapoptotic and antiapoptotic proteins. A strategy combining HDAC with proteasome inhibition warrants further attention in CLL.
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收藏
页码:549 / 558
页数:10
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共 50 条
[1]   Potentiation of tumor necrosis factor-induced NF-κB activation by deacetylase inhibitors is associated with a delayed cytoplasmic reappearance of IκBα [J].
Adam, E ;
Quivy, V ;
Bex, F ;
Chariot, A ;
Collette, Y ;
Vanhulle, C ;
Schoonbroodt, S ;
Goffin, V ;
Nguyên, TLA ;
Gloire, G ;
Carrard, G ;
Friguet, B ;
de Launoit, Y ;
Burny, A ;
Bours, V ;
Piette, J ;
Van Lint, CV .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (17) :6200-6209
[2]   The proteasome: A suitable antineoplastic target [J].
Adams, J .
NATURE REVIEWS CANCER, 2004, 4 (05) :349-360
[3]   The development of proteasome inhibitors as anticancer drugs [J].
Adams, J .
CANCER CELL, 2004, 5 (05) :417-421
[4]   Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein [J].
Aron, JL ;
Parthun, MR ;
Marcucci, G ;
Kitada, S ;
Mone, AP ;
Davis, ME ;
Shen, TS ;
Murphy, T ;
Wickham, J ;
Kanakry, C ;
Lucas, DM ;
Reed, JC ;
Grever, MR ;
Byrd, JC .
BLOOD, 2003, 102 (02) :652-658
[5]   The p65 (RelA) subunit of NF-κB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression [J].
Ashburner, BP ;
Westerheide, SD ;
Baldwin, AS .
MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (20) :7065-7077
[6]   Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 - A novel basis for antileukemia activity of histone deacetylase inhibitors [J].
Bali, P ;
Pranpat, M ;
Bradner, J ;
Balasis, M ;
Fiskus, W ;
Guo, F ;
Rocha, K ;
Kumaraswamy, S ;
Boyapalle, S ;
Atadja, P ;
Seto, E ;
Bhalla, K .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (29) :26729-26734
[7]   Histone deacetylase inhibitors in combinations: Will the preclinical promises be kept? [J].
Bates, Susan E. ;
Piekarz, Richard L. .
CANCER JOURNAL, 2007, 13 (02) :80-83
[8]  
Blagosklonny MV, 2002, MOL CANCER THER, V1, P937
[9]   Anticancer activities of histone deacetylase inhibitors [J].
Bolden, Jessica E. ;
Peart, Melissa J. ;
Johnstone, Ricky W. .
NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (09) :769-784
[10]   Treatment of relapsed chronic lymphocytic leukemia: Old and new therapies [J].
Byrd, JC ;
Lin, TS ;
Grever, MR .
SEMINARS IN ONCOLOGY, 2006, 33 (02) :210-219