Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585

被引：53

作者：

Stuehmer, Thorsten ^{[1
]}

Arts, Janine ^{[2
]}

Chatterjee, Manik ^{[1
]}

Borawski, Johanna ^{[1
]}

Wolff, Andre ^{[1
]}

King, Peter ^{[2
]}

Einsele, Hermann ^{[1
]}

Leo, Eugen ^{[2
]}

Bargou, Ralf C. ^{[1
]}

机构：

[1] Univ Hosp Wurzburg, Dept Internal Med 2, Div Haematol, D-97080 Wurzburg, Germany

[2] Ortho Biotech Oncol Res & Dev, Beerse, Belgium

来源：

BRITISH JOURNAL OF HAEMATOLOGY | 2010年 / 149卷 / 04期

关键词：

multiple myeloma; histone deacetylase inhibitor; novel agent; HISTONE DEACETYLASE INHIBITORS; MULTIPLE-MYELOMA; VORINOSTAT; MECHANISMS; POTENT; P53;

D O I：

10.1111/j.1365-2141.2010.08126.x

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

P>Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti-cancer agents and may be useful to enhance the therapeutic efficiency of established anti-myeloma treatments. This study preclinically evaluated the effects of the 'second generation' pan-HDAC inhibitor JNJ-26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n = 42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2-family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl-1 depletion and Hsp72 induction were the most reliable features observed in JNJ-26481585-treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ-26481585 with anti-myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC-inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.

引用

页码：529 / 536

页数：8

共 25 条

[1] JNJ-26481585, a Novel "Second-Generation" Oral Histone Deacetylase Inhibitor, Shows Broad-Spectrum Preclinical Antitumoral Activity [J].

Arts, Janine ;

King, Peter ;

Marien, Ann ;

Floren, Wim ;

Belien, Ann ;

Janssen, Lut ;

Pilatte, Isabelle ;

Roux, Bruno ;

Decrane, Laurence ;

Gilissen, Ron ;

Hickson, Ian ;

Vreys, Veronique ;

Cox, Eugene ;

Bol, Kees ;

Talloen, Willem ;

Goris, Ilse ;

Andries, Luc ;

Du Jardin, Marc ;

Janicot, Michel ;

Page, Martin ;

van Emelen, Kristof ;

Angibaud, Patrick .

CLINICAL CANCER RESEARCH, 2009, 15 (22) :6841-6851

[2] Isoform-specific histone deacetylase inhibitors: The next step? [J].

Balasubramanian, Sriram ;

Verner, Erik ;

Buggy, Joseph J. .

CANCER LETTERS, 2009, 280 (02) :211-221

[3] 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

[4] NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma [J].

Catley, L ;

Weisberg, E ;

Tai, YT ;

Atadja, P ;

Remiszewski, S ;

Hideshima, T ;

Mitsiades, N ;

Shringarpure, R ;

LeBlanc, R ;

Chauhan, D ;

Munshi, NC ;

Schlossman, R ;

Richardson, P ;

Griffin, J ;

Anderson, KC .

BLOOD, 2003, 102 (07) :2615-2622

[5] Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies [J].

Chou, Ting-Chao .

PHARMACOLOGICAL REVIEWS, 2006, 58 (03) :621-681

[6] The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models [J].

Deleu, S. ;

Lemaire, M. ;

Arts, J. ;

Menu, E. ;

Van Valckenborgh, E. ;

King, P. ;

Vande Broek, I. ;

De Raeve, H. ;

Van Camp, B. ;

Croucher, P. ;

Vanderkerken, K. .

LEUKEMIA, 2009, 23 (10) :1894-1903

[7] Clinical development of histone deacetylase inhibitors as anticancer agents [J].

Drummond, DC ;

Noble, CO ;

Kirpotin, DB ;

Guo, ZX ;

Scott, GK ;

Benz, CC .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2005, 45 :495-528

[8] HDACs, histone deacetylation and gene transcription:: from molecular biology to cancer therapeutics [J].

Gallinari, Paola ;

Di Marco, Stefania ;

Jones, Phillip ;

Pallaoro, Michele ;

Steinkuhler, Christian .

CELL RESEARCH, 2007, 17 (03) :195-211

[9]

Kaiser M, 2006, HAEMATOL-HEMATOL J, V91, P248

[10] Improved survival in multiple myeloma and the impact of novel therapies [J].

Kumar, Shaji K. ;

Rajkumar, S. Vincent ;

Dispenzieri, Angela ;

Lacy, Martha Q. ;

Hayman, Suzanne R. ;

Buadi, Francis K. ;

Zeldenrust, Steven R. ;

Dingli, David ;

Russell, Stephen J. ;

Lust, John A. ;

Greipp, Philip R. ;

Kyle, Robert A. ;

Gertz, Morie A. .

BLOOD, 2008, 111 (05) :2516-2520

← 1 2 3 →