The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-cell malignancies in vitro and in vivo.
BACKGROUND
While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies.


RESULTS
In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity.


CONCLUSIONS
Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies.
Lucas
David M
DM
Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Alinari
Lapo
L
West
Derek A
DA
Davis
Melanie E
ME
Edwards
Ryan B
RB
Johnson
Amy J
AJ
Blum
Kristie A
KA
Hofmeister
Craig C
CC
Freitas
Michael A
MA
Parthun
Mark R
MR
Wang
Dasheng
D
Lehman
Amy
A
Zhang
Xiaoli
X
Jarjoura
David
D
Kulp
Samuel K
SK
Croce
Carlo M
CM
Grever
Michael R
MR
Chen
Ching-Shih
CS
Baiocchi
Robert A
RA
Byrd
John C
JC
D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000473:pathology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000473:pathology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*
D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates