The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-Cell malignancies In Vitro and In Vivo

42Citations
Citations of this article
34Readers
Mendeley users who have this article in their library.

Abstract

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. Principal Findings: In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC50 (50% growth inhibitory concentration) of AR-42 is 0.61 μM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC50 (concentration lethal to 50%) of AR-42 is 0.76 μM. 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/Significance: 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. © 2010 Lucas et al.

Cite

CITATION STYLE

APA

Lucas, D. M., Alinari, L., West, D. A., Davis, M. E., Edwards, R. B., Johnson, A. J., … Byrd, J. C. (2010). The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-Cell malignancies In Vitro and In Vivo. PLoS ONE, 5(6). https://doi.org/10.1371/journal.pone.0010941

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free