The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-cell malignancies in vitro and in vivo
| Autor: | Craig C. Hofmeister, Michael A. Freitas, Mark R. Parthun, Samuel K. Kulp, Robert A. Baiocchi, Ching-Shih Chen, Dasheng Wang, Ryan B. Edwards, Lapo Alinari, Michael R. Grever, Melanie E. Davis, Kristie A. Blum, Derek A. West, Amy J. Johnson, David Jarjoura, Amy Lehman, Carlo M. Croce, Xiaoli Zhang, David M. Lucas, John C. Byrd |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Stromal cell
Chronic lymphocytic leukemia Drug Evaluation Preclinical lcsh:Medicine Apoptosis Lymphoma Mantle-Cell Phenylbutyrate Cell Biology/Cell Signaling 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor hemic and lymphatic diseases medicine Humans Cell Biology/Leukocyte Signaling and Gene Expression lcsh:Science B cell 030304 developmental biology 0303 health sciences Multidisciplinary Chemistry lcsh:R Cell Biology Cell Biology/Cellular Death and Stress Responses Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Burkitt Lymphoma Phenylbutyrates 3. Good health Lymphoma Histone Deacetylase Inhibitors medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Cancer research Mantle cell lymphoma lcsh:Q Research Article |
| Zdroj: | PLoS ONE, Vol 5, Iss 6, p e10941 (2010) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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 mM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC50 (concentration lethal to 50%) of AR-42 is 0.76 mM. 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. |
| Databáze: | OpenAIRE |
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