Histone deacetylase inhibitor potentiates chemotherapy-induced apoptosis through Bim upregulation in Burkitt's lymphoma cells.

Abstract

PURPOSE:

Although polychemotherapy regiments have improved clinical outcome for Burkitt's lymphoma (BL) patients, salvage treatment of patients with refractory disease remains very poor. Combined therapies protocols have been emerging to improve treatment strategies to circumvent responseless BL patients. We evaluate the cell death effect of histone deacetylase inhibitor (HDACI) combined with etoposide (VP-16) and cisplatin (CDDP) on BL cell lines.

METHODS:

3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay was performed to assess drug toxicity. To establish the concentrations and time of incubation for the combined treatment, a kinetic analysis was performed for each drug on BL41 and Raji BL cell lines for 24, 48 and 72 h. Apoptosis was assessed by flow cytometry using Annexin V/propidium iodide (PI) and cleaved caspase 3 labeling assays. Caspase 9 activation and levels of Bcl-2 family proteins were analyzed by Western blot.

RESULTS:

The doses of NaB (1.0 mM), CDDP (1.0 and 2.5 μM), and VP-16 (0.1 and 0.3 μM) after 24 h of incubation were chosen for the evaluation of combined therapy. The apoptotic effects on BL cell lines of NaB/VP-16 and NaB/CDDP were followed by upregulation of Bim protein (P < 0.05), activation of caspase-3 and caspase-9, followed by Mcl-1 downregulation (P < 0.05). However, Bim overexpression was not correlated with Bcl-2 inhibition (P > 0.05) and was accompanied by increase in Bax expression (P < 0.05). The combination effects of NaB/VP-16 and NaB/CDDP were found to be synergistic and additive, respectively, in both the cell lines.

CONCLUSIONS:

The study provides strong evidence for the synergistic effects of the association with HDCI and chemotherapy in BL cells.

• Authors: Ana Carolina Dos Santos Ferreira, Renan Amphilophio Fernandes, Jolie Kiemlian Kwee, Claudete Esteves Klumb
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 138 Issue 2 Pg. 317-25 (Feb 2012) ISSN: 1432-1335 [Electronic] Germany
• PMID: 22131152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BAX protein, human
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Butyrates
• Histone Deacetylase Inhibitors
• Membrane Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• Etoposide
• Caspase 3
• Caspase 9
• Cisplatin

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (biosynthesis, genetics, metabolism)
• Bcl-2-Like Protein 11
• Burkitt Lymphoma (drug therapy, genetics, metabolism, pathology)
• Butyrates (administration & dosage, pharmacology)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cisplatin (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Synergism
• Etoposide (administration & dosage, pharmacology)
• Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
• Humans
• Membrane Proteins (biosynthesis, genetics, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins (biosynthesis, genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Up-Regulation (drug effects)
• bcl-2-Associated X Protein (biosynthesis, genetics, metabolism)