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Histone deacetylase inhibitor potentiates chemotherapy-induced apoptosis through Bim upregulation in Burkitt's lymphoma cells.
J Cancer Res Clin Oncol 2012; 138(2):317-25JC

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+Show Affiliations

Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação Geral Técnico-Científica, Instituto Nacional de Câncer-INCA, Rio de Janeiro, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22131152

Citation

Dos Santos Ferreira, Ana Carolina, et al. "Histone Deacetylase Inhibitor Potentiates Chemotherapy-induced Apoptosis Through Bim Upregulation in Burkitt's Lymphoma Cells." Journal of Cancer Research and Clinical Oncology, vol. 138, no. 2, 2012, pp. 317-25.
Dos Santos Ferreira AC, Fernandes RA, Kwee JK, et al. Histone deacetylase inhibitor potentiates chemotherapy-induced apoptosis through Bim upregulation in Burkitt's lymphoma cells. J Cancer Res Clin Oncol. 2012;138(2):317-25.
Dos Santos Ferreira, A. C., Fernandes, R. A., Kwee, J. K., & Klumb, C. E. (2012). Histone deacetylase inhibitor potentiates chemotherapy-induced apoptosis through Bim upregulation in Burkitt's lymphoma cells. Journal of Cancer Research and Clinical Oncology, 138(2), pp. 317-25. doi:10.1007/s00432-011-1093-y.
Dos Santos Ferreira AC, et al. Histone Deacetylase Inhibitor Potentiates Chemotherapy-induced Apoptosis Through Bim Upregulation in Burkitt's Lymphoma Cells. J Cancer Res Clin Oncol. 2012;138(2):317-25. PubMed PMID: 22131152.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Histone deacetylase inhibitor potentiates chemotherapy-induced apoptosis through Bim upregulation in Burkitt's lymphoma cells. AU - Dos Santos Ferreira,Ana Carolina, AU - Fernandes,Renan Amphilophio, AU - Kwee,Jolie Kiemlian, AU - Klumb,Claudete Esteves, Y1 - 2011/12/01/ PY - 2011/06/22/received PY - 2011/11/03/accepted PY - 2011/12/2/entrez PY - 2011/12/2/pubmed PY - 2012/5/24/medline SP - 317 EP - 25 JF - Journal of cancer research and clinical oncology JO - J. Cancer Res. Clin. Oncol. VL - 138 IS - 2 N2 - 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. SN - 1432-1335 UR - https://www.unboundmedicine.com/medline/citation/22131152/Histone_deacetylase_inhibitor_potentiates_chemotherapy_induced_apoptosis_through_Bim_upregulation_in_Burkitt's_lymphoma_cells_ L2 - https://dx.doi.org/10.1007/s00432-011-1093-y DB - PRIME DP - Unbound Medicine ER -