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. 2015:2015:675053.
doi: 10.1155/2015/675053. Epub 2015 Nov 16.

Developing a Novel Indolocarbazole as Histone Deacetylases Inhibitor against Leukemia Cell Lines

Wenjing Wang  1 , Maomin Lv  1 , Xiong Zhao  1 , Jingang Zhang  1
Affiliations

Developing a Novel Indolocarbazole as Histone Deacetylases Inhibitor against Leukemia Cell Lines

Wenjing Wang et al. J Anal Methods Chem. 2015.

Abstract

A novel indolocarbazole (named as ZW2-1) possessing HDAC inhibition activity was synthesized and evaluated against human leukemia cell lines HL-60 and NB4. ZW2-1 performed anti-population growth effect which was in a concentration-dependent manner (2-12 μM) by inducing both apoptosis and autophagy in cells. The compound also caused differentiation of HL-60 and NB4 cells as shown by increasing expression of CD11b, CD14, and CD38 at moderate concentration (4 μM). At relatively high concentration (8 μM), ZW2-1 significantly decreased intracellular histone deacetylase 1 level which was also observed. All the results indicated that ZW2-1 could be a novel antileukemia lead capable of simultaneously inducing apoptosis, autophagy, and differentiation.

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Figures

Figure 1
Figure 1
Structure of ZW2-1 and its effects on cell proliferation. (a) Chemical structure of ZW2-1. (b) Effects of ZW2-1 on cell proliferation of human leukemia cell line HL-60, NB4, and immortal human keratinocyte cell line Haca T. The values are represented as mean ± SD of three independent experiments with five replicates in each.
Figure 2
Figure 2
Effects of ZW2-1 on apoptosis of HL-60 and NB4 cells. Annexin V and PI double staining for apoptosis of cells 48 h after incubation with ZW2-1 in comparison to the untreated control cells. All experiments are presented as mean ± SD of at least three independent experiments performed in replicates.
Figure 3
Figure 3
Effects of ZW2-1 on mitochondria membrane electrochemical potential of HL-60 cells. HL-60 cells were stained with JC-1 dye (P2: aggregated JC-1, red fluorescence (PE); P3: monomeric JC-1, green fluorescence (FITC)) which was measured by flow cytometry. The value represents the average percentage of cells in each gate (n = 3).
Figure 4
Figure 4
TEM images of HL-60 cells treated with ZW2-1 and western blots analysis of autophagy marker protein LC3. (a) Control group. (b, d) Cells were exposed to ZW2-1. (c, e) The magnification of selected area. (f) Effect of ZW2-1 on the LC3-I/LC3-II conversion.
Figure 5
Figure 5
Effects of ZW2-1 on CD11b, CD14, and CD38 expression. Flow cytometric analysis of expression of CD11b and CD14 at 0, 48, and 72 hr after treatment with ZW2-1, respectively, and expression of CD38 at 0, 6, and 12 hr after treatment with ZW2-1. To measure the percent positive signal, control group was set to exclude about 95% of the live cell population peak. All experiments are presented as mean ± SD of three independent experiments performed in replicates.
Figure 6
Figure 6
Effects of ZW2-1 on histone acetylation 1 in HL-60 cells. Colorimetric sandwich ELISA assay was used to detect the HDAC1 level in HL-60 and NB4 cells after treatment with ZW2-1 for 0, 24, 48, and 72 h. (a) Standard curve for samples of HL-60 cells. (b) HDAC1 concentrations of HL-60 cells treated with ZW2-1. (c) Standard curve for samples of NB4 cells. (d) HDAC1 concentrations of NB4 cells treated with ZW2-1. Data represents the means of three repeats ± SD.
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