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Tetraarsenictetrasulfide and Arsenic Trioxide Exert Synergistic Effects on Induction of Apoptosis and Differentiation in Acute Promyelocytic Leukemia Cells.

Wang S, Zhou M, Ouyang J, Geng Z, Wang Z - PLoS ONE (2015)

Bottom Line: Since arsenic trioxide (As3+) has been successfully used in the treatment of acute promyelocytic leukemia (APL), its adverse effects on patients have been problematic and required a solution.Moreover, the combination of low concentrations of As4S4 and As3+ enhanced degradation of the promyelocytic leukemia-retinoic acid receptor α oncoprotein.In summary, As4S4 and As3+ synergistically induce the apoptosis and differentiation of NB4 and primary APL cells.

View Article: PubMed Central - PubMed

Affiliation: State key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210093, China.

ABSTRACT
Since arsenic trioxide (As3+) has been successfully used in the treatment of acute promyelocytic leukemia (APL), its adverse effects on patients have been problematic and required a solution. Considering the good therapeutic potency and low toxicity of tetraarsenictetrasulfide (As4S4) in the treatment of APL, we investigated the effects of combining As4S4 and As3+ on the apoptosis and differentiation of NB4 and primary APL cells. As4S4, acting similarly to As3+, arrested the G1/S transition, induced the accumulation of cellular reactive oxygen species, and promoted apoptosis. Additionally, low concentrations of As4S4 (0.1-0.4 μM) induced differentiation of NB4 and primary APL cells. Compared with the As4S4- or As3+-treated groups, the combination of As4S4 and As3+ obviously promoted apoptosis and differentiation of NB4 and primary APL cells. Mechanistic studies suggested that As4S4 acted synergistically with As3+ to down-regulate Bcl-2 and nuclear factor-κB expression, up-regulate Bax and p53 expression, and induce activation of caspase-12 and caspase-3. Moreover, the combination of low concentrations of As4S4 and As3+ enhanced degradation of the promyelocytic leukemia-retinoic acid receptor α oncoprotein. In summary, As4S4 and As3+ synergistically induce the apoptosis and differentiation of NB4 and primary APL cells.

No MeSH data available.


Related in: MedlinePlus

The effects of combining As3+ and As4S4 on the apoptosis of NB4 and primary APL cells.(A) The apoptosis of NB4 cells. (B) The apoptosis of primary APL cells. (C) The percentage of apoptotic cells in NB4 and primary APL cells. After 48 h of treatment, the cells were stained with Annexin V-FITC and PI. Q1 and Q3, represent the dead cells and living cells, respectively. Q2 and Q4 were used to calculate the proportion of apoptotic cells. Figures show a representative experiment of three independent experiments. *P<0.05 and **P<0.01 compared with As3+ and As4S4 combination treated cells.
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pone.0130343.g002: The effects of combining As3+ and As4S4 on the apoptosis of NB4 and primary APL cells.(A) The apoptosis of NB4 cells. (B) The apoptosis of primary APL cells. (C) The percentage of apoptotic cells in NB4 and primary APL cells. After 48 h of treatment, the cells were stained with Annexin V-FITC and PI. Q1 and Q3, represent the dead cells and living cells, respectively. Q2 and Q4 were used to calculate the proportion of apoptotic cells. Figures show a representative experiment of three independent experiments. *P<0.05 and **P<0.01 compared with As3+ and As4S4 combination treated cells.

Mentions: Cell death comprises two major pathways: apoptosis and necrosis [20]. We investigated the effects of As4S4 on As3+-induced apoptosis in NB4 and primary APL cells by flow cytometry. As shown in Fig 2, Q2 and Q4 represent the percentages of Annexin V-FITC(+)/PI(+) and Annexin V-FITC(+)/PI(-) cells, respectively. After 48 h of treatment, both As3+ and As4S4 obviously induced NB4 cell apoptosis (Fig 2A). Compared with the control, the percentage of apoptotic cells in the group treated with 2.0 μM As4S4 increased from 3.7±1.3% to 19.4±2.6%, and the percentage reached 16.3±2.0% in the 2.0 μM As3+-treated group. Subsequently, we investigated the effects of combining 1.0 μM As4S4 and 1.0 μM As3+ on NB4 cell apoptosis. Compared with the groups treated with either 2.0 μM As4S4 or 2.0 μM As3+, the combination of 1.0 μM As4S4 and 1.0 μM As3+ markedly increased the proportion of apoptotic cells to 29.9±1.9% (Fig 2A and 2C). Similarly, As4S4 acted synergistically effects with As3+ on primary APL cell apoptosis (Fig 2B). Compared with the control, 2.0 μM As4S4 increased the percentage of apoptotic cells from 4.8±1.6% to 17.6±0.7%, and 2.0 μM As3+ increased the percentage of apoptotic cells to 16.8±2.6%. Furthermore, 1.0 μM As4S4 and 1.0 μM As3+ acted synergistically to increase the percentage of apoptotic cells to 28.0±1.5% (Fig 2B and 2C). The combination of As4S4 and As3+ synergistically promoted NB4 and primary APL cell apoptosis.


Tetraarsenictetrasulfide and Arsenic Trioxide Exert Synergistic Effects on Induction of Apoptosis and Differentiation in Acute Promyelocytic Leukemia Cells.

Wang S, Zhou M, Ouyang J, Geng Z, Wang Z - PLoS ONE (2015)

The effects of combining As3+ and As4S4 on the apoptosis of NB4 and primary APL cells.(A) The apoptosis of NB4 cells. (B) The apoptosis of primary APL cells. (C) The percentage of apoptotic cells in NB4 and primary APL cells. After 48 h of treatment, the cells were stained with Annexin V-FITC and PI. Q1 and Q3, represent the dead cells and living cells, respectively. Q2 and Q4 were used to calculate the proportion of apoptotic cells. Figures show a representative experiment of three independent experiments. *P<0.05 and **P<0.01 compared with As3+ and As4S4 combination treated cells.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4481354&req=5

pone.0130343.g002: The effects of combining As3+ and As4S4 on the apoptosis of NB4 and primary APL cells.(A) The apoptosis of NB4 cells. (B) The apoptosis of primary APL cells. (C) The percentage of apoptotic cells in NB4 and primary APL cells. After 48 h of treatment, the cells were stained with Annexin V-FITC and PI. Q1 and Q3, represent the dead cells and living cells, respectively. Q2 and Q4 were used to calculate the proportion of apoptotic cells. Figures show a representative experiment of three independent experiments. *P<0.05 and **P<0.01 compared with As3+ and As4S4 combination treated cells.
Mentions: Cell death comprises two major pathways: apoptosis and necrosis [20]. We investigated the effects of As4S4 on As3+-induced apoptosis in NB4 and primary APL cells by flow cytometry. As shown in Fig 2, Q2 and Q4 represent the percentages of Annexin V-FITC(+)/PI(+) and Annexin V-FITC(+)/PI(-) cells, respectively. After 48 h of treatment, both As3+ and As4S4 obviously induced NB4 cell apoptosis (Fig 2A). Compared with the control, the percentage of apoptotic cells in the group treated with 2.0 μM As4S4 increased from 3.7±1.3% to 19.4±2.6%, and the percentage reached 16.3±2.0% in the 2.0 μM As3+-treated group. Subsequently, we investigated the effects of combining 1.0 μM As4S4 and 1.0 μM As3+ on NB4 cell apoptosis. Compared with the groups treated with either 2.0 μM As4S4 or 2.0 μM As3+, the combination of 1.0 μM As4S4 and 1.0 μM As3+ markedly increased the proportion of apoptotic cells to 29.9±1.9% (Fig 2A and 2C). Similarly, As4S4 acted synergistically effects with As3+ on primary APL cell apoptosis (Fig 2B). Compared with the control, 2.0 μM As4S4 increased the percentage of apoptotic cells from 4.8±1.6% to 17.6±0.7%, and 2.0 μM As3+ increased the percentage of apoptotic cells to 16.8±2.6%. Furthermore, 1.0 μM As4S4 and 1.0 μM As3+ acted synergistically to increase the percentage of apoptotic cells to 28.0±1.5% (Fig 2B and 2C). The combination of As4S4 and As3+ synergistically promoted NB4 and primary APL cell apoptosis.

Bottom Line: Since arsenic trioxide (As3+) has been successfully used in the treatment of acute promyelocytic leukemia (APL), its adverse effects on patients have been problematic and required a solution.Moreover, the combination of low concentrations of As4S4 and As3+ enhanced degradation of the promyelocytic leukemia-retinoic acid receptor α oncoprotein.In summary, As4S4 and As3+ synergistically induce the apoptosis and differentiation of NB4 and primary APL cells.

View Article: PubMed Central - PubMed

Affiliation: State key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210093, China.

ABSTRACT
Since arsenic trioxide (As3+) has been successfully used in the treatment of acute promyelocytic leukemia (APL), its adverse effects on patients have been problematic and required a solution. Considering the good therapeutic potency and low toxicity of tetraarsenictetrasulfide (As4S4) in the treatment of APL, we investigated the effects of combining As4S4 and As3+ on the apoptosis and differentiation of NB4 and primary APL cells. As4S4, acting similarly to As3+, arrested the G1/S transition, induced the accumulation of cellular reactive oxygen species, and promoted apoptosis. Additionally, low concentrations of As4S4 (0.1-0.4 μM) induced differentiation of NB4 and primary APL cells. Compared with the As4S4- or As3+-treated groups, the combination of As4S4 and As3+ obviously promoted apoptosis and differentiation of NB4 and primary APL cells. Mechanistic studies suggested that As4S4 acted synergistically with As3+ to down-regulate Bcl-2 and nuclear factor-κB expression, up-regulate Bax and p53 expression, and induce activation of caspase-12 and caspase-3. Moreover, the combination of low concentrations of As4S4 and As3+ enhanced degradation of the promyelocytic leukemia-retinoic acid receptor α oncoprotein. In summary, As4S4 and As3+ synergistically induce the apoptosis and differentiation of NB4 and primary APL cells.

No MeSH data available.


Related in: MedlinePlus