Abstract
The objective of this study was to evaluate the effects of tetramethylpyrazine (TMP) in combination with arsenic trioxide (As2O3) on the proliferation and differentiation of HL-60 cells. The HL-60 cells were treated with 300 µg/mL TMP, 0.5 µM As2O3, and 300 µg/mL TMP combined with 0.5 µM As2O3, respectively. The proliferative inhibition rates were determined with MTT. Differentiation was detected by the nitroblue tetrazolium (NBT) reduction test, Wright's staining and the distribution of CD11b and CD14. Flow cytometry was used to analyze cell cycle distribution. RT-PCR and Western blot assays were employed to detect the expressions of c-myc, p27, CDK2, and cyclin E1. Combination treatment had synergistic effects on the proliferative inhibition rates. The rates were increased gradually after the combination treatment, much higher than those treated with the corresponding concentration of As2O3 alone. The cells exhibited characteristics of mature granulocytes and a higher NBT-reducing ability, being a 2.6-fold increase in the rate of NBT-positive ratio of HL-60 cells within the As2O3 treatment versus almost a 13-fold increase in the TMP + As2O3 group. Cells treated with both TMP and As2O3 expressed far more CD11b antigens, almost 2-fold compared with the control group. Small doses of TMP potentiate As2O3-induced differentiation of HL-60 cells, possibly by regulating the expression and activity of G0/G1 phase-arresting molecules. Combination treatment of TMP with As2O3 has significant synergistic effects on the proliferative inhibition of HL-60 cells.
Highlights
A recent study revealed that differentiation may be associated with the induction of apoptosis, and differentiation-inducing therapy may be useful in combination with intensive chemotherapy to increase the susceptibility of leukemia blast cells to drug-induced apoptosis [1]
Www.bjournal.com.br μg/mL TMP and 0.5 μM As2O3 had a synergistic effect on inhibiting the proliferation of HL-60 cells
HL-60 cells incubated with TMP combined with As2O3 for 3 days was significantly increased when compared with either the control group or the As2O3-alone group
Summary
A recent study revealed that differentiation may be associated with the induction of apoptosis, and differentiation-inducing therapy may be useful in combination with intensive chemotherapy to increase the susceptibility of leukemia blast cells to drug-induced apoptosis [1]. In vitro studies have shown that micromolar concentrations of As2O3 can induce apoptosis of leukemia cells, while at lower concentrations (0.1-0.5 μM) As2O3 induces cell differentiation [3,4]. These preclinical studies were confirmed by controlled clinical trials showing that treatment with As2O3 led to complete remission in acute PML patients [5]. Combination treatment using two chemotherapeutic agents at low concentrations has been reported to have improved cytotoxic effects on cancer cells with minimal side effects
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