Abstract
The present study examined the effects of simvastatin on the proliferation, apoptosis and gene expression levels involved in the nuclear factor-κB (NF-κB) signaling pathway in the human acute promyelocytic leukemia NB4 cell line by methyl thiazolyl tetrazolium assay, flow cytometry and the Human NF-κB Signaling Pathway RT2 Profiler™ PCR Array profiles. The results showed that simvastatin significantly inhibited proliferation and induced apoptosis of the NB4 cells in a time- and dose-dependent manner. Changes were noted in the expression levels of 56 genes involved in the NF-κB signaling pathways in the NB4 cells treated with 15 μm simvastatin at 48 h post-incubation, among which, 47 genes were downregulated and 9 were upregulated. In conclusion, simvastatin potentially inhibits the proliferation and induces the apoptosis of NB4 cells through the regulation of the expression levels of genes involved in the NF-κB signaling pathway.
Highlights
Statins as a pharmacological inhibitor of 3‐hydroxy‐3‐methylglutaryl‐CoAreductase are widely used in the treatment of hypercholesterolemia in humans
Studies that analyzed the use of atorvastatin and fluvastatin in the NB4 acute promyelocytic leukemia (APL) cell line found that the drugs are potent inducers of cell differentiation and apoptosis, establishing the fact that statins demonstrate potent antileukemic properties in vitro and indicating the possibility that statins in combination with all‐trans retinoic acid (ATRA) could be effective in overcoming ATRA resistance in the leukemic cells [6]
Univariate analysis assays were performed using an Annexin V‐fluorescein of variance of the methyl thiazolyl tetrazolium (MTT) results revealed that when treated with simvastatin, the NB4 cell growth inhibition rates gradually increased with time (F=6.638, P=0.03) and dose (F=14.111, P=0.004), indicating that simvastatin potentially inhibits NB4 cell proliferation in a time and dose‐dependent manner (Fig. 1)
Summary
Statins as a pharmacological inhibitor of 3‐hydroxy‐3‐methylglutaryl‐CoAreductase are widely used in the treatment of hypercholesterolemia in humans. Various statins have been shown to exert several beneficial antineoplastic properties, Key words: simvastatin, NB4 cell, NF‐κB signaling pathway, proliferation, apoptosis, PCR array including antiproliferative effects on tumor cells, the inhibition of tumor growth, the induction of cell differentiation and apoptosis and the inhibition of the angiogenesis and metastasis of malignant cells, such as breast cancer, leukemia, prostate cancer and colon cancer cells [1,2,3,4,5,6]. Several studies have shown that, in UCN‐01‐treated cells, simvastatin suppressed the activation of NF‐κB and potentiated the apoptosis induced by doxorubicin, paclitaxel and 5‐fluorouracil [9], acting via a Ras farnesylation‐associated mechanism to create signaling perturbations, the prevention of Ras and ERK1/2 activation, culminating in the synergistic induction of cell death [10]. The cytotoxic potency of simvastatin against NB4 cells and the changes in the NF‐κB signaling pathway are not well clarified
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