Arsenic trioxide induces cell cycle arrest and affects Trk receptor expression in human neuroblastoma SK-N-SH cells

Abstract

BackgroundArsenic trioxide (As2O3), a drug that has been used in China for approximately two thousand years, induces cell death in a variety of cancer cell types, including neuroblastoma (NB). The tyrosine kinase receptor (Trk) family comprises three members, namely TrkA, TrkB and TrkC. Various studies have confirmed that TrkA and TrkC expression is associated with a good prognosis in NB, while TrkB overexpression can lead to tumor cell growth and invasive metastasis. Previous studies have shown that As2O3 can inhibit the growth and proliferation of a human NB cell line and can also affect the N-Myc mRNA expression. It remains unclear whether As2O3 regulates Trks for the purposes of treating NB.MethodsThe aim of the present study was to investigate the effect of As2O3 on Trk expression in NB cell lines and its potential therapeutic efficacy. SK-N-SH cells were grown with increasing doses of As2O3 at different time points. We cultured SK-N-SH cells, which were treated with increasing doses of As2O3 at different time points. Trk expression in the NB samples was quantified by immunohistochemistry, and the cell cycle was analyzed by flow cytometry. TrkA, TrkB and TrkC mRNA expression was evaluated by real-time PCR analysis.ResultsImmunohistochemical and real-time PCR analyses indicated that TrkA and TrkC were over-expressed in NB, and specifically during stages 1, 2 and 4S of the disease progression. TrkB expression was increased in stage 3 and 4 NB. As2O3 significantly arrested SK-N-SH cells in the G2/M phase. In addition, TrkA, TrkB and TrkC expression levels were significantly upregulated by higher concentrations of As2O3 treatment, notably in the 48-h treatment period. Our findings suggested that to achieve the maximum effect and appropriate regulation of Trk expression in NB stages 1, 2 and 4S, As2O3 treatment should be at relatively higher concentrations for longer delivery times;however, for NB stages 3 and 4, an appropriate concentration and infusion time for As2O3 must be carefully determined.ConclusionThe present findings suggested that As2O3 induced Trk expression in SK-N-SH cells to varying degrees and may be a promising adjuvant to current treatments for NB due to its apoptotic effects.

Arsenic Trioxide Increases Apoptosis of SK-N-BE (2) Cells Partially by Inducing GPX4-mediated Ferroptosis

“…The neuroblastoma cell line SK-N-BE (2) were cultured with gradient concentration of ATO for 24hours. Consistent with our previous research [24,25], the results revealed that ATO inhibited SK-N-BE(2) cells (Fig. 1).…”

“…Our previous studies con rmed the anti-tumor growth effect of ATO in NB cells. ATO could inhibit the NB cells growth in vitro by means of arresting NB cells in G2/M phase [24], increasing TrkA/C receptors which related to the good prognosis of NB [25] and reducing multidrug-resistance protein [26]. Our previous work [27]found that ATO can restore the sensitivity of chemotherapy in some relapsed/refractory NB patients.…”

Role of the BDNF/TrkB/CREB signaling pathway in the cytotoxicity of bisphenol S in SK‐N‐SH cells

“…The present study has investigated the effect and mechanism of the BDNF/TrkB/CREB signaling pathway in the cytotoxicity of BPS in SK-N-SH cells, which is a kind of human neuroblastoma cell and has been used in many previous studies of neurotoxicity. [21,22] This is one of the few studies in the literature exploring the neurotoxic mechanisms of BPS.…”

“…The present study has investigated the effect and mechanism of the BDNF/TrkB/CREB signaling pathway in the cytotoxicity of BPS in SK-N-SH cells, which is a kind of human neuroblastoma cell and has been used in many previous studies of neurotoxicity. [21,22] These findings indicate that the apoptotic effect of BPS involved the mitochondria-mediated pathway of apoptosis, which involves an increase in the permeability of the mitochondrial membrane through damage to the membrane. Our results are similar to Qihua Pang's, which found that 100 μM BPS increase the ROS levels and apoptosis rates, and damage the cell membrane for HT-22 cells.…”

Improved Outcomes with Induction Chemotherapy Combined with Arsenic Trioxide in Stage 4 Neuroblastoma: A Case Series

“…6 Our previous study along with others 1 demonstrated that treatment with ATO alone or combined with chemotherapeutic drugs exhibits a satisfactory cytotoxic effect on chemoresistant NB cells. TrkA, TrkB, and TrkC gene expression levels in an NB cell line are upregulated with increasing concentrations of ATO, 9 and treatment with ATO also reduces the expression of the resistance-associated protein, P-glycoprotein (P-gp). 7,8 We also found that preincubation with ATO followed by a mitosis-phase specific agent (vinorelbine or docetaxel) may have a higher anticancer ability compared with single drug treatment or followed by a non-mitosis-phase-specific agent (etoposide or cisplatin), 13 suggested that the combination strategy of ATO and different chemotherapeutics can lead to different tumor killing effects, and it might have clinical implications.…”