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Published on: April 13, 2018
Arsenic trioxide induces cell cycle arrest and affects Trk receptor expression in human neuroblastoma SK-N-SH cells
Xilin Xiong1,2, Yang Li3,4, Ling Liu1,5
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Background:
Arsenic 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.
Methods:
The 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.
Results:
Immunohistochemical 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.
Conclusion:
The 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.
Insights
Arsenic trioxide (As2O3) upregulates TrkA, TrkB, and TrkC expression in neuroblastoma (NB) cells, showing potential as an adjuvant therapy. Treatment requires careful dose and time determination for optimal efficacy in different NB stages.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Neuroblastoma (NB) is a pediatric cancer with varied prognosis linked to tyrosine kinase receptor (Trk) expression.
- TrkA and TrkC expression correlate with good prognosis, while TrkB overexpression is linked to tumor progression.
- Arsenic trioxide (As2O3) is a traditional Chinese medicine with known anti-cancer effects, but its impact on Trk receptors in NB is not fully understood.
Purpose of the Study:
- To investigate the effect of As2O3 on Trk receptor expression in NB cell lines.
- To evaluate the potential therapeutic efficacy of As2O3 in regulating Trk expression for NB treatment.
Main Methods:
- SK-N-SH neuroblastoma cells were treated with varying doses of As2O3 over different time intervals.
- Trk receptor expression (TrkA, TrkB, TrkC) was quantified using immunohistochemistry and real-time PCR.
- Cell cycle analysis was performed using flow cytometry to assess As2O3's impact on cell proliferation.
Main Results:
- As2O3 treatment led to significant cell cycle arrest at the G2/M phase in SK-N-SH cells.
- Both TrkA and TrkC were over-expressed in NB, particularly in stages 1, 2, and 4S.
- TrkB expression was elevated in advanced NB stages (3 and 4).
- As2O3 significantly upregulated TrkA, TrkB, and TrkC expression, especially at higher concentrations and after 48 hours of treatment.
Conclusions:
- As2O3 induces varying degrees of Trk expression in neuroblastoma cells.
- The findings suggest As2O3 may serve as a promising adjuvant therapy for NB, leveraging its apoptotic effects.
- Optimizing As2O3 dosage and treatment duration is crucial for maximizing therapeutic benefits across different NB stages.
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