Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

Wang, Hongtao; Gao, Peng; Zheng, Jie

doi:10.1016/j.bbrc.2014.08.014

Cited by 25 publications

(20 citation statements)

References 33 publications

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“…In this study, we used HEK293 cell lines transfected with AP-1 luciferase reporter construct to detect the activity of AP-1 after As 2 O 3 treatment. We showed that As 2 O 3 inhibit AP-1 in dose- dependent manner and this in line with previous study in HeLa, CaSki, and C33A cells ( Wang et al, 2014 ).…”

Section: Discussionsupporting

confidence: 92%

Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology

2018

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Arsenic trioxide is a traditional remedy in Chinese Medicine since ages. Nowadays, it is clinically used to treat acute promyelocytic leukemia (APL) by targeting PML/RARA. However, the drug’s activity is broader and the mechanisms of action in other tumor types remain unclear. In this study, we investigated molecular modes of action by classical and network pharmacological approaches. CEM/ADR5000 resistance leukemic cells were similar sensitive to As2O3 as their wild-type counterpart CCRF-CEM (resistance ratio: 1.88). Drug-resistant U87.MG ΔEGFR glioblastoma cells harboring mutated epidermal growth factor receptor were even more sensitive (collateral sensitive) than wild-type U87.MG cells (resistance ratio: 0.33). HCT-116 colon carcinoma p53-/- knockout cells were 7.16-fold resistant toward As2O3 compared to wild-type cells. Forty genes determining cellular responsiveness to As2O3 were identified by microarray and COMPARE analyses in 58 cell lines of the NCI panel. Hierarchical cluster analysis-based heat mapping revealed significant differences between As2O3 sensitive cell lines and resistant cell lines with p-value: 1.86 × 10-5. The genes were subjected to Galaxy Cistrome gene promoter transcription factor analysis to predict the binding of transcription factors. We have exemplarily chosen NF-kB and AP-1, and indeed As2O3 dose-dependently inhibited the promoter activity of these two transcription factors in reporter cell lines. Furthermore, the genes identified here and those published in the literature were assembled and subjected to Ingenuity Pathway Analysis for comprehensive network pharmacological approaches that included all known factors of resistance of tumor cells to As2O3. In addition to pathways related to the anticancer effects of As2O3, several neurological pathways were identified. As arsenic is well-known to exert neurotoxicity, these pathways might account for neurological side effects. In conclusion, the activity of As2O3 is not restricted to acute promyelocytic leukemia. In addition to PML/RARA, numerous other genes belonging to diverse functional classes may also contribute to its cytotoxicity. Network pharmacology is suited to unravel the multifactorial modes of action of As2O3.

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Section: Discussionsupporting

confidence: 92%

Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology

2018

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“…demonstrated that As 2 O 3 could be highly effective in the treatment of acute promyelocytic leukemia (APL), and increasing studies have shown that it can induce complete remission, even in patients with relapsed APL, at low doses and with minimal general toxicity [ 8 ]. In other studies, As 2 O 3 has been shown to exert cytotoxic effects on a variety of tumors, such as lung cancer [ 9 ], nasopharyngeal carcinoma [ 10 ], osteosarcoma [ 11 ], neurogliocytoma [ 12 ], hepatoma [ 13 ], cervical cancer [ 14 ], cholangiocarcinoma [ 15 ], breast cancer [ 16 ], gastric cancer [ 17 ] and ovarian cancer [ 18 ]. These effects have been documented in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

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

Xiong

Liu

et al. 2018

Biol Res

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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.

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“…Since the remarkable therapeutic effect of As 2 O 3 on acute promyelocytic leukemia (APL) was recognized (2), an increasing number of researchers have reported its potential anticancer activity in solid tumors, including hepatocellular carcinoma (3,4), and pancreatic (5), prostate (6) and cervical cancer (7). However, the effect of As 2 O 3 on lung cancer, which is the leading cause of cancer mortality worldwide (8), has been poorly explored.…”

Section: Introductionmentioning

confidence: 99%

Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation

et al. 2017

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Abstract. Arsenic trioxide (As 2 O 3 ) exhibits a remarkable effect on leukemia treatment; however, its effect on solid tumors remains poorly explored. The present study demonstrated the inhibitory effect of As 2 O 3 on lung cancer and explored its possible mechanism. It was observed that As 2 O 3 significantly inhibited the growth of lung cancer xenografts and tumor angiogenesis in vivo. The inhibitory effect of As 2 O 3 on cell proliferation in vitro was more remarkable in vascular endothelial cells than in lung cancer cells. It was also observed that As 2 O 3 inhibited the migration of vascular endothelial cells and disrupted vascular tube formation on Matrigel assays. In addition, a series of key signaling factors involved in multiple stages of angiogenesis, including matrix metalloproteinase (MMP)-2, MMP-9, platelet-derived growth factor (PDGF)-BB/PDGF receptor-β, vascular endothelial growth factor (VEGF)-A/VEGF receptor-2, basic fibroblast growth factor (FGF)/FGF receptor-1 and delta like canonical Notch ligand 4/Notch-1, were regulated by As 2 O 3 . These findings suggested that anti-angiogenesis may be an underlying mechanism of As 2 O 3 anticancer activity in lung cancer.

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Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

Cited by 25 publications

References 33 publications

Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology

Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology

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

Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation

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