Arsenic trioxide concentration determines the fate of Ewing's sarcoma family tumors and neuroblastoma cells in vitro

Jung, Hyun Hwan; Kim, Han Seong; Lee, Minjae; Shin, Hee Young; Ahn, Hyo Seop; Ryu, Kyung Ha; Seoh, Ju Young; Kim, Chong Jai; Jang, Ja June

doi:10.1016/j.febslet.2006.07.077

Cited by 15 publications

(8 citation statements)

References 29 publications

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“…It has been reported that ATO promotes apoptotic cell death and phosphorylation of JNK [27]. Although western blot analysis showed that ATO treatment increased the amount of phosphorylated JNK, inhibition of JNK activity had no effect on osteosarcoma cell proliferation with or without ATO, as seen with Ewing sarcoma cells (Figure S1) [23].…”

Section: Resultsmentioning

confidence: 93%

Arsenic Trioxide Prevents Osteosarcoma Growth by Inhibition of GLI Transcription via DNA Damage Accumulation

et al. 2013

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The Hedgehog pathway is activated in various types of malignancies. We previously reported that inhibition of SMO or GLI prevents osteosarcoma growth in vitro and in vivo. Recently, it has been reported that arsenic trioxide (ATO) inhibits cancer growth by blocking GLI transcription. In this study, we analyzed the function of ATO in the pathogenesis of osteosarcoma. Real-time PCR showed that ATO decreased the expression of Hedgehog target genes, including PTCH1, GLI1, and GLI2, in human osteosarcoma cell lines. WST-1 assay and colony formation assay revealed that ATO prevented osteosarcoma growth. These findings show that ATO prevents GLI transcription and osteosarcoma growth in vitro. Flow cytometric analysis showed that ATO promoted apoptotic cell death. Comet assay showed that ATO treatment increased accumulation of DNA damage. Western blot analysis showed that ATO treatment increased the expression of γH2AX, cleaved PARP, and cleaved caspase-3. In addition, ATO treatment decreased the expression of Bcl-2 and Bcl-xL. These findings suggest that ATO treatment promoted apoptotic cell death caused by accumulation of DNA damage. In contrast, Sonic Hedgehog treatment decreased the expression of γH2AX induced by cisplatin treatment. ATO re-induced the accumulation of DNA damage attenuated by Sonic Hedgehog treatment. These findings suggest that ATO inhibits the activation of Hedgehog signaling and promotes apoptotic cell death in osteosarcoma cells by accumulation of DNA damage. Finally, examination of mouse xenograft models showed that ATO administration prevented the growth of osteosarcoma in nude mice. Because ATO is an FDA-approved drug for treatment of leukemia, our findings suggest that ATO is a new therapeutic option for treatment of patients with osteosarcoma.

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Section: Resultsmentioning

confidence: 93%

Arsenic Trioxide Prevents Osteosarcoma Growth by Inhibition of GLI Transcription via DNA Damage Accumulation

et al. 2013

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“…Arsenic concentrations < 1 μM inhibit NF transport into axons in NB2/d1 cells and cultured dorsal root ganglion neurons (DeFuria and Shea 2007). However, some studies have reported that low As concentrations (0.5–1 μM) stimulate neurite outgrowth (Jung et al 2006). One explanation for the observed differences in results is the differing cell culture conditions used during the differentiation treatments, most notably the presence or absence of serum.…”

Section: Discussionmentioning

confidence: 99%

Arsenic Inhibits Neurite Outgrowth by Inhibiting the LKB1–AMPK Signaling Pathway

Wang

Meng

Chang

et al. 2010

Environ Health Perspect

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BackgroundArsenic (As) is an environmental pollutant that induces numerous pathological effects, including neurodevelopmental disorders.Objectives and MethodsWe evaluated the role of the LKB1–AMPK pathway in As-induced developmental neurotoxicity using Neuro-2a (N2a) neuroblastoma cells as a model of developing neurons.ResultsThe addition of low concentrations of As (≤ 5 μM) during differentiation caused an inhibitory effect on the neurite outgrowth in N2a cells in the absence of cell death. Activation of adenosine monophosphate–activated kinase (AMPK) induced by retinoic acid in differentiating cells was blocked by As. Pretreatment with the AMPK-specific activator 5-aminoimidazole-4-carboxamide riboside or overexpression of a constitutively active AMPK-α1 plasmid reversed As-induced inhibition of neurite outgrowth. The activation of LKB1 (serine/threonine kinase 11), a major AMPK kinase, was also suppressed by As by inhibiting both the phosphorylation and the translocation of LKB1 from nucleus to cytoplasm. Antioxidants, such as N-acetyl cysteine and superoxide dismutase, but not catalase, protected against As-induced inactivation of the LKB1–AMPK pathway and reversed the inhibitory effect of As on neurite outgrowth.ConclusionsReduced neurite outgrowth induced by As results from deficient activation of AMPK as a consequence of a lack of activation of LKB1. Oxidative stress induced by As, especially excessive superoxide, plays a critical role in blocking the LKB1–AMPK pathway. Our studies provide insight into the mechanisms underlying As-induced developmental neurotoxicity, which is important for designing a new strategy for protecting children against this neurotoxic substance.

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“…To determine whether Shank 2 expression is related to the neuronal differentiation via ERK 1/2 activation, we assessed Shank 2 expression in differentiated retinoblastoma cells treated with all-trans retinoic acid (Kim et al, 2007a) and addressed the relationship with ERK 1/2 activation (Jung et al, 2006). As shown in Figure 4A, with treatment of all-trans retinoic acid (10 μM) in SNUOT-Rb1 cells, the expression of neurofilament and Shank 2 were increased together.…”

Section: Shank 2 Expression In Neuronal Differentiation Via Erk 1/2 Amentioning

confidence: 99%

Shank 2 expression coincides with neuronal differentiation in the developing retina

Kim

Yang

et al. 2009

Exp Mol Med

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The retinal activity for vision requires a precise synaptic connectivity. Shank proteins at postsynaptic sites of excitatory synapses play roles in signal transmission into the postsynaptic neuron. However, the correlation of Shank 2 expression with neuronal differentiation in the developing retina remains to be elucidated regardless of previous evidences of Shank 2 expression in retina. Herein, we demonstrated that with progression of development, Shank 2 is initially detected in the inner plexiform layer at P2, and then intensively detected in inner plexiform layer, outer plexiform layer, and ganglion cell layer at P14, which was closely colocalized to the neurofilament expression. Shank 2 was, however, not colocalized with glial fibrillary acidic protein. Shank 2 expression was increased in the differentiated retinoblastoma cells, which was mediated by ERK 1/2 activation. Moreover, Shank 2 expression was colocalized with neurofilament at the dendritic region of cells. In conclusion, our data suggests that Shank 2 is expressed in the neurons of the developing retina and could play a critical role in the neuronal differentiation of the developing retina.

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Arsenic trioxide concentration determines the fate of Ewing's sarcoma family tumors and neuroblastoma cells in vitro

Cited by 15 publications

References 29 publications

Arsenic Trioxide Prevents Osteosarcoma Growth by Inhibition of GLI Transcription via DNA Damage Accumulation

Arsenic Trioxide Prevents Osteosarcoma Growth by Inhibition of GLI Transcription via DNA Damage Accumulation

Arsenic Inhibits Neurite Outgrowth by Inhibiting the LKB1–AMPK Signaling Pathway

Shank 2 expression coincides with neuronal differentiation in the developing retina

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