Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic trioxide (As2O3) induces clinical remission in acute promyelocytic leukemia, even in all-trans retinoic acid-refractory cases, with minimal toxicity at low (1-2 microM) concentration. We exposed various neuroblastoma cell lines to As2O3 at a concentration of 2 microM: as a result, seven of 10 neuroblastoma cell lines underwent apoptosis characterized by morphological changes and nucleosomal DNA fragmentation. As2O3-induced apoptosis in neuroblastoma cells was shown to occur through the activation of caspase 3, as judged from Western blot analysis and apoptosis inhibition assay. It seemed that the sensitivity of neuroblastoma cells to As2O3 was inversely proportional to their intracellular level of reduced glutathione. Taken together these results indicate that As2O3 would be a candidate as a therapeutic agent for treatment of neuroblastoma, which is a solid tumor, not only by systemic therapy but also by local therapy.
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PMID:Arsenic trioxide induces apoptosis in neuroblastoma cell lines through the activation of caspase 3 in vitro. 1042 72

Arsenic trioxide-induced apoptosis was identified by morphological change and nucleosomal DNA fragmentation in hematopoietic malignant cells and neuroblastoma cells. Arsenic trioxide directly induced apoptosis in the acute promyelocytic cell line NB4 cells at a low dose of 1 microM, whereas all-trans-retinoic acid caused the cells to differentiate and finally induced apoptosis. In addition to the involvement of caspase 3 in arsenic trioxide-induced apoptosis of NB4 cells, the activation of caspase 8 was also shown to be involved by Western blot analysis or by apoptosis inhibition assay using caspase 8 inhibitor Ac-IETD-CHO. The down-regulation of Bcl-2 protein was shown in arsenic trioxide-treated pre-apoptotic and early apoptotic mouse B-cell line LyH7 cells, which overexpress Bcl-2 protein, by the studies of Western blot and immunoelectron microscopy. Arsenic trioxide also induced apoptosis in the majority of neuroblastomas cell lines. The arsenic-induced apoptosis in neuroblastoma cell lines was mediated by the activation of caspase 3 in all cases tested. In regard to the intracellular content of reduced glutathione in various neuroblastoma cell lines, the level in the cells sensitive to arsenic trioxide was under 40 nmol/mg protein, but the cells having more than 40 nmol/mg protein did not undergo apoptosis. N-acetylcysteine protected neuroblastoma cells from arsenic-induced apoptosis. Therefore, the intracellular glutathione content may be a good indicator of application of arsenic trioxide for various kinds of cancer cells. Our results raise the possibility that arsenic trioxide will be effective even against a solid tumor such as neuroblastoma and warrants clinical trials for patients with other kinds of tumors not only by systemic therapy but also using local therapy.
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PMID:Arsenic-induced apoptosis in malignant cells in vitro. 1072 69

The aims of the present study were to assess the effects of arsenic trioxide on the nuclear matrix protein profiles of mouse neuroblastoma cells. Arsenic trioxide induces apoptosis of acute promyelocytic leukemia cells. Our results demonstrated that 2 microM As2O3 could significantly inhibit the growth of Neuro-2a cells. As early as 24 hours after As2O3 treatment, we began to observe the alteration of nuclear matrix proteins and apoptosis in tumor cells by TUNEL assay but not by DNA ladder. An increase expression of Hsc in nuclear matrix proteins of 2 microM As2O3 treated cells was also noted. Our results also showed that before a mass range of apoptosis occurred, the composition of nuclear matrix proteins had altered. Hence the alteration of nuclear matrix proteins, such as increased expression of Hsc, may be a sensitive indicator for the detection of early apoptosis.
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PMID:Alteration of nuclear matrix protein composition of neuroblastoma cells after arsenic trioxide treatment. 1129 86

Arsenic trioxide (As(2)O(3)) at low concentrations (1-10 microM) is effective in the treatment of acute promyelocytic leukemia (APL) and lymphoma and is in clinical trials for treatment of solid tumors. Paclitaxel, an antimicrotubule agent, is highly efficacious in the treatment of adult tumors and is in clinical evaluation in childhood tumors. This study is the first to investigate the combination of arsenic and paclitaxel in the range of clinically achievable concentrations. We found that the simultaneous combination was antagonistic on proliferation of the neuroblastoma SK-N-SH cell line by using the combination index (CI) method. Moreover, a 40+/-5% decrease in paclitaxel-induced apoptosis in cells co-treated with As(2)O(3) confirmed the antagonism. The mechanism of antagonism was studied at the cellular level with 200 nM paclitaxel, twice the IC(50) value, and with 1 microM As(2)O(3) which administered singly did not affect cell survival or the microtubule network. As(2)O(3) antagonized the effects of paclitaxel on tubulin and microtubules. Paclitaxel-induced mitotic block was decreased by 20+/-2% and bundles induced by 200 nM paclitaxel were less condensed in the presence of 1 microM As(2)O(3). As(2)O(3) (10-200 microM) induced a concentration-dependent inhibition of tubulin polymerization in vitro which was maintained in presence of paclitaxel. Spectrophotometric and spectrofluorometric measurements indicated an interaction of As(2)O(3) with tubulin SH groups, without modification of the stoichiometry of paclitaxel binding to tubulin. Moreover, 4 microM As(2)O(3) inhibited the release of cytochrome c from isolated mitochondria by 78+/-10%. Our results show that As(2)O(3) and paclitaxel act antagonistically on mitochondria and microtubules and illustrate the need for careful evaluation of drug combinations.
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PMID:Involvement of microtubules and mitochondria in the antagonism of arsenic trioxide on paclitaxel-induced apoptosis. 1203 67

Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in a variety of hematologic malignancies, but very little is known about its effects on solid tumors and especially on neuroblastoma cells that have self-differentiating characteristics. To demonstrate the growth inhibition induced in neuroblastoma cells (the SH-SY5Y and SK-N-AS cell line) and acute promyelocytic leukemia cells (HL-60) by arsenic trioxide (As2O3), the viable cell numbers were counted after trypan blue staining. Apoptosis was assessed by the cell morphology, by flow cytometry with annexin-V staining, and by Western blot analysis for the apoptosis-related proteins (bcl-2 and PARP). To decide the dose for the clinical application of As2O3, normal peripheral blood lymphocytes were also examined. The growth and survival of the SH-SY5Y and SK-N-AS cells were markedly inhibited by As2O3 treatment at a 3 microM concentration before the changes of the normal lymphocytes were observed. The apoptotic cells showed a shrunken cell nucleus, and an increase in the number and balloon-like swelling of the mitochondria at 72 h after the As2O3 was added. Apoptosis of the annexin-V-positive cell proportion in the neuroblastoma cell lines was increased with increasing the exposure time and the concentration of As2O3, just like the HL-60 cells. Bcl-2 downregulation and PARP degradation were also noted all the cell lines, but these changes were not statistically significant among the 3 cell lines. Taken together, these results indicate that As2O3 is an excellent candidate as a therapeutic agent for the treatment of neuroblastoma.
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PMID:Morphological and biochemical changes induced by arsenic trioxide in neuroblastoma cell lines. 1616 54

Arsenic trioxide (As(2)O(3)) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner. We assessed the effects of As(2)O(3) in CADO-ES Ewing's sarcoma (ES), JK-GMS peripheral primitive neuroectodermal tumor (PNET), and SH-SY5Y neuroblastoma cells, as they share common histogenetic backgrounds. As(2)O(3) at low concentrations (0.1-1 microM) induced SH-SY5Y differentiation, and whereas PNET cells acquired a slightly differentiated phenotype, change was minimal in ES cells. Extracellular signal-regulated kinase 2 (ERK2) was activated at low As(2)O(3) concentrations, and PD98059, an inhibitor of MEK-1, blocked SH-SY5Y cell differentiation by As(2)O(3). High concentrations (2-10 microM) of As(2)O(3) induced the apoptosis in all three cell lines, and this was accompanied by the activation of c-jun N-terminal kinase. The generation of H(2)O(2) and activation of caspase 3 were identified as critical components of As(2)O(3)-induced apoptosis in all of the above cell lines. Fibroblast growth factor 2 enhanced As(2)O(3)-induced apoptosis in JK-GMS cells. The overall effects of As(2)O(3) strongly suggest that it has therapeutic potential for the treatment of ES/PNET.
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PMID:Arsenic trioxide concentration determines the fate of Ewing's sarcoma family tumors and neuroblastoma cells in vitro. 1693 May 95

Arsenic trioxide (As(2)O(3)) has anticancer properties; however, its use also leads to neuro-, hepato- or nephro-toxicity, and therefore, it is important to understand the mechanism of As(2)O(3) toxicity. We studied As(2)O(3) influence on intracellular calcium ([Ca(2+)](i)) homeostasis of human neuroblastoma SY-5Y and embryonic kidney cells (HEK 293). We also relate the As(2)O(3) induced [Ca(2+)](i) modifications with cytotoxicity. We used Ca(2+) sensitive dyes (fluo-4 and rhod-2) combined with laser scanning microscopy or fluorescence activated cell sorting to measure Ca(2+) changes during the application of As(2)O(3) and we approach evaluation of cytotoxicity. As(2)O(3) (1 microM) increased [Ca(2+)](i) in SY-5Y and HEK 293 cells. Three forms of [Ca(2+)](i)-elevations were found: (1) steady-state increases, (2) transient [Ca(2+)](i)-elevations and (3) Ca(2+)-spikes. [Ca(2+)](i) modifications were independent from extracellular Ca(2+) but dependent on internal calcium stores. The effect was not reversible. Inositol triphosphate (IP(3)) and ryanodine (Ry) receptors are involved in regulation of signals induced by As(2)O(3). 2-APB and dantrolene significantly reduced the [Ca(2+)](i)-rise (p<0.001, t-test) but did not completely abolish [Ca(2+)](i)-elevation or spiking. This indicates that other Ca(2+) regulating mechanisms are involved. In cytotoxicity tests As(2)O(3) significantly reduced cell viability in both cell types. Staining with Hoechst 33342 showed occurrence of apoptosis and DNA damage. Our data suggest that [Ca(2+)](i) is an important messenger in As(2)O(3) induced cell death.
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PMID:Arsenic trioxide (As2O3) induced calcium signals and cytotoxicity in two human cell lines: SY-5Y neuroblastoma and 293 embryonic kidney (HEK). 1737 98

Arsenic trioxide (As(2)O(3)) is toxic to multidrug-resistant neuroblastoma cells in vivo and in vitro. In neuroblastoma, As(2)O(3) does not exert its cell death-promoting effects via a classical apoptotic pathway. A death mechanism involving proteolytic cleavage of Bax to a p18 form seems to be of importance, because inhibition of Bax cleavage coincides with diminished cell death. As existing models of cell death implicate Bax in the intrinsic apoptotic pathway, triggering death after Bax translocation to the mitochondria, we investigated the cellular localization of p18 Bax by subcellular fractionation. After As(2)O(3) treatment, p18 Bax was only present in nuclei-enriched, mitochondria-depleted fractions. Cytoplasmic p21 Bax levels decreased, whereas total (p21 and p18) nuclear Bax increased. Overexpressed p21 Bax localized to the cytoplasm and nuclei, whereas overexpressed p18 Bax localized to extra-nuclear structures only. The inability of overexpressed p18 Bax to locate to the nucleus, and the As(2)O(3)-induced reduction of p21 Bax in the cytosol, suggest an As(2)O(3)-induced mechanism where p18 Bax gets cleaved and 'trapped' in the nucleus. This model is strengthened by the observation that calpain, the protease responsible for p18 Bax generation, is present in the nuclei, and that nuclear calpain is induced by increasing As(2)O(3) and Ca(2+) levels.
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PMID:Arsenic trioxide-induced neuroblastoma cell death is accompanied by proteolytic activation of nuclear Bax. 1740 72

The majority of aggressive forms of the childhood tumor neuroblastoma can with current treatment protocols not be cured and possess a major challenge in pediatric oncology. After initial rounds of chemotherapy, surgery and irradiation, which in most cases result in tumor regression, these aggressive neuroblastomas relapse and frequently develop drug resistance. As approximately 50% of the children with neuroblastoma have an aggressive form, there is a compelling demand for new treatment strategies. Arsenic trioxide has the capacity to kill multidrug-resistant neuro-blastoma cells in vitro and in vivo and the drug is currently being evaluated in clinical trials. In this report we discuss the background to the use of arsenic trioxide in cancer therapy and the currently known mechanisms by which arsenic trioxide kills human neuroblastoma cells.
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PMID:Arsenic trioxide and neuroblastoma cytotoxicity. 1754 41

Arsenic trioxide (ATO) is known to have concentration-dependent dual effects on acute promyelocytic leukemia (APL) cells, preferentially inducing apoptosis at relatively high concentrations and promoting partial differentiation at low concentrations. Protein phosphatase 2A (PP2A) has been demonstrated to take part in the differentiation and apoptosis of malignant hematological cells induced by commonly used medicines, such as all-transretinoic acid (ATRA), interferon, arsenic sulfide, etc. However, there are almost no data on the role PP2A plays in ATO-induced APL cell differentiation/apoptosis. In this report, our goal was to show that ATO inhibited the proliferation and induced the apoptosis and differentiation of neuroblastoma NB4 cells. Okadaic acid (OKA), a specific inhibitor of protein phosphatase activity, markedly increased these effects of ATO on cells. To further elucidate the regulation of PP2A during ATO-induced differentiation/apoptosis of NB4 cells, we measured the phosphatase activity and protein expression of PP2A. The activity of PP2A in NB4 cells decreased with increasing concentration of ATO. This decrease of PP2A activity appeared to parallel phenotypic and functional changes of NB4 cells. Western blot analysis showed that the levels of the PP2A structural subunit PP2A-A decreased during the course of ATO-induced differentiation/apoptosis, whereas the expression of the B and C subunits of PP2A was relatively unaltered. In conclusion, the decrease of PP2A activity may be involved in ATO-induced apoptosis and differentiation of APL cells, and this decrease is predicted to be related to the repression of PP2A-A subunit expression.
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PMID:Involvement of protein phosphatase 2A in arsenic trioxide-induced differentiation and apoptosis of NB4 cells. 1885 42


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