Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroblastoma is a common pediatric malignancy that metastasizes to the liver, bone, and other organs. Children with metastatic disease have a less than 50% chance of survival with current treatments. Insulin-like growth factors (IGFs) stimulate neuroblastoma growth, survival, and motility, and are expressed by neuroblastoma cells and the tissues they invade. Thus, therapies that disrupt the effects of IGFs on neuroblastoma tumorigenesis may slow disease progression. We show that NVP-AEW541, a specific inhibitor of the IGF-I receptor (IGF-IR), potently inhibits neuroblastoma growth in vitro. Nordihydroguaiaretic acid (NDGA), a phenolic compound isolated from the creosote bush (Larrea divaricata), has anti-tumor properties against a number of malignancies, has been shown to inhibit the phosphorylation and activation of the IGF-IR in breast cancer cells, and is currently in Phase I trials for prostate cancer. In the present study in neuroblastoma, NDGA inhibits IGF-I-mediated activation of the IGF-IR and disrupts activation of ERK and Akt signaling pathways induced by IGF-I. NDGA inhibits growth of neuroblastoma cells and induces apoptosis at higher doses, causing IGF-I-resistant activation of caspase-3 and a large increase in the fraction of sub-G0 cells. In addition, NDGA inhibits the growth of xenografted human neuroblastoma tumors in nude mice. These results indicate that NDGA may be useful in the treatment of neuroblastoma and may function in part via disruption of IGF-IR signaling.
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PMID:Nordihydroguaiaretic acid inhibits insulin-like growth factor signaling, growth, and survival in human neuroblastoma cells. 1748 36

Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC(50) values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.
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PMID:The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo. 1787 40

Neuroblastoma is the second most common solid tumour during childhood, characterized by rapid disease progression. Most children with metastasized neuroblastoma die despite intensive chemotherapy due to an intrinsic or acquired chemotherapy resistance. Thus, new therapeutic strategies are urgently needed. Here, we demonstrate that the novel compound nemorosone isolated from alcoholic extracts of Clusia rosea resins by reverse phase high pressure liquid chromatography (RP-HPLC) exerts cytotoxic activity in neuroblas-toma cell lines both parental and their clones selected for resistance against adriamycin, cisplatin, etoposide or 5-fluorouracil. Cell cycle studies revealed that nemorosone induces an accumulation in G0/G1- with a reduction in S-phase population combined with a robust up-regulation of p21Cip1. Furthermore, a dose-dependent apoptotic DNA laddering accompanied by an activation of caspase-3 activity was detected. Nemorosone induced a significant dephosphorylation of ERK1/2 in LAN-1 parental cells probably by the inhibition of its upstream kinase MEK1/2. No significant modulation of signal transducers JNK, p38 MAPK and Akt/PKB was detected. The enzymatic activity of immunoprecipitated Akt/PKB was strongly inhibited in vitro, suggesting that nemorosone exerts its anti-proliferative activity at least in part by targeting Akt/PKB in the cell lines studied. In addition, a synergistic effect with Raf-1 inhibitor BAY 43-9006 was found. Finally, nemorosone induced a considerable down-regulation of N-myc protein levels in parental LAN-1 and an etoposide resistant sub-line at the same drug-concentrations.
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PMID:Cytotoxic activity of nemorosone in neuroblastoma cells. 1819 46

Neuroblastoma is the most common solid tumor in children. Despite aggressive chemotherapy, the prognosis of patients with advanced neuroblastoma is still very poor. Our recent study showed that xanthoangelol, a major chalcone constituent of the stem exudates of Angelica keiskei, induced caspase-3-dependent apoptosis in neuroblastoma cells. However, details of the mechanism underlying its apoptotic action are still unclear. Here we show that xanthoangelol triggers oxidative stress by generation of reactive oxygen species and induces apoptosis through release of cytochrome c and activation of caspase-9 in IMR-32 cells. Pretreatment with an antioxidant, vitamin E, prevented the increase of reactive oxygen species and apoptosis induced by xanthoangelol. Proteomic analysis using 2-dimensional electrophoresis and MALDI-TOF-MS revealed that DJ-1 protein was involved in xanthoangelol-induced apoptosis. DJ-1 responded to its oxidative stress status by being oxidized itself. Furthermore, DJ-1 was down-regulated by xanthoangelol, leading to loss of antioxidant function and acceleration of apoptosis. We also show that xanthoangelol has a cytotoxic effect on drug-resistant LA-N-1 and NB-39 cells as well as drug-sensitive IMR-32 and SK-N-SH cells. These findings suggest that xanthoangelol induces apoptosis by increasing reactive oxygen species and targeting DJ-1, and such mechanism may be an effective therapeutic approach for advanced neuroblastoma.
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PMID:Proteomic analysis of apoptosis induced by xanthoangelol, a major constituent of Angelica keiskei, in neuroblastoma. 1837 52

Oxyresveratrol (OXY) is a polyhydroxylated stilbene existing in mulberry. Increasing lines of evidence have shown its neuroprotective effects against Alzheimer disease and stroke. However, little is known about its neuroprotective effect in Parkinson disease (PD). Owing to its antioxidant activity, blood-brain barrier permeativity, and water solubility, we hypothesized that OXY may exert neuroprotective effects against parkinsonian mimetic 6-hydroxydopamine (6-OHDA) neurotoxicity. Neuroblastoma SH-SY5Y cells have long been used as dopaminergic neurons in PD research. We found that both pretreatment and posttreatment with OXY on SH-SY5Y cells significantly reduced the release of lactate dehydrogenase, the activity of caspase-3, and the generation of intracellular reactive oxygen species triggered by 6-OHDA. Compared to resveratrol, OXY exhibited a wider effective dosage range. We proved that OXY could penetrate the cell membrane by HPLC analysis of cell extracts. These results suggest that OXY may act as an intracellular antioxidant to reduce oxidative stress induced by 6-OHDA. Western blot analysis demonstrated that OXY markedly attenuated 6-OHDA-induced phosphorylation of JNK and c-Jun. Furthermore, we proved that OXY increased the basal levels of SIRT1, which may disclose new pathways accounting for the neuroprotective effects of OXY. Taken together, our results suggest OXY, a dietary phenolic compound, as a potential nutritional candidate for protection against neurodegeneration in PD.
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PMID:Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity. 1867

Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, carries a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant, and radiation, long-term survival remains at 30% and new therapies are needed. Recently, a patient with neuroblastoma who acquired Chagas disease was treated with nifurtimox with subsequent reduction in tumor size. The effect of nifurtimox on the neuroblastoma cell lines CHLA-90, LA1-55n, LA-N2, SMS-KCNR, and SY5Y was examined. Nifurtimox decreased cell viability in a concentration-dependent manner. Cell morphology, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay, and caspase-3 activation indicate that cell death was primarily due to apoptosis. Nifurtimox also suppressed basal and TrkB-mediated Akt phosphorylation, and the cytotoxicity of nifurtimox was attenuated by a tyrosine hydroxylase inhibitor (alpha-methyl-tyrosine). Nifurtimox killed catecholaminergic, but not cholinergic, autonomic neurons in culture. In vivo xenograft models showed inhibition of tumor growth with a histologic decrease in proliferation and increase in apoptosis. These results suggest that nifurtimox induces cell death in neuroblastoma. Therefore, further studies are warranted to develop nifurtimox as a promising new treatment for neuroblastoma.
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PMID:Nifurtimox induces apoptosis of neuroblastoma cells in vitro and in vivo. 1926 45

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. The majority of children suffers from high risk neuroblastoma and has disseminated disease at the time of diagnosis. Despite recent advances in chemotherapy, the prognoses for children with high risk NB remain poor. Therefore, new treatment modalities are urgently needed. GD2 ganglioside is an antigen that is highly expressed on NB cells with only limited distribution on healthy tissues. Consequently, it appears to be an ideal target for both active and passive immunotherapy. The immunological effector mechanisms mediated by anti-GD2 monoclonal antibodies (mAbs) have been already well characterized. However, a growing number of reports suggest that GD2-specific antibodies may exhibit anti-proliferative effects without the immune system involvement. Here, we have shown that anti-GD2 14G2a mAb is capable of decreasing survival of IMR-32 human neuroblastoma cells in a dose-dependent manner. Death induced by this antibody exhibited several characteristics typical for apoptosis such as increased number of Annexin V- and propidium iodide-positive cells, cleavage of caspase 3 and prominent rise in caspase activity. The use of a pan caspase inhibitor Z-VAD-fmk suggested that the killing potential of this mAb is partially caspase-dependent. 14G2a mAb was rapidly endocytosed upon antigen binding. Employment of chloroquine, an inhibitor of lysosomal degradation, did not rescue IMR-32 cells from antibody-induced cell death suggesting lack of ceramide involvement in the observed effect. Most importantly, our studies showed that at particular drug concentrations 14G2a mAb exerts a synergistic effect with doxorubicin and topotecan, as well as an additive effect with carboplatin in killing IMR-32 cells in vitro. Our results provide guidance regarding how to best combine GD2-specific 14G2a antibody with existing cancer therapeutic agents to improve available treatment modalities for neuroblastoma.
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PMID:The GD2-specific 14G2a monoclonal antibody induces apoptosis and enhances cytotoxicity of chemotherapeutic drugs in IMR-32 human neuroblastoma cells. 1933 5

Neuroblastoma is a pediatric extracranial tumor and a major cause of death in children under age 2. Conventional therapy shows inefficacy in most cases and thus development of new therapeutic strategies is urgently needed. We explored the efficacy of combination of the small molecule Bcl-2 inhibitor HA14-1 (HA) and the isoflavonoid genistein (GST) in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells. Combination of 10 microM HA and 250 microM GST was optimal for SK-N-BE2 cells and combination of 5 microM HA and 100 microM GST was optimal for SH-SY5Y cells for induction of apoptosis. Phase-contrast microscopy and Wright staining showed morphological features of apoptosis. Cell cycle analysis and Annexin V-FITC/PI binding assay showed that combination of HA and GST was more effective in inducing apoptosis in both cell lines than either HA or GST alone. Western blotting showed that combination of HA and GST caused upregulation of Bax and down regulation of Bcl-2 resulting in increased Bax:Bcl-2 ratio and mitochondrial release of cytochrome c, Smac, and AIF. Down regulation of survival factors such as NF-kappaB, N-Myc, and survivin promoted apoptosis. Activation of caspase-8, calpain, and caspase-3 occurred in course of apoptosis. Increased calpain and caspase-3 activities were confirmed in the degradation of alpha-spectrin to 145 kD spectrin break down product (SBDP) and 120 kD SBDP, respectively. Thus, combination of HA and GST could serve as a promising therapeutic strategy for increasing apoptosis in different human malignant neuroblastoma cells.
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PMID:Bcl-2 inhibitor HA14-1 and genistein together adeptly down regulated survival factors and activated cysteine proteases for apoptosis in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells. 1950 41

Neuroblastoma is the childhood malignancy that mainly occurs in adrenal glands and is found also in the neck, chest, abdomen, and pelvis. New therapeutic strategies are urgently needed for successful treatment of this pediatric cancer. In this investigation, we examined efficacy of the retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) and the isoflavonoid genistein (GST) alone and also in combination for controlling the growth of human malignant neuroblastoma SK-N-BE2 and SH-SY5Y xenografts in nude mice. Combination of 4-HPR and GST significantly reduced tumor volume in vivo due to overwhelming apoptosis in both neuroblastoma xenografts. Time-dependently, combination of 4-HPR and GST caused reduction in body weight, tumor weight, and tumor volume. Combination of 4-HPR and GST increased Bax:Bcl-2 ratio, mitochondrial release of Smac, downregulation of baculovirus inhibitor-of-apoptosis repeat containing (BIRC) proteins including BIRC-2 and BIRC-3, and activation of caspase-3 and apoptosis inducing factor (AIF). Further, downregulation of nuclear factor-kappa B (NF-kappaB), vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF2) was also detected. In situ immunofluorescent labelings of tumor sections showed overexpression of calpain, caspase-12, and caspase-3, and also AIF in the course of apoptosis. Combination therapy increased apoptosis in the xenografts but did not induce kidney and liver toxicities in the animals. Results demonstrated that combination of 4-HPR and GST induced multiple molecular mechanisms for apoptosis and thus could be highly effective for inhibiting growth of malignant neuroblastoma in preclinical animal models.
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PMID:Combination of N-(4-hydroxyphenyl) retinamide and genistein increased apoptosis in neuroblastoma SK-N-BE2 and SH-SY5Y xenografts. 1954 Mar 15

Neuroblastoma is the most common extracranial solid tumor in infants and young children. Current treatments are not always effective and new therapies are needed. We examined efficacy of combination of the small molecule Bcl-2 inhibitor HA14-1 (HA) and the dietary isoflavonoid apigenin (APG) in human malignant neuroblastoma cells. Dose-response studies indicated that treatment with HA and APG for 24 h synergistically reduced cell viability in human malignant neuroblastoma SK-N-DZ, SH-SY5Y, and IMR32 cells. For further studies, we selected SK-N-DZ cells that showed the highest sensitivity following treatment with 2.5 microM HA, 100 microM APG, or combination (2.5 microM HA+100 microM APG). Wright staining showed increase in morphological features of apoptosis. Cell cycle distribution and Annexin V assay showed that combination therapy caused more apoptosis than either treatment alone. Western blotting revealed that combination therapy downregulated angiogenic factors and also induced extrinsic pathway of apoptosis with activation of caspase-8 for Bid cleavage to tBid. Alterations in Bax and Bcl-2 levels resulted in an increase in Bax:Bcl-2 ratio to activate intrinsic pathway of apoptosis with mitochondrial release of cytochrome c into the cytosol and activation of proteases. Increases in calpain and caspase-3 activities generated 145 kD spectrin break down product (SBDP) and 120 kD SBDP, respectively. Results showed that combination of HA and APG could be used for downregulation of angiogenic factors and activation of extrinsic and intrinsic pathways of apoptosis in malignant neuroblastoma cells.
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PMID:Bcl-2 inhibitor and apigenin worked synergistically in human malignant neuroblastoma cell lines and increased apoptosis with activation of extrinsic and intrinsic pathways. 1969 21


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