2-Chloro-2'-deoxyadenosine-induced apoptosis in T leukemia cells is mediated via a caspase-3-dependent mitochondrial feedback amplification loop

Conrad, David M.; Robichaud, Matthew; Boudreau, Robert M.; Richardson, Angela M.; Giacomantonio, Carman A.

doi:10.3892/ijo.32.6.1325

Cited by 12 publications

(19 citation statements)

References 26 publications

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“…Moreover, the silencing of the FADD gene using a FADD-specific siRNA did not inhibit the etoposideinduced processing of caspase-8, indicating that etoposide triggers the activation of caspase-8 by a death receptor-independent pathway (data not shown). These results are in agreement with previous reports showing that genotoxic agents can trigger the caspase-3-dependent activation of caspase-8 by a mitochondrial amplification loop (Slee et al, 2000;von Haefen et al, 2003;Wang et al, 2006;Conrad et al, 2008). It is noteworthy that we showed the expression of caspase-8 to be required for the etoposide-induced activation of caspase-2 in SK-N-AS cells.…”

Section: Discussionsupporting

confidence: 93%

Etoposide Induces Protein Kinase Cδ- and Caspase-3-Dependent Apoptosis in Neuroblastoma Cancer Cells

Day

Safa

2009

Mol Pharmacol

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In this report, we reveal that etoposide inhibits the proliferation of SK-N-AS neuroblastoma cancer cells and promotes protein kinase C␦ (PKC␦)-and caspase-dependent apoptosis. Etoposide induces the caspase-3-dependent cleavage of PKC␦ to its active p40 fragment, and active PKC␦ triggers the processing of caspase-3 by a positive-feedback mechanism. Treatment of cells with the caspase-3-specific inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone or caspase-3-specific small interacting RNA (siRNA) prevented the etoposide-induced activation of caspase-8 and inhibited apoptosis. The silencing of the caspase-2 or caspase-8 genes using siRNAs did not affect the etoposide-induced processing of caspase-3, indicating that these caspases lie downstream of caspase-3 in this signaling pathway. Furthermore, the etoposide-induced processing of caspase-2 required the expression of caspase-8, and the etoposide-mediated processing of caspase-8 required the expression of caspase-2, indicating that these two caspases activate each other after etoposide treatment. We also observed that etoposide-mediated apoptosis was decreased by treating the cells with the caspase-6-specific inhibitor benzyloxycarbonyl-Val-Glu(OMe)-Ile-Asp-(OMe)-fluoromethyl ketone and that caspase-6 was activated by a caspase-8-dependent mechanism. Finally, we show that rottlerin blocks etoposide-induced apoptosis by inhibiting the PKC␦-mediated activation of caspase-3 and by degrading caspase-2, which prevents caspase-8 activation. Our results add important insights into how etoposide mediates apoptotic signaling and how targeting these pathways may lead to the development of novel therapeutics for the treatment of neuroblastomas.

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Section: Discussionsupporting

confidence: 93%

Etoposide Induces Protein Kinase Cδ- and Caspase-3-Dependent Apoptosis in Neuroblastoma Cancer Cells

Day

Safa

2009

Mol Pharmacol

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“…Numerous publications show the increased activity of caspase 9 (Bastin-Coyette et al 2008; Conrad et al 2008; Klöpfer et al 2004). Individual data also reveal the activation of the FAS receptor and caspase 8 through 2-CdA (Nomura et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical evaluation of cell proliferation and apoptosis markers in ovarian surface epithelial cells of cladribine-treated rats

et al. 2013

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Cladribine has been used in the treatment of hairy cell leukemia for about 30 years. In addition, the number of indications for the application of 2-CdA is constantly increasing. The treatment with cladribine, of younger persons and even children, appears to be a major factor stimulating the more exact recognition of its activities. However, till now, little has been known about the impact of cladribine on the reproductive system. The aim of the study was to evaluate the immunohistochemical expression of cell proliferation and apoptosis markers in ovarian surface epithelial (OSE) cells. In our study, ten rats were placed into two equal groups. The study group received daily subcutaneous injections of cladribine in a dose of 0.10 mg/kg of weight/day for one cycle lasting 7 days. The control group received only saline injections. The rats were sacrificed 24 h after the last injection, and their ovaries were extracted. The sections were immunohistochemically stained with cell proliferation marker Ki-67 and the apoptosis marker caspase 3. The expressions of the markers were evaluated using a light microscope. An analysis was made using an image analysis system and the CellAD software. The results were then statistically explored by way of the Mann–Whitney U test. The proliferative index (Ki-67) of ovarian surface epithelial cells was significantly lower in the study group than in the control group (p < 0.05). These results suggest that cladribine treatment has a potential to inhibit the OSE cell proliferation in rats. The apoptosis marker demonstrated a significant increase after the cladribine treatment. These suggest that cladribine induces apoptosis in OSE cells.

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“…Flow cytometric analysis of Jurkat T-leukemia cells stained with 3,3'-dihexyloxacarbocyanine (DiOC 6 ; Molecular Probes, Eugene, Oregon, USA) was performed to determine changes in Δψ m (Conrad et al, 2008). Jurkat T-cells were exposed to PEI or PAMAM polymers for 6 hours and then incubated with DiOC 6 (40 nM) for 30 minutes at 37°C.…”

Section: Flow Cytometrymentioning

confidence: 99%

Comparative studies on the genotoxicity and cytotoxicity of polymeric gene carriers polyethylenimine (PEI) and polyamidoamine (PAMAM) dendrimer in Jurkat T-cells

Choi

Kang

Kim

et al. 2010

Drug and Chemical Toxicology

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A safe alternative to the viral system used in gene therapy is a nonviral gene delivery system. Although polyethylenimine (PEI) and polyamidoamine (PAMAM) dendrimer are among the most promising gene-carrier candidates for efficient nonviral gene delivery, safety concerns regarding their toxicity remain. The aim of this study was to scrutinize the underlying mechanism of the cytotoxicity and genotoxicity of PEI (25 kDa) and PAMAM (G4). To our knowledge, this is the first study to explore the genotoxic effect of polymeric gene carriers. To evaluate cell death by PEI and PAMAM, we performed propidium-iodide staining and lactate-dehydrogenase release assays. The genotoxicity of the polymers was measured by comet assay and cytokinesis-block micronucleus assay. PEI- and PAMAM-treated groups induced both necrotic and apoptotic cell death. In the comet assay and micronuclei formation, significant increases in DNA damage were observed in both treatments. We conclude that PEI and PAMAM dendrimer can induce not only a relatively weak apoptotic and a strong necrotic effect, but also a moderate genotoxic effect.

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2-Chloro-2'-deoxyadenosine-induced apoptosis in T leukemia cells is mediated via a caspase-3-dependent mitochondrial feedback amplification loop

Cited by 12 publications

References 26 publications

Etoposide Induces Protein Kinase Cδ- and Caspase-3-Dependent Apoptosis in Neuroblastoma Cancer Cells

Etoposide Induces Protein Kinase Cδ- and Caspase-3-Dependent Apoptosis in Neuroblastoma Cancer Cells

Immunohistochemical evaluation of cell proliferation and apoptosis markers in ovarian surface epithelial cells of cladribine-treated rats

Comparative studies on the genotoxicity and cytotoxicity of polymeric gene carriers polyethylenimine (PEI) and polyamidoamine (PAMAM) dendrimer in Jurkat T-cells

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