Autophagy inhibition enhances etoposide-induced cell death in human hepatoma G2 cells

Yao, Xin

doi:10.3892/ijmm.2011.607

Cited by 34 publications

(21 citation statements)

References 24 publications

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“…Findings of a recent study showed that berberine extracts promoted autophagy by activating beclin 1 expression and activated caspase-9 to induce apoptosis in hepatoma cells (25). Plant lectin from Polygonatum cyrtonema induced apoptosis and autophagy by inhibiting the Ras/Raf and PI3K/Akt signaling pathways in murine fibrosarcoma cells (26). In this study, the selective COX-2 inhibitor celecoxib, not only generated morphological changes indicative of apoptosis, but also typical changes of autophagy to include cytoplasmic autophagic vacuoles and autophagosomes.…”

Section: Discussionmentioning

confidence: 99%

Celecoxib regulates apoptosis and autophagy via the PI3K/Akt signaling pathway in SGC-7901 gastric cancer cells

Liu

Chen

et al. 2014

International Journal of Molecular Medicine

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Gastric cancer, one of the most common malignancies worldwide, typically has a poor prognosis and poor survival rate. Previous studies have investigated the chemopreventive effect of celecoxib. In the present study, the SGC-7901 human gastric cancer cell line was utilized to examine the chemopreventive mechanisms of celecoxib. The inhibition of cell proliferation was determined using MTT assay, cell apoptosis was monitored by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) and flow cytometry, and cell ultrastructural changes were assessed via transmission electron microscopy. The mRNA expression of Akt, caspase-8 and -9 was examined using quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) and p-Akt, procaspase-8 and -9 were analyzed via western blotting. The results showed that celecoxib inhibited the proliferation of SGC-7901 cells in a time- and dose-dependent manner. Additionally, celecoxib induced apoptosis as substantiated by typical apoptotic bodies, autophagosomes and an increased apoptotic rate. It was found that following celecoxib treatment, Akt mRNA expression was not significantly altered, and that p-Akt protein levels decreased in a time- and dose-dependent manner. Additionally, caspase-8 and -9 mRNA expression was significantly increased, while procaspase-8 and -9 protein expression decreased relative to the time- and dose-dependent effects. These results demonstrated that celecoxib induced apoptosis and autophagy of gastric cancer cells in vitro through the PI3K/Akt signaling pathway. Moreover, our findings suggested that celecoxib induces apoptosis in gastric cancer cells through the mitochondrial and death receptor pathways, providing additional understanding regarding the chemopreventive behaviors of celecoxib and its uses in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Celecoxib regulates apoptosis and autophagy via the PI3K/Akt signaling pathway in SGC-7901 gastric cancer cells

Liu

Chen

et al. 2014

International Journal of Molecular Medicine

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“…This increase of autophagy in the glaucomatous retina may act to recycle damaged material and lead to cell death. Depending on the cellular milieu, autophagy, as a lysosome-mediated self-degradation process of eukaryotic cells, can either promote survival or act as an alternative mechanism of PCD for neurons ( 6 , 22 ). Autophagy, as a defense mechanism for the removal of toxic multimeric complexes and aggregated proteins in neurodegenerative diseases, may also occur for self-digestion and self-clearance and the suppression of basal autophagy may cause neurodegeneration ( 6 , 8 ).…”

Section: Discussionmentioning

confidence: 99%

Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats

Wei

Kang

et al. 2014

Experimental and Therapeutic Medicine

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Glaucoma is a neurodegenerative disease characterized by elevated intraocular pressure (IOP), which causes retinal ischemia and progressive neuronal death. Retinal ischemia/reperfusion (RIR) injury is a common clinical condition representing the main cause of irreversible visual field defects in humans. The aim of this study was to investigate whether non-apoptotic forms of programmed cell death (PCD) have an effect on RIR injury in an experimental model that replicates features of acute hypertensive glaucoma and to explore the possible underlying mechanisms. The activation of autophagy was investigated in retinal ganglion cells (RGCs) following RIR in comparison with a control group, using immunofluorescence against microtubule-associated protein 1 light chain 3 (LC3). RIR injury increased LC3 expression in the cytoplasm of RGCs in the ganglion cell layer (GCL) 6 h after the insult, and the increased expression was sustained throughout the experimental period. Following RIR insult, the number of neurons in the GCL significantly decreased. Ultra-structural analyses showed that double- or multiple-membrane autophagosomes were markedly accumulated in the cytoplasm of RGCs following IOP elevation. Since there are no known markers for paraptosis, its identification was based on morphological criteria. Electron microscopy (EM) analysis revealed severe structural alterations associated with cytoplasmatic vacuolization within the 6 h after RIR injury and RGC death. EM also revealed that vacuoles were derived predominantly from the progressive swelling of the endoplasmic reticulum (ER) and/or mitochondria in RGCs after RIR injury. The results provide novel evidence implicating an important role of autophagy and paraptosis in the pathogenesis of RIR injury. Autophagy and paraptosis take place during developmental cell death in the nervous system as well as in certain cases of neurodegeneration. Therefore, targeting autophagy and paraptosis could have therapeutic potential for the prevention of glaucoma involving RIR injury.

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“…However, it is worth noting that other cell death pathways, such as autophagy, necrosis or pyroptosis (caspase-1-dependent inflammation), could also contribute to the enhanced efficacy of the combination in vivo. Etoposide has been reported to induce autophagy in certain cells 36 and it is known that caspase activation can also be induced in glioma cells undergoing autophagy 37 . The differences in the extent of apoptosis amongst the cells may potentially be due to p53 status or activation of Cdk1 checkpoint but further studies may be required to understand this 38 .…”

Section: Discussionmentioning

confidence: 99%

Enhanced Antitumor Efficacy of Low-Dose Etoposide with Oncolytic Herpes Simplex Virus in Human Glioblastoma Stem Cell Xenografts

Cheema

Kanai

Kim

et al. 2011

Clinical Cancer Research

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Purpose Glioblastoma (GBM) inevitably recurs despite surgery, radiation and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSCs), has been implicated in this recurrence. The chemotherapeutic agent, etoposide is generally reserved for treating recurrent tumors, however its effectiveness is limited due to acute and cumulative toxicities to normal tissues. We investigate a novel combinatorial approach of low dose etoposide with an oncolytic HSV to enhance anti-tumor activity and limit drug toxicity. Experimental design In vitro, human GBM cell lines and GSCs were treated with etoposide alone, oHSV-G47Δ alone or the combination. Cytotoxic interactions were analyzed using the Chou-Talalay method and changes in caspase-dependent apoptosis and cell cycle were determined. In vivo, the most etoposide-resistant human GSC, BT74, was implanted intracranially and treated with either treatment alone or the combination. Analysis included effects on survival, therapy-associated adverse events and histological detection of apoptosis. Results GSCs varied in their sensitivity to etoposide by over 50-fold in vitro, while their sensitivity to G47Δ was similar. Combining G47Δ with low dose etoposide was moderately synergistic in GSCs and GBM cell lines. This combination did not enhance virus replication, but significantly increased apoptosis. In vivo, the combination of a single cycle of low dose etoposide with G47Δ significantly extended survival of mice bearing etoposide-insensitive intracranial human GSC-derived tumors. Conclusions The combination of low dose etoposide with G47Δ increases survival of mice bearing intracranial human GSC-derived tumors without adverse side effects. These results establish this as a promising combination strategy to treat resistant and recurrent GBM.

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Autophagy inhibition enhances etoposide-induced cell death in human hepatoma G2 cells

Cited by 34 publications

References 24 publications

Celecoxib regulates apoptosis and autophagy via the PI3K/Akt signaling pathway in SGC-7901 gastric cancer cells

Celecoxib regulates apoptosis and autophagy via the PI3K/Akt signaling pathway in SGC-7901 gastric cancer cells

Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats

Enhanced Antitumor Efficacy of Low-Dose Etoposide with Oncolytic Herpes Simplex Virus in Human Glioblastoma Stem Cell Xenografts

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