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)

We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and ionizing radiation on the proliferation and survival of nonestablished human glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN and p53 molecules, activated ERBB1VIII, overexpressing wild type ERBB1 or without receptor overexpression were selected. In MTT assays, GST-MDA-7 caused a dose-dependent reduction in the proliferation of nonestablished glioma cells; however only at higher concentrations did GST-MDA-7 reduce cell viability. The anti-proliferative and cytotoxic effects of GST-MDA-7 were enhanced by radiation in a greater than additive fashion that correlated with JNK1/2/3 activation. The reduction in cell growth and enhancement in cell killing by the combination of GST-MDA-7 and radiation were blocked by an ROS scavenger, N-acetyl cysteine (NAC), a JNK1/2/3 inhibitor SP600125, a pan-caspase inhibitor (zVAD) and by an inhibitor of caspase 9 (LEHD), but not by an inhibitor of caspase 8 (IETD). Low concentrations of either GST-MDA-7 or radiation reduced clonogenic survival, however colony formation ability was significantly further decreased when the two treatments were combined, which was also blocked by inhibition of caspase 9 function. In general agreement with activation of the intrinsic caspase pathway, cell death correlated with reduced BCL-XL expression and with increased levels of the pro-apoptotic proteins BAD and BAX. Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and inhibition of ERK1/2 activity. In contrast, incubation with NAC blocked JNK1/2/3 activation and cell killing, but not the increases in BAD and BAX expression. These findings argue that after combination treatment JNK1/2/3 activation is a primary pro-apoptotic event and loss of BCL-XL expression and ERK1/2 activity are secondary caspase-dependent processes. This data also argues that GST- MDA-7 induces two parallel pro-apoptotic pathways via ROS-dependent and -independent mechanisms. Infection of primary human astrocytes with a recombinant adenovirus to express MDA-7, Ad.mda-7, but not infection with either Ad.cmv or Ad.mda-7SP- lacking MDA-7 secretion, resulted in the suppression of GBM cell colony formation in soft agar overlay assays, an effect that was enhanced in a greater than additive fashion by radiation. Collectively, our findings demonstrate that MDA-7 reduces proliferation and enhances the radiosensitivity of nonestablished human GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs independently of basal EGFR/ERK1/2/AKT activity or the functions of PTEN and p53.
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PMID:MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. 1532 89

It has been demonstrated that interleukin 24 (IL-24, also called melanoma differentiation associated gene 7) exerts antitumor activity. In this study, we investigated whether oncolytic adenovirus-mediated gene transfer of IL-24 could induce strong antitumor activity. A tumor-selective replicating adenovirus expressing IL-24 (ZD55-IL-24) was constructed by insertion of an IL-24 expression cassette into the ZD55 vector, which is based on deletion of the adenoviral E1B 55-kDa gene. ZD55-IL-24 could express substantially more IL-24 than Ad-IL-24 because of replication of the vector. It has been shown that ZD55-IL-24 exerted a strong cytopathic effect and significant apoptosis in tumor cells with p53 dysfunction. Moreover, no cytotoxic and apoptotic effects could be seen in normal cells infected with ZD55-IL-24. Expression of IL-24 did not interfere with viral replication induced by oncolytic adenovirus. Activation of caspase 3 and caspase 9, and induction of bax gene expression, were involved in tumor cell apoptosis induced by ZD55-IL-24. Treatment of established tumors with ZD55-IL-24 showed much stronger antitumor activity than that induced by ONYX-015 or Ad-IL- 24. These data indicated that oncolytic adenovirus expressing IL-24 could exert potential antitumor activity and offer a novel approach to cancer therapy.
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PMID:Potent antitumor activity of oncolytic adenovirus expressing mda-7/IL-24 for colorectal cancer. 1600 66

Nuclear factor-kappaB (NF-kappaB) activation promotes cell survival and growth. Reports show that chemotherapeutic agents and cytokines that are used for cancer therapy activate NF-kappaB expression in tumor cells and its suppression enhanced the antitumor activity. We hypothesized that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda7/IL-24) induces NF-kappaB expression and that inhibition of this expression results in enhanced tumor cell killing. Treatment of human lung tumor (H1299 and A549) cells with Ad-mda7 resulted in NF-kappaB activation in a dose- and time-dependent manner before activation of cell death pathways. To establish that inhibition of Ad-mda7-mediated NF-kappaB activation results in enhanced tumor cell killing, H1299 cells that overexpress the dominant-negative I kappa B alpha (dnI kappa B alpha) were treated with Ad-mda7 in vitro. An enhanced growth arrest and apoptosis was observed in Ad-mda7-treated H1299-dnI kappa B alpha compared with H1299-Neo cells. This Ad-mda7-mediated enhanced killing of H1299-dnI kappa B alpha cells involved cleavage of mitogen-activated protein kinase kinase kinase 1 (MEKK1) and caspase-3 in a feedback loop mechanism. The inhibition of MEKK1 or caspase-3 cleavage in H1299-dnI kappa B alpha cells resulted in reduced Ad-mda7-mediated cell killing. In vivo, the treatment of H1299-dnI kappa B alpha s.c. tumors with Ad-mda7 resulted in increased drug sensitivity and delayed the tumor growth rate compared with Ad-mda7-treated H1299-Neo tumors. Molecular analysis of Ad-mda7-treated H1299-dnI kappa B alpha tumors showed increased MEKK1 cleavage and activation of caspase-3 compared with Ad-mda7-treated H1299-Neo tumors. Our findings thus showed that the NF-kappaB activation induced by Ad-mda7 treatment of lung cancer cells is an intrinsic survival mechanism and that the inhibition of this NF-kappaB expression results in enhanced tumor cell killing.
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PMID:Inhibition of nuclear factor-kappaB augments antitumor activity of adenovirus-mediated melanoma differentiation-associated gene-7 against lung cancer cells via mitogen-activated protein kinase kinase kinase 1 activation. 1743 Nov 23

Previous studies have shown that interleukin (IL)-24 as a novel tumor suppressor gene has tumor-suppressor activity in a broad spectrum of human cancer cells both in vitro and in vivo. In this study, we explored the potential effect of adenovirus-mediated IL-24 gene therapy on human hepatocellular carcinoma (HCC) by using a HCC cell line, SMMC-7721. We constructed a recombinant adenovirus, AdVGFP/IL-24 expressing the marker green fluorescent protein (GFP) and the tumor-suppressor gene, IL-24. We demonstrated that AdVGFP/IL-24 treatment of SMMC-7721 cells in vitro significantly induced HCC cell cytotoxicity and apoptosis, and altered HCC cell cycling with an S-phase reduction and G2/M phase arrest, compared with AdVGFP, without IL-24 expresssion (p < 0.05). Furthermore, we also showed that the treatment of SMMC-7721 tumors by an intratumoral injection of AdVGFP/IL-24 significantly suppressed in vivo HCC growth in athymic nude mice, compared with AdVGFP treatment (p < 0.05). In addition, we also elucidated the molecular mechanism responsible for AdVGFP/IL-24-associated tumor suppression. These include: (1) upregulation of p53-independent apoptosis-associated caspase-3 and (2) downregulation of angiogenesis-associated vascular endothelial growth factor and CD34. Therefore, this study will provide a framework for future clinical applications of AdVGFP/IL-24 in HCC gene therapy.
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PMID:Adenovirus-mediated Il-24 expression suppresses hepatocellular carcinoma growth via induction of cell apoptosis and cycling arrest and reduction of angiogenesis. 1762 14

Melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) is a cytokine displaying selective apoptosis-inducing activity in tumors, including glioblastoma (GBM), without damaging normal cells. The present studies focused on defining whether an adenovirus expressing MDA-7/IL-24, Ad.mda-7, infused into pre-formed invasive primary human GBM tumors growing in athymic mouse brains altered tumor cell growth and animal survival, and whether Ad.mda-7 radiosensitized GBM cells and enhanced the survival benefit of irradiation. Ad.mda-7 directly radiosensitized glioma cells in vitro in a JNK1-3- and caspase 9-dependent fashion and demonstrated bystander-effect killing and radiosensitization of GBM cells when primary human astrocytes were infected with Ad.mda-7. Infusion of Ad.mda-7 into pre-formed glioma tumors caused a rapid decrease in proliferation and blood vessel density and an increase in cell killing. Irradiation of Ad.mda-7 infected tumors enhanced cell death. Cell killing correlated with pro-caspase 3 cleavage, enhanced phosphorylation of JNK1-3 and reduced phosphorylation of ERK1/2. Ad.mda-7 enhanced the survival of animals implanted with GBM6 and GBM12 tumors, and significantly increased the survival benefit of irradiation in animals bearing GBM12 tumors. Ad.mda-7 toxicity was evident against CD133+ and CD133- GBM cells; upon tumor re-growth approximately 70-100 days after virus infusion, the relative CD133+ level within the tumor was profoundly reduced with lower Ki67 reactivity and increased beta-galactosidase staining. Infusion of Ad.mda-7 into an immune competent rat brain did not cause normal tissue toxicity 1-4 weeks after infusion using T1 and T2 weighted MRI and H&E staining. Our data demonstrate that Ad.mda-7 prolongs the survival of animals bearing GBM tumors and does so through multiple mechanisms including direct tumor cell killing and selection for surviving cells that are more differentiated and potentially displaying a putatively senescent phenotype.
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PMID:MDA-7/IL-24 plus radiation enhance survival in animals with intracranial primary human GBM tumors. 1837 44

mda-7/IL-24 shows tumor-suppressor activity in a broad spectrum of human cancer cells. However, the molecular mechanism by which mda-7/IL-24 induces apoptosis is not well understood and most likely involves different pathways depending on the tumor. We examined the apoptotic effect of the adenovirus-mediated mda-7/IL-24 (Ad.mda-7) on human HepG2 hepatoma cells. We found that blocking the endoplasmic reticulum (ER) stress inhibited apoptosis induced by Ad.mda-7 and down-regulated the expression of caspase-12, Bax and caspase-3. The treatment of subcutaneous tumor xenografts of HepG2 cells with Ad.mda-7 inhibited tumor growth and angiogenesis. As in the in vitro studies, we found that blocking ER stress prevented Ad.mda-7 from inducing apoptosis in liver cancer cells in vivo. Our studies suggest that Ad.mda-7 induces apoptosis of HepG2 cells mainly through activation of the ER stress pathway.
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PMID:mda-7/IL-24 induces apoptosis in human HepG2 hepatoma cells by endoplasmic reticulum stress. 1863 9

Interleukin (IL)-24 is an excellent therapeutic gene for cancer therapy. In this work, IL-24 was inserted into Ad.sp-E1A(Delta24), an oncolytic adenovirus with a 24-bp deletion in the E1A gene, which was driven by the survivin promoter to form Ad.sp-E1A(Delta24)-IL-24. Ad.sp-E1A(Delta24)-IL-24 has an excellent antitumor effect in vitro for human nasopharyngeal, liver, lung, and cervical carcinoma cell lines but does no or little damage to normal cell lines L-02 and WI38. Furthermore, it achieved nearly complete inhibition (although not elimination) of NCI-H460 lung carcinoma growth in nude mice. The antitumor efficacy of Ad.sp-E1A(Delta24)-IL-24 on NCI-H460 cells was clearly mediated by apoptosis, because it induced caspase-3 and poly(ADP-ribose) polymerase cleavage. This is the first report of Ad.sp-E1A(Delta24)-IL-24 with such an excellent, broad, and specific antitumor effect in vitro and nearly complete inhibition of lung tumor growth in vivo.
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PMID:Potent antitumor effect of interleukin-24 gene in the survivin promoter and retinoblastoma double-regulated oncolytic adenovirus. 1932 May 63

To investigate the inhibitory effect and anti-cancer mechanism of adenovirus mediated IL-24 gene expression on the human U251 glioma cell. U251 glioma cells were infected with Ad-IL-24 at various multiplicity of infection (MOIs). Cell proliferation was determined by MTT assay. Cell apoptosis was detected by flow cytometry and Hochest staining. The transcription of apoptosis-related genes was analyzed by reverse transcription-PCR (RT-PCR), and the expression of Cleaved Caspase-3 was analyzed by Western blotting. The result showed that the growth of U251 glioma cells was significantly inhibited by Ad-IL-24 at the MOI of 100. The apoptotic rate of U251 glioma cells was 42% 72 h after infection with Ad-IL-24. Four days after infection, the growth of the U251 glioma cells was inhibited to 50%. RT-PCR showed that Ad-IL-24 not only up-regulated expression of bax/bcl-2, ICE, C-myc, p53 and down-regulated the expression of HIF-1alpha, but also enhanced Caspase-3 activation, eventually resulting apoptosis. Taken together, these results suggest that infection of U251 glioma cells with Ad-IL-24 can inhibit growth and induce apoptosis significantly by the regulation of apoptosis-related genes.
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PMID:[Adenovirus mediated IL-24 gene expression inhibits growth of human glioma cell in vitro]. 1945 36

To study the inhibitory effect of a recombinant adenoviral vector carrying human IL-24 gene on SGC-7901 human gastric cancer cell. We infected the SGC-7901 gastric cancer cells with Ad blank adenovirus at various multiplicity of infection (MOIs) to find the optimal infective dose. The SGC-7901 tumor cells were infected with Ad-IL-24 at the optimal MOI in the following experiments. Adenovirus-mediated IL-24 transcription expression in SGC-7901 cells was examined by RT-PCR. The growth-suppressing effect of Ad-IL-24 on SGC-7901 tumor cells was assessed by MTT assay. Apoptosis and cell cycle of SGC-7901 tumor cells infected with Ad-IL-24 was evaluated by flow cytometer (FCM), respectively. The karyomorphology of apoptotic SGC-7901 tumor cells was examined using Hoechst33258 staining under fluorescence microscopy. The expression of apoptosis-related genes was future determined by semi-quantification RT-PCR; We demonstrated that the MOI of 100 was the optimal infective dose in the study on adenovirus-mediated IL-24 gene transfer into SGC-7901 gastric cancer cell; IL-24 gene mediated by adenovirus could successfully transcribe in SGC-7901 tumor cells; Ad-IL-24 could significantly inhibit SGC-7901 tumor cell growth and induce apoptosis, it also can up-regulate the express of bax, caspase-3 and p53 whilst down-regulate the bcl-2 expression. Thus, adenovirus-mediated IL-24 expression had marked anti-tumor effect in suppressing SGC-7901 human gastric cancer cell growth and inducing apoptosis, which may be closely associated with its up-regulation of bax/bcl-2, caspase-3 and p53.
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PMID:[Adenovirus mediated IL-24 gene expression suppresses gastric cancer cell growth in vitro]. 2011 6

mda-7/IL-24 has tumor-suppressor activity in a broad spectrum of human cancer cells. However, the therapeutic effect of the recombinant human IL-24 protein on human gallbladder carcinoma has rarely been explored. In this study, we used a human gallbladder carcinoma cell line (GBC-SD) to explore the effect of adenovirus-mediated IL-24 (Ad-IL24) gene therapy on GBC-SD cells. We show that Ad-IL24 treatment of GBC-SD cells in vitro conspicuously induced apoptosis of GBC-SD cells. We also demonstrate that the in vivo treatment of GBC tumor-bearing athymic nude mice intratumorally injected with Ad-IL24 significantly suppressed GBC growth. To further explore the mechanism that mda-7/IL-24 utilized in tumor cell apoptosis, we examined molecules and pathways involved in apoptotic regulation and found that Ad-IL24 induced the down-regulation of anti-apoptotic gene Bcl-2 and the release of cytochrome c, which subsequently activated caspase-9, caspase-3 and PARP to induce apoptosis. In summary, adenovirus (AdV)-mediated IL-24 overexpression exerted potent antitumor activity via stimulating mitochondrial apoptotic pathway in GBC-SD. Therefore, mda-7/IL-24 has the potential to serve as a tool for targeted gene therapy in the treatment of gallbladder cancer.
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PMID:mda-7/IL-24 induces apoptosis in human GBC-SD gallbladder carcinoma cells via mitochondrial apoptotic pathway. 2110 77


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