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)

The protease inhibitor ritonavir is an integral part of current antiretroviral therapy targeting human immunodeficiency virus. Recent studies demonstrate that ritonavir induces apoptotic cell death with high efficiency in lymphoblastoid cell lines. Moreover, ritonavir can suppress activation of the transcription factor nuclear factor-kappaB and is an inhibitor of interleukin-1beta and tumor necrosis factor-alpha production in peripheral blood mononuclear cells. Thus, ritonavir appears to have anti-inflammatory properties. In the present study, we investigated in DLD-1 colon carcinoma cell effects of ritonavir on apoptotic cell death and expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme that may be critically involved in the modulation of colonic inflammation. Compared to unstimulated control, ritonavir resulted in a moderate increase in the rate of apoptotic cell death as observed after 20 h of incubation. Notably, ritonavir potently synergized with the short-chain fatty acid butyrate for induction of caspase-3-dependent apoptosis in DLD-1 cells. Ritonavir enhanced mRNA and protein expression of HO-1 in DLD-1 cells. Ritonavir-induced HO-1 protein was suppressed by SB203580 or SB202190 and preceded by immediate upregulation of cellular c-Fos and c-Jun protein levels. This process was associated with induction of activator protein-1 as detected by electrophoretic mobility shift analysis. The present data suggest that ritonavir has the potential to curb colon carcinogenesis by reducing cell growth via mechanisms that include apoptosis and by simultaneously modulating colonic inflammation via induction of anti-inflammatory HO-1.
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PMID:The HIV protease inhibitor ritonavir synergizes with butyrate for induction of apoptotic cell death and mediates expression of heme oxygenase-1 in DLD-1 colon carcinoma cells. 1550 50

The thymidylate synthase inhibitor 5-fluorouracil (5-FU) is used widely for chemotherapy of colorectal carcinoma. Recent studies showed that 5-FU affects polyamine metabolism in colon carcinoma cells. We therefore examined whether combinations of 5-FU with drugs that specifically target polyamine metabolism, i.e. N1,N11-diethylnorspermine (DENSPM) or alpha-difluoromethylornithine (DFMO), have synergistic effects in killing HCT116 colon carcinoma cells with wild-type or absent p53. Our results showed that simultaneous 5-FU and DENSPM, a spermine analogue, synergistically increased transcript levels of the polyamine catabolism enzyme spermidine/spermine N1-acetyltransferase, depleted spermine and spermidine, increased acetylated spermidine, and produced synergistic tumor cell apoptosis in both p53 wild-type and p53-null variants. By contrast, simultaneous combination of 5-FU with DFMO, an inhibitor of the polyamine biosynthetic enzyme ornithine decarboxylase, depleted putrescine but did not produce synergistic cell killing. Some pre-treatment and post-treatment regimens of DENSPM and DFMO were antagonistic to 5-FU depending on cellular p53 status. Protein and transcriptome expression analysis showed that combined 5-FU and DENSPM treatment activated caspase 9, but not caspase 3, and significantly suppressed NADH dehydrogenases and cytochrome c oxidases, consistent with the observed increase in hydrogen peroxide, loss of mitochondrial membrane potential, and release of cytochrome c. Our findings demonstrate the importance of the polyamine pathway in 5-FU effects and suggest that the combination of 5-FU with DENSPM has potential for development as therapy for colorectal carcinoma.
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PMID:Combination of 5-fluorouracil and N1,N11-diethylnorspermine markedly activates spermidine/spermine N1-acetyltransferase expression, depletes polyamines, and synergistically induces apoptosis in colon carcinoma cells. 1554 79

6-methoxydihydrosanguinarine (6ME), a benzophenanthridine alkaloid derived from the methanol extracts of Hylomecon hylomeconoides, showed a dose-dependent effect at 1-10 microM on causing apoptotic cell death in HT29 colon carcinoma cells (IC50 = 5.0+/-0.2 microM). Treatment of HT-29 cells with 6ME resulted in the formation of internucleosomal DNA fragmentation. Treatment of the cells with 6ME caused activation of caspase-3, -8 and 9 protease and subsequent proteolytic cleavage of poly(ADP-ribose)polymerase. 6ME increased the expression of p53 and Bax and decreased the expression of Bid. These results indicate that p53 and proapoptotic Bcl-2 family proteins might participate in the antiproliferative activity of 6ME in HT29 cells.
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PMID:Apoptosis inducing effects of 6-methoxydihydrosanguinarine in HT29 colon carcinoma cells. 1564

NF-kappaB and the upstream kinase PKB/Akt are highly expressed in chemoresistance tumor cells and may hamper the apoptotic pathway. CF101, a specific agonist to the A3 adenosine receptor (A3AR), inhibits the development of colon carcinoma growth in cell cultures and xenograft murine models. Because CF101 has been shown to downregulate PKB/Akt and NF-kappaB protein expression level, we presumed that its combination with chemotherapy will enhance the antitumor effect of the cytotoxic drug. In this study, we utilized 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays and a colon carcinoma xenograft model. It has been shown that a combined treatment of CF101 and 5-fluorouracil (5-FU) enhanced the cytotoxic effect of the latter on HCT-116 human colon carcinoma cell proliferation and tumor growth. Downregulation of PKB/Akt, NF-kappaB, and cyclin D1, and upregulation of caspase-3 protein expression level were observed in cells and tumor lesions on treatment with a combination of CF101 and 5-FU. Moreover, in mice treated with the combined therapy, myelotoxicity was prevented as was evidenced by normal white blood cell and neutrophil counts. These results show that CF101 potentiates the cytotoxic effect of 5-FU, thus preventing drug resistance. The myeloprotective effect of CF101 suggests its development as an add-on treatment to 5-FU.
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PMID:CF101, an agonist to the A3 adenosine receptor, enhances the chemotherapeutic effect of 5-fluorouracil in a colon carcinoma murine model. 1572 Aug 20

Apples contain several classes of polyphenols: monomers (catechins, epicatechins) and oligomers/polymers, such as the procyanidins. Our aim was (i) to study anti-proliferative mechanisms on human metastatic colon carcinoma (SW620 cells) of apple polyphenol fractions (monomers or procyanidins) and (ii) to evaluate their anti-carcinogenic properties in vivo. Two polyphenol-enriched fractions were isolated from apples. Fraction non-procyanidins contained 73% phenolic monomers and no procyanidins, while fraction procyanidins contained 78% procyanidins and no monomers. Inhibition of SW620 cell growth was only observed with fraction P (IC50 = 45 microg/ml). After a 24-h exposure of cells to fraction P, protein kinase C activity was inhibited by 70% and a significant increase in extracellular signal-regulated kinases 1 and 2 and c-jun N-terminal kinases expression was observed together with the down-regulation of polyamine biosynthesis and the activation of caspase-3. Colon carcinogenesis was induced in rats by intraperitoneal injections of azoxymethane, once a week for 2 weeks. Seven days after the last injection, Wistar rats received fraction P (0.01%) dissolved in drinking water. After 6 weeks of treatment, the colon of rats receiving procyanidins showed a significant (P < 0.01) reduction of the number of preneoplastic lesions when compared with controls receiving water. The total number of hyperproliferative crypts and of aberrant crypt foci was reduced by 50% in rats receiving 0.01% apple procyanidins in their drinking water. Our results show that apple procyanidins alter intracellular signaling pathways, polyamine biosynthesis and trigger apoptosis in tumor cells. These compounds antagonize cancer promotion in vivo. In contrast with absorbable drugs, these natural, non toxic, dietary constituents reach the colon where they are able to exert their antitumor effects.
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PMID:Chemopreventive properties of apple procyanidins on human colon cancer-derived metastatic SW620 cells and in a rat model of colon carcinogenesis. 1579 May 89

The anti-cancer drug bleomycin (BLM) induces lung injury and triggers apoptosis of alveolar epithelial cells. In epithelia, among other functions, the adhesion protein CD44 promotes the contact to components of the extracellular matrix like hyaluronate. A functional link between apoptosis and the loss of CD44 has been observed in colon carcinoma cells and involvement of CD44 in apoptosis of lung cells has been reported in several studies. The present in vitro study examined the expression of CD44s (CD44 standard) in two human epithelial lung cell lines, L132 and A549, during BLM-induced apoptosis. A loss of CD44s by lung epithelial cells and an increase of the soluble form of this adhesion protein in culture supernatants upon exposure to BLM were observed. Apoptosis was characterized by an activation of caspase-3 as well as by release of cytochrome C into the cytosol as shown for L132 cells. Inhibition of apoptosis by the broad-range caspase inhibitor Z-VAD-fmk reduced CD44 release by both cell lines demonstrating that CD44 release is a result of apoptotic processes. Kinetic experiments failed to discriminate between the initiation of apoptosis and CD44 release. Blocking experiments using antagonistic anti-CD95 receptor antibodies revealed that BLM may cause apoptosis and CD44 release in a CD95-independent manner.
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PMID:Apoptosis and release of CD44s in bleomycin-treated L132 cells. 1584 16

Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, exhibits both anti-proliferative and anti-angiogenic activities. Atiprimod inhibited proliferation of all human cancer cell lines included in the National Cancer Institute panel with IC50 values in the low micromolar range. Notably, metastatic cell lines were more sensitive to the compound compared to the non-metastatic cell lines derived from the same tumor tissue types. Atiprimod also induced apoptosis and activated both caspase-9 and caspase-3 in T84 colon carcinoma cells. Hence, the anti-proliferative activity could partly be due to its pro-apoptotic activity. Regarding angiogenesis in vitro, atiprimod inhibited both bFGF and VEGF induced proliferation and migration of human umbilical vein endothelial cells (HUVECs), resulting in disruption of cord formation. In addition, atiprimod also suppressed formation of new blood vessels in a chorioallantoic membrane assay. Previous studies have also shown that atiprimod treatment reduced production of IL-6, VEGF and inhibited activation of Stat3, a constitutively activated protein in majority of human cancers. Together these findings suggest that atiprimod acts on several molecules that are essential for tumor growth, invasion and metastasis.
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PMID:Atiprimod is an inhibitor of cancer cell proliferation and angiogenesis. 1584 57

Kahalalide F (KF) is a novel marine-derived antitumor agent that is currently undergoing phase II clinical trials. The mechanism of action of KF is not well understood. In line with previous reports, we show that KF caused rapid and potent cytotoxicity in the breast cancer cell lines SKBR3 and BT474, characterized by cytoplasmic swelling and DNA clumping. Several markers of caspase-dependent apoptosis, such as phosphatidyl-serine externalization, cytochrome c release, and caspase-3 and poly-(ADP-ribose) polymerase cleavage were negative after KF exposure. Inhibitors of caspases or cathepsins failed to protect against KF cytotoxicity. Altogether, these data indicate that KF-induced cell death is a necrosis-like process. The sensitivity to KF in a panel of human tumor cell lines derived from breast (SKBR3, BT474, and MCF7), vulval (A431), non-small-cell lung (H460, A549, SW1573, and H292), and hepatic (Skhep1, HepG2, and Hep3B) carcinomas positively correlated with ErbB3 (HER3) protein levels. A KF-resistant subline of colon carcinoma cells, HT29/KF, expressed significantly reduced levels of all ErbB receptors, but short-term KF exposure of sensitive cell lines such as SKBR3 selectively induced down-regulation of ErbB3. On the other hand, stable transfection of an ErbB3-expressing plasmid increased the KF sensitivity of H460 cells, the most resistant cell line in our panel. Finally, we found that KF efficiently inhibited the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway in sensitive cell lines and that ectopic expression of a constitutively active Akt mutant reduced KF cytotoxicity in this cell line. In summary, our results identify ErbB3 and the downstream PI3K-Akt pathway as important determinants of the cytotoxic activity of KF in vitro.
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PMID:Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling. 1590 15

Previous studies have shown that constitutive activation of epidermal growth factor receptor (EGFR) and ErbB2 by elevated autocrine transforming growth factor-alpha (TGF-alpha) expression plays an important role in colon cancer progression. Coexpression of EGFR and ErbB2 is found in a subset of colon cancers and may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. In this study, the EGFR-selective tyrosine kinase inhibitor (TKI) AG1478 inhibited cell growth of an aggressive human colon carcinoma cell line, FET6alphaS26X, which harbors constitutively activated EGFR after stable transfection with TGF-alpha cDNA. However, AG1478 failed to induce apoptosis in FET6alphaS26X cells at concentrations sufficient for cell growth inhibition and complete suppression of EGFR phosphorylation. Similarly, AG879, a selective ErbB2 TKI, was incapable of inducing apoptosis in FET6alphaS26X cells at concentrations sufficient to inhibit cell growth and ErbB2 phosphorylation. To test the hypothesis that targeting both ErbB family members would show better efficacy than targeting the single receptors, combinations of inhibitors at fixed ratios of 1:1, 5:1, and 10:1 of AG1478 and AG879, respectively, were compared with single drugs for inhibition of cell growth. All combinations resulted in synergistic effects as indicated by combination index analysis. Synergistic inhibition was associated with induction of apoptosis as reflected by poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Annexin V staining. Finally, Western blot analysis showed significant inhibition of phosphorylation of both EGFR and ErbB2 by the combination treatment. These data suggest that the strategy to target both EGFR and ErbB2 simultaneously might result in more efficient inhibition of tumor growth than to target single receptor alone.
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PMID:Synergy of epidermal growth factor receptor kinase inhibitor AG1478 and ErbB2 kinase inhibitor AG879 in human colon carcinoma cells is associated with induction of apoptosis. 1599 62

We have assessed the effect of exogenous human tumor necrosis factor alpha (hTNFalpha) in three human cancer cell lines; MDA-MB-361 (breast adenocarcinoma), HCT 116 (colon carcinoma) and 8-MG-BA (glioma). In vitro transfection of a plasmid containing hTNFalpha under the control of a hybrid promoter resulted in expression of hTNFalpha gene in all three cell lines and secretion into the culture medium was seen with MDA-MB-361 cells. Flow cytometric analysis showed a significant increase in apoptotic and necrotic cells in MDA-MB-361 and to a lesser extent in HCT 116 cells. Increased apoptosis was confirmed by an increase in pro-caspase 3 activation. No effects of hTNFalpha expression were seen in 8-MG-BA cells. Intratumoral delivery of the hTNFalpha expression plasmid into MDA-MB-361 tumor xenografts grown in nude mice caused hemorrhagic tumor necrosis. This strategy may be a simple and promising gene therapy approach to the treatment of some human tumors.
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PMID:Tumor targeted gene therapy with plasmid expressing human tumor necrosis factor alpha in vitro and in vivo. 1605 53


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