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)

Epidemiological data suggest that epigallocatechin-3-gallate (EGCG) possesses chemopreventive properties against cancer. In this study, we examined the molecular mechanisms of EGCG in human pancreatic cancer cells. EGCG caused growth arrest at G1 stage of cell cycle through regulation of cyclin D1, cdk4, cdk6, p21/WAF1/CIP1 and p27/KIP1, and induced apoptosis through generation of reactive oxygen species and activation of caspase-3 and caspase-9. EGCG inhibited expressions of Bcl-2 and Bcl-XL and induced expressions of Bax, Bak, Bcl-XS and PUMA. Mouse embryonic fibroblasts (MEFs) derived from Bax and Bak double knockout mice exhibited greater protection against EGCG-induced apoptosis than wild-type or single knockout MEFs. EGCG caused Bax activation in p53 -/- MEFs, suggesting that EGCG can induce apoptosis in the absence of p53. Furthermore, the activities of Ras, Raf-1 and ERK1/2 were inhibited, whereas the activities of MEKK1, JNK1/2 and p38 MAP kinases were induced by EGCG. Inhibition of cRaf-1 or ERK enhanced EGCG-induced apoptosis, whereas inhibition of JNK or p38 MAP kinase inhibited EGCG-induced apoptosis. EGCG inhibited the activation of p90 ribosomal protein S6 kinase, and induced the activation of cJUN. Our results suggest that EGCG induces growth arrest and apoptosis through multiple mechanisms, and can be used for pancreatic cancer prevention.
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PMID:Epigallocatechin-3-gallate inhibits cell cycle and induces apoptosis in pancreatic cancer. 1756 28

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that is characterized by a particularly marked resistance to chemotherapy. We previously showed an association between decreased expression of BNIP3 and chemoresistance in PDAC cell lines. To further explore the molecular basis of chemoresistance in PDAC, we analyzed microarray data obtained from normal pancreas and PDAC tumor samples to identify genes exhibiting a negative correlation with the expression profile of BNIP3. This analysis identified several S100 family proteins, of which two, S100A2 and S100A4, showed in vitro the ability to repress exogenous BNIP3 promoter activity. We subsequently showed that RNA interference-mediated S100A4 knockdown resulted in an elevated expression of BNIP3 in PDAC cell lines that possess an unmethylated BNIP3 promoter, suggesting that, in addition to hypermethylation, S100A4 overexpression may represent an alternative mechanism for inhibiting BNIP3 function in PDAC. S100A4 knockdown also resulted in an increased sensitivity of PDAC cell lines to gemcitabine treatment, which was coupled with an increase in apoptosis and cell cycle arrest. To investigate the underlying mechanisms mediating these effects, we studied the effect of silencing the expression of S100A4 on the induction of apoptosis, cell cycle arrest, and the activation of apoptotic mediators. Knockdown of S100A4 clearly induced apoptosis with increased fragmentation of DNA and phosphatidyl serine externalization; activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase; and release of cytochrome c into the cytosol. These findings provide evidence that supports a novel role for S100A4 as a prosurvival factor in pancreatic cancer.
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PMID:S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer. 1763 90

The prognosis of advanced pancreatic cancer is poor. Established chemotherapy shows only limited efficacy and significant side effects. We investigated how far a combination of trichostatin A (TSA) and gemcitabine synergizes to inhibit proliferation and promotion of apoptosis of pancreatic adenocarcinoma cells in vitro. The human pancreatic carcinoma cells YAPC, DANG and Panc-89 and primary human foreskin fibroblasts as non-malignant controls were cultured under standardized conditions and incubated with gemcitabine und TSA alone (10(-4) to 10(-8) M) or together (10(-6) to 10(-7) M). After 24-72 h the apoptotic rate was analyzed by flow cytometry (propidium iodide, FACS). DNA-synthesis was assessed using bromodeoxyuridine (BrdU) incorporation. Protein was separated for Western blotting against caspase-3 and -8, p21, bax and bcl-2. The combination of TSA und gemcitabine leads to better pro-apoptotic effects than the employment of single substances. Bcl-2, a mitochondrial protein, which protects against apoptosis, was not expressed. Bax, an apoptosis inducing protein, which destabilizes the mitochondrial membrane potential, was increasingly expressed. Combination of TSA and gemcitabine shows promise for treatment of pancreatic cancer in vivo.
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PMID:The combination of the histone-deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells. 1767 83

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it is capable of preferentially inducing apoptosis in human cancer over normal cells. The majority of human pancreatic cancers, unfortunately, are resistant to TRAIL treatment. Here, we show that the inhibition of caspase-8 cleavage is the most upstream event in TRAIL resistance in pancreatic cancers. TRAIL treatment led to the cleavage of caspase-8 and downstream caspase-9, caspase-3, and DNA fragmentation factor 45 (DFF45) in TRAIL-sensitive pancreatic cancer cell lines (BXPC-3, PACA-2). This caspase-8-initiated caspase cascade, however, was inhibited in TRAIL-resistant pancreatic cancer cell lines (PANC-1, ASPC-1, CAPAN-1, CAPAN-2). The long and short forms of cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP(L), c-FLIP(S)) were highly expressed in the TRAIL-resistant as compared to the sensitive cells; knockdown of c-FLIP(L) and c-FLIP(S) by a short hairpin RNA (shRNA) rendered the resistant cells sensitive to TRAIL-induced apoptosis through the cleavage of caspase-8 and activation of the mitochondrial pathway. Receptor-interacting protein (RIP) has been reported in TRAIL-induced activation of NF-kappaB and we show here that knockdown of RIP sensitized the resistant cells to TRAIL-induced apoptosis. These results indicate the role of c-FLIP and RIP in caspase-8 inhibition and thus TRAIL resistance. Treatment of the resistant cells with camptothecin, celecoxib and cisplatin resulted in the downregulation of c-FLIP and caused a synergistic apoptotic effect with TRAIL. These studies therefore suggest that combination treatment with chemotherapy can overcome TRAIL resistance and enhance TRAIL therapeutic efficacy in treating pancreatic cancers.
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PMID:Inhibition of RIP and c-FLIP enhances TRAIL-induced apoptosis in pancreatic cancer cells. 1769 58

Pancreatic cancer is one of the most aggressive malignant diseases. We recently reported that N-cadherin plays a key role in tumor progression and metastasis in pancreatic cancer. For this study, we sought to determine if an N-cadherin-blocking peptide (ADH-1) could prevent N-cadherin-mediated tumor progression in a mouse model for pancreatic cancer. The effect of ADH-1 on N-cadherin-mediated cell scattering and migration on collagen I was examined using pancreatic cancer cells. We also examined the influence of ADH-1 on cell apoptosis. Furthermore, in vivo animal studies were performed using orthotopic injection of N-cadherin overexpressing BxPC-3 cells with or without ADH-1 treatment. BxPC-3 and Capan-1 cells exhibited increased expression of N-cadherin in response to collagen I. This increase in N-cadherin promoted cell scattering and migration in response to collagen I. ADH-1 prevented these changes, but did not inhibit upregulation of N-cadherin. TUNEL assays and immunoblots for caspase-3 showed that ADH-1 induced apoptosis in a concentration dependent and N-cadherin dependent manner in pancreatic cancer cells. ADH-1 treatment resulted in significant reductions in tumor growth and lung metastasis in a mouse model for pancreatic cancer. The N-cadherin antagonist, ADH-1 has significant antitumor activity against N-cadherin-expressing cells using in vitro assays and in an orthotopic mouse model for pancreatic cancer, raising the possibility that N-cadherin antagonists have therapeutic potential for the treatment of pancreatic cancer in humans.
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PMID:ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression. 1772 21

Pancreatic cancer is highly resistant to current chemotherapy agents. We therefore examined the effects of triptolide (a diterpenoid triepoxide) on pancreatic cancer growth and local-regional tumor spread using an orthotopic model of pancreatic cancer. We have recently shown that an increased level of HSP70 in pancreatic cancer cells confers resistance to apoptosis and that inhibiting HSP70 induces apoptosis in these cells. In addition, triptolide was recently identified as part of a small molecule screen, as a regulator of the human heat shock response. Therefore, our aims were to examine the effects of triptolide on (a) pancreatic cancer cells by assessing viability and apoptosis, (b) pancreatic cancer growth and local invasion in vivo, and (c) HSP70 levels in pancreatic cancer cells. Incubation of PANC-1 and MiaPaCa-2 cells with triptolide (50-200 nmol/L) significantly reduced cell viability, but had no effect on the viability of normal pancreatic ductal cells. Triptolide induced apoptosis (assessed by Annexin V, caspase-3, and terminal nucleotidyl transferase-mediated nick end labeling) and decreased HSP70 mRNA and protein levels in both cell lines. Triptolide (0.2 mg/kg/d for 60 days) administered in vivo decreased pancreatic cancer growth and significantly decreased local-regional tumor spread. The control group of mice had extensive local invasion into adjacent organs, including the spleen, liver, kidney, and small intestine. Triptolide causes pancreatic cancer cell death in vitro and in vivo by induction of apoptosis and its mechanism of action is mediated via the inhibition of HSP70. Triptolide is a potential therapeutic agent that can be used to prevent the progression and metastases of pancreatic cancer.
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PMID:Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. 1790 50

Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinoma (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1(-/-) mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras(V12) oncoproteins developed bigger tumors than TP53INP1(+/+) transformed MEFs or TP53INP1(-/-) transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity.
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PMID:Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. 1791 Dec 64

We investigated the ability of the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) to reduce pancreatic cancer cell viability. TPEN was much more efficient to inhibit pancreatic adenocarcinoma cell growth than a panel of anti-cancer drugs, including 5-fluorouracil, irinotecan, cisplatin, edelfosine, trichostatin A, mitomycin C, and gemcitabine, the gold standard chemotherapeutic agent for pancreatic cancer. Moreover, TPEN showed a dose- and time-dependent anti-proliferative effect significantly higher on pancreatic cancer cells than on normal primary fibroblasts. This effect may be explained by a significantly higher zinc depletion by TPEN in pancreatic cancer cells as compared to fibroblasts. Cell viability reduction by TPEN was associated to both G1-phase cell cycle arrest and apoptosis, and to the increased ratio of the expression level of cyclin-Cdk inhibitor versus cyclin genes and apoptotic versus anti-apoptotic genes. Finally, we show that apoptotic cell death induced by TPEN involved mitochondrial injury and caspase 3 and caspase 8 activation. In this study, we suggest that zinc depletion may be an efficient strategy in the treatment of pancreatic cancer because of its reduced antiproliferative effect on normal cells.
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PMID:Zinc depletion efficiently inhibits pancreatic cancer cell growth by increasing the ratio of antiproliferative/proliferative genes. 1797 79

We have shown that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, inhibits growth and induces apoptosis in human pancreatic cancer cells. However, the preclinical potential of EGCG in a suitable mouse model has not been examined. In this study, we examined the molecular mechanisms by which EGCG inhibited growth, invasion, metastasis and angiogenesis of human pancreatic cancer cells in a xenograft model system. EGCG inhibited viability, capillary tube formation and migration of HUVEC, and these effects were further enhanced in the presence of an ERK inhibitor. In vivo, AsPC-1 xenografted tumors treated with EGCG showed significant reduction in volume, proliferation (Ki-67 and PCNA staining), angiogenesis (vWF, VEGF and CD31) and metastasis (MMP-2, MMP-7, MMP-9 and MMP-12) and induction in apoptosis (TUNEL), caspase-3 activity and growth arrest (p21/WAF1). EGCG also inhibited circulating endothelial growth factor receptor 2 (VEGF-R2) positive endothelial cells derived from xenografted mice. Tumor samples from EGCG treated mice showed significantly reduced ERK activity, and enhanced p38 and JNK activities. Overall, our data suggest that EGCG inhibits pancreatic cancer growth, invasion, metastasis and angiogenesis, and thus could be used for the management of pancreatic cancer prevention and treatment.
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PMID:EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. 1798 59

Human pancreatic tumor cells are highly resistant to both tumor necrosis factor (TNF) and to chemotherapeutic agents. HER-2/neu expression has been proposed as a negative prognostic marker in pancreatic intraepithelial neoplasia. Our approach was to utilize HER-2/neu expression on the surface of tumor cells as a therapeutic target employing scFv23/TNF, immunocytokine composed of a single chain Fv antibody (scFv23) targeting the HER-2/neu and the cytokine TNF as the cytotoxic moiety, to deliver TNF directly to TNF-resistant pancreatic tumor cells. Using a panel of human pancreatic cell lines, which overexpress HER-2/neu, we evaluated the in vitro response of cells to TNF, scFv23/TNF, Herceptin, and a combination of scFv23/TNF with various chemotherapeutic agents. We found that all pancreatic cancer cell lines were highly resistant to the cytotoxic effects of TNF and that scFv23/TNF was highly cytotoxic to TNF-resistant HER-2/neu-expressing pancreatic cancer cell lines at levels rivaling that of conventional chemotherapeutic agents. Combination studies demonstrated a synergistic cytotoxic effect of scFv23/TNF with 5-fluorouracil (5-FU) in TNF-resistant pancreatic cancer cell lines. Mechanistic studies demonstrated that the 5-FU plus scFv23/TNF combination specifically resulted in a down-regulation of HER-2/neu, p-Akt and Bcl-2 and up-regulation of TNF-R1. In addition, the combination 5-FU plus scFv23/TNF induced apoptosis and this synergistic effect was dependent on activation of caspase-8 and caspase-3. Delivery of the cytokine TNF to HER-2/neu expressing pancreatic tumor cells, which are inherently resistant to TNF using scFv23/TNF may be an effective therapy for pancreatic cancer especially when utilized in combination with 5-FU.
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PMID:The immunocytokine scFv23/TNF targeting HER-2/neu induces synergistic cytotoxic effects with 5-fluorouracil in TNF-resistant pancreatic cancer cell lines. 1808 72


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