Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Cannabinoids (CBs) are implicated in the control of cell survival in different types of tumors, but little is known about the role of CB system in pancreatic cancer. Herein, we investigated the in vitro antitumor activity of CBs and the potential role of their receptors in human pancreatic cancer cells MIA PaCa-2. Characterization tools used for this study included growth inhibition/cell viability analyses, caspase 3/7 induction, DNA fragmentation, microarray analysis and combination index-isobologram method. Our results demonstrate that CBs produce a significant cytotoxic effect via a receptor-independent mechanism. The CB1 antagonist N-(piperidin-1-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) was the most active compound with an IC50 of 8.6 +/- 1.3 microM after 72 h. AM251 induces apoptosis, causes transcriptional changes of genes in janus kinase/signal transducers and activators of transcription signaling network and synergistically interacts with the pyrimidine analogue, 5-fluorouracil. These findings exclude the involvement of CB receptors in the regulation of MIA PaCa-2 cell growth and put AM251 forward as a candidate for the development of novel compounds worthy to be tested in this type of neoplasia.
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PMID:Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. 1650 Jun 47

2-Methoxyestradiol is a physiologic metabolite of 17beta-estradiol. This orally active compound can inhibit tumor growth or metastasis in tumor models without inducing any clinical sign of toxicity. Our previous studies indicated that 2-methoxyestradiol-mediated apoptosis involves the disappearance of intact 21-kDa Bid protein, cytochrome c release, and predominant procaspase-3 cleavage. Here, using MIA PaCa-2 cells as a model, we investigated whether this estrogen metabolite induces apoptosis by converging two major pathways: the death receptor-mediated extrinsic and the mitochondrial intrinsic pathway. Exogenous expression of dominant-negative caspase-8 or dominant-negative FADD reverts the effect of 2-methoxyestradiol-mediated cell death. In parallel with this observation, Z-IETD-FMK, a cell permeable irreversible inhibitor of caspase-8, can render significant protection against 2-methoxyestradiol-induced apoptosis. RNase protection assay and cell surface receptor analysis by flow cytometry show the up-regulation of members of death receptor family in 2-methoxyestradiol-exposed pancreatic cancer cells. Our mechanistic studies also implicate that oxidative stress precedes 2-methoxyestradiol-mediated c-Jun NH2-terminal kinase activation, leading to elevated Fas level. Because 2-methoxyestradiol is able to trigger death receptor signaling, we were interested in examining the effects of 2-methoxyestradiol and Fas ligand (FasL)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) together on pancreatic cancer cell death. Interestingly, the endogenous angiogenesis inhibitor 2-methoxyestradiol augments FasL/TRAIL-induced apoptosis in these cells. Moreover, the combination of 2-methoxyestradiol and TRAIL reduces the tumor burden in vivo in MIA PaCa-2 tumor xenograft model by caspase-3 activation.
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PMID:Crosstalk between extrinsic and intrinsic cell death pathways in pancreatic cancer: synergistic action of estrogen metabolite and ligands of death receptor family. 1661 56

Echinacea is one of the most widely used alternative medicine in the world. Intake of Echinacea preparations is common among patients with advanced malignancies enrolled onto phase I chemotherapy trials; however, to our knowledge, no data are available regarding the possible direct effect of Echinacea species on human cancer cells. The purpose of the present study was to investigate potential in vitro cytotoxic and pro-apoptotic properties of hexanic root extract of the three medicinal Echinacea (Asteraceae) species (Echinacea pallida (Nutt.) Nutt., Echinacea angustifolia DC. var. angustifolia, Echinacea purpurea (L.) Moench.) on the human pancreatic cancer MIA PaCa-2 and colon cancer COLO320 cell lines. We demonstrated, for the first time, that all the three species reduced cell viability in a concentration- and time-dependent manner; Echinacea pallida was the most active species with IC(50)s of 46.41+/-0.87 and 10.55+/-0.70 microg/ml in MIA PaCa-2 and COLO320 cells, respectively. Echinacea pallida extract was able to induce apoptosis by increasing significantly caspase 3/7 activity and promoting nuclear DNA fragmentation. These results represent the starting point to establish viable scientific evidence on the possible role of Echinacea species in medical oncology.
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PMID:Cytotoxic effects of Echinacea root hexanic extracts on human cancer cell lines. 1705 74

Gemcitabine is a first line agent for pancreatic cancer, but yields minimal survival benefit. This study evaluated in vitro and in vivo effects of a monoclonal antibody (TRA-8) to human death receptor 5, combined with gemcitabine, using two human pancreatic cancer cell lines, S2VP10 and MIA PaCa-2. A subcutaneous model of pancreatic cancer was employed to test in vivo efficacy. S2VP10 and MIA PaCa-2 cells were treated with varying doses of gemcitabine and TRA-8. Cell viability and apoptosis were determined with an adenosine triphosphate assay and annexin V staining, respectively. Mitochondrial membrane destabilization was evaluated with fluorescence-activated cell sorting analysis of JC-1 stained cells. Caspase activation was evaluated by Western blot analysis. MIA PaCa-2 subcutaneous xenografts in athymic nude mice were evaluated for response to treatment with 200 mug of TRA-8 (intraperitoneal on days 9, 13, 16, 20, 23, and 27 postimplant) and 120 mg/kg gemcitabine (I.P. on days 10, 17, and 24). Tumor growth was measured with calipers. MIA PaCa-2 and S2VP10 cells receiving combination treatment with TRA-8 and gemcitabine demonstrated enhanced cytotoxicity, annexin V staining, and mitochondrial destabilization compared to either agent alone. Combination treatment produced enhanced caspase-3 and -8 activation in both cell lines compared with either agent alone. In vivo studies demonstrated mean subcutaneous tumor surface area (produce of two largest diameters) doubling times of 38 days untreated, 32 days gemcitabine, 49 days TRA-8, and 64 days combination treatment. TRA-8 is an apoptosis-inducing agonistic monoclonal antibody that produced synergistic cytotoxicity in combination with gemcitabine in vitro through enhanced caspase activation. These findings, with substantial inhibition of tumor growth in a mouse pancreatic cancer xenograft model receiving combination therapy, are encouraging for anti-death receptor therapy in the treatment of pancreatic cancer.
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PMID:Treatment with gemcitabine and TRA-8 anti-death receptor-5 mAb reduces pancreatic adenocarcinoma cell viability in vitro and growth in vivo. 1757 Feb 34

Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists ("XAntag"; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC(50) in the range of 2 to 5 mumol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream "effector" caspases (caspase-3 and caspase-7) versus the upstream "initiator" caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation.
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PMID:Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein. 1733 66

HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. Roles of HMGA1 in mediating the malignant phenotype of this cancer are poorly understood. We tested the hypothesis that overexpression of HMGA1 promotes resistance to anoikis (apoptosis induced by anchorage deprivation) in pancreatic cancer cells. HMGA1 cDNA was stably transfected into MiaPaCa2 human pancreatic adenocarcinoma cells (which have low baseline expression levels of HMGA1). Cells were grown in suspension on PolyHEMA-coated plates and their susceptibility to anoikis was assayed using flow cytometry. Overexpression of HMGA1 was associated with marked reductions in susceptibility to anoikis in concert with increases in Akt phosphorylation (Ser473) and in Akt kinase activity and with reductions in caspase 3 activation. Inhibition of phosphoinositidyl-3 (PI3-K)/Akt pathway with either the small molecule inhibitor LY294002 or dominant-negative Akt resulted in reversal of anoikis resistance induced by HMGA1 overexpression. Further, RNA interference-mediated HMGA1 silencing in MiaPaCa2 and BxPC3 (a human pancreatic adenocarcinoma cell line with high baseline levels of HMGA1 expression) cells resulted in significant increases in susceptibility to anoikis. Our findings suggest HMGA1 promotes anoikis resistance through a PI3-K/Akt-dependent mechanism. Given the putative associations between anoikis resistance and metastatic potential, HMGA1 represents a potential therapeutic target in pancreatic adenocarcinoma.
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PMID:Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells. 1734 93

MUC4, a transmembrane mucin, is aberrantly expressed in pancreatic adenocarcinomas while remaining undetectable in the normal pancreas. Recent studies have shown that the expression of MUC4 is associated with the progression of pancreatic cancer and is inversely correlated with the prognosis of pancreatic cancer patients. In the present study, we have examined the phenotypic and molecular consequences of MUC4 silencing with an aim of establishing the mechanistic basis for its observed role in the pathogenesis of pancreatic cancer. The silencing of MUC4 expression was achieved by stable expression of a MUC4-specific short hairpin RNA in CD18/HPAF, a highly metastatic pancreatic adenocarcinoma cell line. A significant decrease in MUC4 expression was detected in MUC4-knockdown (CD18/HPAF-siMUC4) cells compared with the parental and scrambled short interfering RNA-transfected (CD18/HPAF-Scr) control cells by immunoblot analysis and immunofluorescence confocal microscopy. Consistent with our previous observation, inhibition of MUC4 expression restrained the pancreatic tumor cell growth and metastasis as shown in an orthotopic mouse model. Our in vitro studies revealed that MUC4-associated increase in tumor cell growth resulted from both the enhanced proliferation and reduced cell death. Furthermore, MUC4 expression was also associated with significantly increased invasiveness (P < or = 0.05) and changes in actin organization. The presence of MUC4 on the cell surface was shown to interfere with the tumor cell-extracellular matrix interactions, in part, by inhibiting the integrin-mediated cell adhesion. An altered expression of growth- and metastasis-associated genes (LI-cadherin, CEACAM6, RAC1, AnnexinA1, thrombomodulin, epiregulin, S100A4, TP53, TP53BP, caspase-2, caspase-3, caspase-7, plakoglobin, and neuregulin-2) was also observed as a consequence of the silencing of MUC4. In conclusion, our study provides experimental evidence that supports the functional significance of MUC4 in pancreatic cancer progression and indicates a novel role for MUC4 in cancer cell signaling.
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PMID:MUC4 mucin potentiates pancreatic tumor cell proliferation, survival, and invasive properties and interferes with its interaction to extracellular matrix proteins. 1740 26

We have previously shown that the leukotriene B4 receptor antagonist, LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells both in vitro and in vivo. In the current study, we investigated the molecular mechanisms of LY293111-induced apoptosis and cell cycle arrest. Two human pancreatic cancer cell lines were used in this study, MiaPaCa-2 and AsPC-1. Cell cycle analysis by flow cytometry showed a dramatic increase in the percentage of apoptotic cells as well as S-phase arrest after treatment with 250 nmol/l LY293111 for up to 48 h. Western blotting indicated that LY293111 treatment induced cytochrome c release from the mitochondria into the cytosol, accompanied by caspase-9, caspase-7 and caspase-3 activation, and cleavage of poly ADP-ribose polymerase. Caspase-8 was not activated by LY293111. A decrease was found in the expression of the antiapoptotic proteins, Bcl-2 and Mcl-1, and an increase in the proapoptotic protein, Bax. LY293111 reduced the expression of CDK2, cyclin A and cyclin E, consistent with the S-phase arrest observed in these cells. The expression of cyclin-dependent kinase inhibitors, p21 and p27 was not affected by LY293111 treatment. In conclusion, LY293111 induces apoptosis in human pancreatic cancer cells through the mitochondria-mediated pathway. LY293111 also induces S-phase arrest with downregulation of CDK2, cyclin A and cyclin E. Blockade of leukotriene B4 metabolic pathway may provide a novel treatment for human pancreatic cancer.
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PMID:Leukotriene B4 receptor antagonist LY293111 induces S-phase cell cycle arrest and apoptosis in human pancreatic cancer cells. 1741 22

Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen the therapeutic armamentarium, not including GEM, are warranted. MIA PaCa2, CFPAC-1 and Capan-1 pancreatic cancer cell lines were treated with GEM, fluouracil (5-FU), docetaxel (DCT), oxaliplatin (OXP), irinotecan (CPT-11), pemetrexed (PMX) and raltitrexed (RTX) as single agent. Pemetrexed, inducing apoptosis with IC50s under the Cmax in the three lines tested, appeared the most effective drug as single agent. Based on these results, schedule- and concentration-dependent drug interactions (assessed using the combination index) of PMX/GEM, PMX/DCT and PMX-CPT-11 were evaluated. The combinatory study clearly indicated the PMX and CPT-11 combination as the most active against pancreatic cancer. To confirm the efficacy of PMX-CPT-11 combination, we extended the study to a panel of 10 pancreatic cancer cell lines using clinically relevant concentrations (PMX 10 microM; CPT-11 1 microm). In eight of 10 lines, the PMX-CPT-11 treatment significantly reduced cell recovery and increased both the subG1 and caspase 3/7 fraction. After a 5-day wash out period, an increased fraction of subG1 and caspase3/7 persisted in PMX-CPT-11-pretreated cell lines and a significant reduction in the clonogenicity capacity was evident. Finally, in vivo, the PMX/CPT-11 combination showed the ability to inhibit xenograft tumours growth as second-line therapy after GEM treatment. The PMX and CPT-11 combination displays a strong schedule-independent synergistic cytotoxic activity against pancreatic cancer, providing experimental basis for its clinical testing as salvage chemotherapy in pancreatic cancer patients.
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PMID:A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer. 1742 6

FTY720, a synthetic compound produced by modification of a metabolite from Isaria sinclairii, is known as a unique immunosuppressive agent that exerts its activity by inducing apoptosis of lymphocytes [S. Suzuki, FTY720: Mechanisms of action and its effect on organ transplantation, Transplant. Proc. 31 (1999) 2779-2782]. Additionally, it has been found that FTY720 has inhibitory effects on various cancer growth and metastasis [J.D. Wang, S. Takahara, N. Nonomura, Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation, Prostate 40 (1999) 50-55]. To investigate its effect on the growth and metastasis of pancreatic cancer, FTY720 was used to treat three pancreatic cancer cell lines (BxPC-3, AsPC-1, and PANC-1). The MTT assay and flow cytometry were used to evaluate the cell death after FTY720 treatment; the wound closure assay, three-dimensional (3D) Matrigel assay, and invasive assay were used to evaluate the migration, colony formation and invasion abilities after FTY720 treatment, respectively. Protein expression in BxPC-3, AsPC-1, and PANC-1 cells after FTY720 treatment was detected by Western blotting. The MTT assay indicated that the growth of pancreatic cancer cells could be inhibited by FTY720 at various concentrations between 0 and 17 microM in a dose-dependent manner, which was also confirmed by flow cytometry. The wound closure assay, 3D Matrigel assay and cell invasion assay all showed that FTY720 significantly suppressed migration, colony formation and invasion ability of cancer cells at concentrations from 5 to 17 microM. After FTY720 treatment, the phospho-Akt, Bcl-2, pro-caspase-3 expression were down-regulated while the caspase-9 protein expression was increased. In conclusion, FTY720 can inhibit the growth, migration and invasion of pancreatic cancer cells. Our study provides a preclinical support for chemotherapeutic approach with FTY720 for the treatment of pancreatic cancer.
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PMID:FTY720, a synthetic compound from Isaria sinclairii, inhibits proliferation and induces apoptosis in pancreatic cancer cells. 1746 18


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