Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer is one of the leading causes of cancer-related death in Western countries. Bcl-x(L) is an anti-apoptotic factor of the Bcl-2 family, which is overexpressed in pancreatic cancer and its presence correlates with shorter patient survival. In this study, sequence-specific antisense oligonucleotides targeting the coding region of Bcl-x(L) were designed to examine whether apoptosis could be induced and chemosensitivity could be increased in pancreatic cancer cells. Five pancreatic cancer cell lines, Panc-1, MIA-PaCa-2, Capan-1, ASPC-1 and T3M4, were treated with Bcl-x(L) sense or antisense oligonucleotides and gemcitabine and the cell viability was examined by the SRB method. Apoptosis was determined using DAPI staining. In all examined pancreatic cancer cells, Bcl-x(L) expression was reduced after transfection of the antisense oligonucleotides. Cell death analysis using DAPI staining revealed that antisense, but not sense oligonucleotides caused apoptotic cell death. Furthermore, Bcl-x(L) antisense oligonucleotides enhanced the cytotoxic effects of gemcitabine in pancreatic cancer cells. Our results indicate that Bcl-x(L) antisense oligonucleotides effectively inhibited pancreatic cancer cell growth and caused apoptosis by reducing Bcl-x(L) protein levels. Bcl-x(L) antisense oligonucleotides also increased the chemosensitivity of pancreatic cancer cells, suggesting that Bcl-x(L) antisense therapy might be a potential future approach in this disease.
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PMID:Bcl-x(L) antisense oligonucleotides induce apoptosis and increase sensitivity of pancreatic cancer cells to gemcitabine. 1166 8

Mild metabolic stress may increase resistance of neurons in the brain to subsequent, more severe insults, as demonstrated by the ability of ischemic pre-conditioning and dietary restriction to protect neurons in experimental models of stroke- and age-related neurodegenerative disorders. In the present study we employed iodoacetic acid (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, to test the hypothesis that inhibition of glycolysis can protect neurons. Pre-treatment of cultured hippocampal neurons with IAA can protect them against cell death induced by glutamate, iron and trophic factor withdrawal. Surprisingly, protection occurred with concentrations of IAA (2-200 nM) much lower than those required to inhibit glycolysis. Pre-treatment with IAA results in suppression of oxyradical production and stabilization of mitochondrial function in neurons after exposure to oxidative insults. Levels of the stress heat-shock proteins HSP70 and HSP90, and of the anti-apoptotic protein Bcl-2, were increased in neurons exposed to IAA. Our data demonstrate that IAA can stimulate cytoprotective mechanisms within neurons, and suggest the possible use of IAA and related compounds in the prevention and/or treatment of neurodegenerative conditions.
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PMID:Iodoacetate protects hippocampal neurons against excitotoxic and oxidative injury: involvement of heat-shock proteins and Bcl-2. 1167 64

The antiproliferative action of 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite is specific for cancer cells and is mediated by the induction of programmed cell death or apoptosis. But the identity of the downstream effectors of apoptotic signaling induced by 2-ME is not known. In the present study, we explored the effect of 2-ME on apoptosis in a panel of human pancreatic cancer cell lines. We have identified two categories of pancreatic cancer cell lines, which are either sensitive to 2-ME such as MIA PaCa-2, CFPAC-1, PANC-1, or non-sensitive to 2-ME such as Hs 766T. The results presented here indicated that the cell lines responsive to 2-ME could undergo apoptosis either by G2-M arrest (PANC-1) with Bcl-x(L) phosphorylation or by the accumulation of tetraploid cells in G1-S region (MIA PaCa-2) without Bcl-2/ Bcl-x(L) phosphorylation. Furthermore, 2-ME induced apoptosis in pancreatic cancer cells is mitochondria dependent as evident by the release of cytochrome c into the cytosol. 2-ME exposed cells exhibit Bid cleavage that is accompanied by the translocation of Bax into the mitochondria. Also 2-ME could induce phosphorylation of Bcl-x(L) in G2-M arrested cells, thus indicating the involvement of various anti- and pro-apoptotic regulators in the signaling cascade. The dissection of differential response of pancreatic cancer cell lines holds promise for future therapeutic intervention.
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PMID:2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells. 1203 71

Pancreatic cancer is often resistant to conventional chemotherapy. In this study, we examined the role of adenovirus-mediated overexpression of E2F-1 in inducing apoptosis and increasing the sensitivity of pancreatic cancer cells to chemotherapeutic agents. MIA PaCa-2 pancreatic head exocrine adenocarcinoma cells (mutant p53) were treated by mock infection or adenoviruses expressing beta-galactosidase or E2F-1 (Ad-E2F-1) alone or in combination with sublethal concentrations of each chemotherapeutic drug. Cell growth and viability were assessed at selected time points. Apoptosis was evaluated by flow cytometry, characteristic changes in cell morphology and poly (ADP-ribose) polymerase (PARP) cleavage. Western blot analysis was used to examine the expression of E2F-1 and Bcl-2 family member proteins and PARP cleavage. Western blot analysis revealed marked overexpression of E2F-1 at a multiplicity of infection (MOI) of 20 and 70. By 3 days after infection, Ad-E2F-1 treatment at an MOI of 70 resulted in approximately a 20-fold reduction in cell growth and 60% reduction in cell viability as compared to mock-infected cells. Cell cycle analysis, PARP cleavage and changes in cell morphology supported apoptosis as the mechanism of cell death in response to E2F-1. In order to test the efficacy of treatment with a combination of gene therapy and chemotherapy, we utilized concentrations of Ad-E2F-1 which reduced viability to 50% in combination with each chemotherapeutic agent. Cotreatment of the cells with E2F-1 virus and roscovitine (ROS) or etoposide resulted in an additive effect on cell growth inhibition and induction of apoptosis. Interestingly, 5-fluorouracil did not cooperate with Ad-E2F-1 in the mediation of tumor death or inhibition of cell growth. Immunoblotting for Bcl-2 family members revealed no significant changes in the expression levels of Bcl-2, Bcl X(L), Bax or Bak following gene or 'chemogene' therapy with E2F-1. However, a Bax cleavage product was noted which was substantially increased by cotreatment with ROS or etoposide. E2F-1 overexpression initiates apoptosis and suppresses growth in pancreatic MIA PaCa-2 cells in vitro. E2F-1-mediated apoptosis was not associated with significant changes in the expression of Bcl-2 family member proteins in these pancreatic cancer cells. ROS and etoposide, when combined with E2F-1 overexpression, induce apoptosis in an additive manner. This chemogene combination may provide a potentially useful therapeutic strategy for advanced pancreatic cancer.
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PMID:E2F-1 gene therapy induces apoptosis and increases chemosensitivity in human pancreatic carcinoma cells. 1206 45

We investigated the ability of thymidine phosphorylase (TP) to confer cancer cells resistance to MIA (microtubule-interfering agents)-induced apoptosis. Jurkat cells were stably transfected with TP cDNA (Jurkat/TP) and the sensitivity to MIAs were examined. Jurkat/TP cells were more resistant to apoptosis induced by nocodazole, vincristine, vinblastine, paclitaxel and 2-methoxyestradiol than mock-transfected Jurkat/CV cells. TP enzymatic activity was not required for this effect of TP. Jurkat/TP cells showed weak phosphorylation of Bcl-2, and kinase inhibitors staurosporine and genistein attenuated not only MIA-induced Bcl-2 phosphorylation but also cytotoxicity of MIA in Jurkat/CV, but not in Jurkat/TP. MIAs diminished expression of FasL in Jurkat/TP but not in Jurkat/CV, and neutralization of FasL by anti-FasL antibody considerably attenuated the cytotoxic effect of the MIAs in Jurkat/CV, but the effect of the antibody was marginal in Jurkat/TP cells. Our study provides further evidence that TP functions in conferring resistance on cancer cells to the stress induced by MIAs. In addition, we show that TP-induced inhibition of Bcl-2 phosphorylation and suppression of FasL may contribute to the protective function of TP in cancer cells.
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PMID:Thymidine phosphorylase suppresses apoptosis induced by microtubule-interfering agents. 1590 5

The aim of this study was to investigate the anticancer effects of the phenoxazine derivatives, 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1), 3-amino-1,4alpha-dihydro-4alpha,8-dimethyl-2H-phenoxazine-2-one (Phx-2), and 2-aminophenoxazine-3-one (Phx-3) on human pancreatic cancer cell lines, KLM-1 and MIA-PaCa-2, in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily of cytokines. Of these three phenoxazines, Phx-1 and Phx-3 inhibited proliferation of KLM-1 dose-dependently, but Phx-2 did not. Phx-3 caused both apoptosis and necrosis in KLM-1 cells, as evidenced by the phosphatidylserine externalization and propidium iodide permeable cells detected by a flow cytometric method using annexin-V and propidium iodide. Down-regulation of Bcl-2 expression appeared to be involved in the Phx-3-induced cell death. TRAIL did not affect proliferation of KLM-1, and the inhibitory effects of Phx-1 and Phx-3 on the KLM-1 cell line were not augmented by the combination with TRAIL. On the other hand, proliferation of the MIA-PaCa-2 cell line was not affected by Phx-1, Phx-2 and Phx-3, although it was significantly inhibited by TRAIL in a dose-dependent manner. Inhibitory effects of TRAIL on MIA-PaCa-2 were synergistically augmented by the addition of Phx-1 and Phx-3, but not by Phx-2. These results suggest that both Phx-1 and Phx-3 exert anticancer effects against human pancreatic cancer cells, KLM-1 and MIA-PaCa-2, through distinct action modes. Phx-1 and Phx-3 may be effective for the treatment of pancreatic cancer.
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PMID:Anticancer effects of phenoxazine derivatives combined with tumor necrosis factor-related apoptosis-inducing ligand on pancreatic cancer cell lines, KLM-1 and MIA-PaCa-2. 1652 69

Crocetin, a carotenoid compound derived from saffron, has long been used as a traditional ancient medicine against different human diseases including cancer. The aim of the series of experiments was to systematically determine whether crocetin significantly affects pancreatic cancer growth both in vitro and/or in vivo. For the in vitro studies, first, MIA-PaCa-2 cells were treated with crocetin and in these sets of experiments, a proliferation assay using H(3)-thymidine incorporation and flow cytometric analysis suggested that crocetin inhibited proliferation. Next, cell cycle proteins were investigated. Cdc-2, Cdc-25C, Cyclin-B1, and epidermal growth factor receptor were altered significantly by crocetin. To further confirm the findings of inhibition of proliferation, H(3)-thymidine incorporation in BxPC-3, Capan-1, and ASPC-1 pancreatic cancer cells was also significantly inhibited by crocetin treatment. For the in vivo studies, MIA-PaCa-2 as highly aggressive cells than other pancreatic cancer cells used in this study were injected into the right hind leg of the athymic nude mice and crocetin was given orally after the development of a palpable tumor. The in vivo results showed significant regression in tumor growth with inhibition of proliferation as determined by proliferating cell nuclear antigen and epidermal growth factor receptor expression in the crocetin-treated animals compared with the controls. Both the in vitro pancreatic cancer cells and in vivo athymic nude mice tumor, apoptosis was significantly stimulated as indicated by Bax/Bcl-2 ratio. This study indicates that crocetin has a significant antitumorigenic effect in both in vitro and in vivo on pancreatic cancer.
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PMID:Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model. 1920 26

Interleukin (IL)-32 is a recently described proinflammatory cytokine characterized by the induction of nuclear factor (NF)-kappaB activation. We studied IL-32 expression in human pancreatic tissue and pancreatic cancer cell lines. Tissue samples were obtained surgically. IL-32 expression was evaluated by standard immunohistochemical procedures. IL-32 mRNA expression was analyzed by Northern blotting and real time PCR analyses. IL-32 was weakly immunoexpressed by pancreatic duct cells. In the inflamed lesions of chronic pancreas, the ductal expression of IL-32 was markedly increased. A strong expression of IL-32alpha was detected in the pancreatic cancer cells. In pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and BxPC-3 cells), the expression of IL-32 mRNA and protein was enhanced by IL-1beta, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha. An inhibitor of phosphatidylinositol 3-kinase (LY294002) significantly suppressed the IL-1beta-, IFN-gamma- and TNF-alpha-induced IL-32 mRNA expression. The blockade of NF-kappaB and activated protein-1 activation markedly suppressed the IL-1beta-, IFN-gamma-, and/or TNF-alpha-induced IL-32 mRNA expression. Furthermore, IL-32-specific small interfering RNA significantly decreased the uptake of [3H]thymidine and increased the annexin V-positive population (apoptotic cells) in PANC-1 cells. IL-32 knockdown also suppressed the mRNA expression of antiapoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1). Pancreatic duct cells are the local source of IL-32, and IL-32 may play an important role in inflammatory responses and pancreatic cancer growth.
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PMID:Interleukin-32 expression in the pancreas. 1938 2

PERIOD1 (PER1) is a clock gene. We examined the effect of knockdown of PER1 on apoptosis in pancreatic cancer (MIA PaCa-2 and PANC-1) and hepatocellular carcinoma (HepG2) cells. Transfection of siRNA against PER1 into these cells increased the cleaved forms of caspases and poly-ADP-ribose-polymerase and induced apoptosis in all three cell lines. In the two pancreatic cancer cell lines, PER1 knockdown resulted in upregulation of Bax and downregulation of Bcl-2. Expression of p53 was not altered in the two pancreatic cancer cell lines containing mutated p53, but was upregulated in the HepG2 cells containing wild-type p53. Cell proliferation of MIA PaCa-2 and HepG2 was inhibited by PER1 knockdown. We also examined, by immunohistochemical staining, the expression of PER1 in pancreatic cancer tissue and found that PER1 was strongly expressed in pancreatic cancer cells. These results indicate that PER1 acts as an anti-apoptotic factor in pancreatic cancer cells.
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PMID:PERIOD1 is an anti-apoptotic factor in human pancreatic and hepatic cancer cells. 1967 98

Apoptosis has been shown to be induced by many agents, including the clinically useful Sorafenib and K vitamins (VKs). Since few agents have activity against pancreas cancer cell growth, we evaluated the role of naturally occurring K vitamins and Sorafenib both independently and together on the growth in culture of pancreas adenocarcinoma cell lines, including PL-5, PANC-1, and MIA PaCa-2. We found that when a K vitamin was combined with Sorafenib, the dose of Sorafenib required for growth inhibition was substantially reduced. Furthermore, growth could be inhibited at doses of each VK plus Sorafenib in combination that were ineffective when used alone. This effect was seen using vitamins K1, K2, and K5. The combination of VK1 plus Sorafenib-induced apoptosis, as determined by both FACS and TUNEL staining. Phospho-ERK and Bcl-2 levels were decreased, but not levels of other bcl-2 family members. Cleavage of caspases 3 and 8, PARP and Bid were all induced by this combination. Vitamin K1 plus Sorafenib combination also resulted in elevated levels of activated c-Jun N-terminal kinase (JNK) and its substrates c-Jun and FasL. JNK inhibition partly antagonized the induction of apoptosis. Thus, combination VK1 plus Sorafenib strongly induced growth inhibition and apoptosis in pancreas cancer cells, involving both inhibition of the RAF/MEK/ERK pathway as well as activation of the JNK, c-Jun and FasL apoptotic pathway. Since both agents are available for human use, the combination is attractive for evaluation against pancreas cancer growth in vivo.
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PMID:Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways. 2030 Nov 94


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