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:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is known that cancer is associated with altered immune function. We demonstrated earlier that black tea inhibits tumor growth in a dose-dependent manner. Here, we report that apoptosis was the cause of immunocyte death in Ehrlich's ascites carcinoma (EAC)-bearing mice and anti-tumor dose of black tea restored EAC-induced immunosuppression by inhibiting apoptosis. A search for the molecular mechanism revealed that EAC burden increased the expression of the pro-apoptotic proteins p53 and Bax in splenic lymphocytes although did not change the level of pro-proliferative protein Bcl-2. Interestingly, anti-tumor dose of black tea down-regulated p53, decreased Bax while augmenting Bcl-2 in these cells. As a result, Bcl-2/Bax ratio was increased and the immunocytes were protected from tumor-induced apoptosis. Thus, unlike many other anti-cancer agents, black tea is not only devoid of immunosuppressive effect but also acts as immuno-restorer in tumor-bearing host. These results, thus, raise the possibility of inclusion of black tea in successful therapeutic regimen against cancer.
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PMID:Black tea protects immunocytes from tumor-induced apoptosis by changing Bcl-2/Bax ratio. 1515 16

Susceptibility of dendritic cells (DCs) to tumor-induced apoptosis reduces their efficacy in cancer therapy. Here we show that delivery within exponentially growing B16 melanomas of DCs treated ex vivo with nitric oxide (NO), released by the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), significantly reduced tumor growth, with cure of 37% of animals. DETA-NO-treated DCs became resistant to tumor-induced apoptosis because DETA-NO prevented tumor-induced changes in the expression of Bcl-2, Bax, and Bcl-xL; activation of caspase-9; and a reduction in the mitochondrial membrane potential. DETA-NO also increased DC cytotoxic activity against tumor cells and DC ability to trigger T-lymphocyte proliferation. All of the effects of DETA-NO were mediated through cGMP generation. NO and NO-generating drugs may therefore be used to increase the anticancer efficacy of DCs.
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PMID:Nitric oxide confers therapeutic activity to dendritic cells in a mouse model of melanoma. 1517 82

Angiogenesis is required for multistage carcinogenesis. The inducible enzyme cyclooxygenase-2 (COX-2) is an important mediator of angiogenesis and tumor growth. COX-2 expression occurs in a wide range of preneoplastic and malignant conditions; and the enzyme has been localized to the neoplastic cells, endothelial cells, immune cells, and stromal fibroblasts within tumors. The proangiogenic effects of COX-2 are mediated primarily by three products of arachidonic metabolism: thromboxane A(2) (TXA(2)), prostaglandin E(2) (PGE(2)), and prostaglandin I(2) (PGI(2)). Downstream proangiogenic actions of these eicosanoid products include: (1) production of vascular endothelial growth factor; (2) promotion of vascular sprouting, migration, and tube formation; (3) enhanced endothelial cell survival via Bcl-2 expression and Akt signaling; (4) induction of matrix metalloproteinases; (5) activation of epidermal growth factor receptor-mediated angiogenesis; and (6) suppression of interleukin-12 production. Selective inhibition of COX-2 activity has been shown to suppress angiogenesis in vitro and in vivo. Because these agents are safe and well tolerated, selective COX-2 inhibitors could have clinical utility as antiangiogenic agents for cancer prevention, as well as for intervention in established disease alone or in combination with chemotherapy, radiation, and biological therapies.
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PMID:Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. 1517 20

The hypoxic environment in solid tumors results from oxygen consumption by rapid proliferation of tumor cells. Hypoxia has been shown to facilitate the survival of tumor cells and to be a cause of malignant transformation. Hypoxia also is well known to attenuate the therapeutic activity of various therapies in cancer management. These observations indicate that hypoxia plays a critical role in tumor biology. However, little is known about the effects of hypoxia on apoptosis, especially on apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent apoptosis inducer that has been shown to specifically limit tumor growth without damaging normal cells and tissues in vivo. To address the effects of hypoxia on TRAIL-induced apoptosis, HCT116 human colon carcinoma cells were exposed to hypoxic or normoxic conditions and treated with soluble TRAIL protein. Hypoxia dramatically inhibited TRAIL-induced apoptosis in HCT116 cells, which are highly susceptible to TRAIL in normoxia. Hypoxia increased antiapoptotic Bcl-2 family member proteins and inhibitors of apoptosis proteins. Interestingly, these hypoxia-increased antiapoptotic molecules were decreased by TRAIL treatment to the levels lower than those of the untreated conditions, suggesting that hypoxia inhibits TRAIL-induced apoptosis via other mechanisms rather than up-regulation of these antiapoptotic molecules. Additional characterization revealed that hypoxia significantly inhibits TRAIL-induced translocation of Bax from the cytosol to the mitochondria in HCT116 and A549 cells, with the concomitant inhibition of cytochrome c release from the mitochondria. Bax-deficient HCT116 cells were completely resistant to TRAIL regardless of oxygen content, demonstrating a pivotal role of Bax in TRAIL-induced apoptotic signaling. Thus, our data indicate that hypoxia inhibits TRAIL-induced apoptosis by blocking Bax translocation to the mitochondria, thereby converting cells to a Bax-deficient state.
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PMID:Hypoxia inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by blocking Bax translocation. 1520 14

Increased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF-kappaB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF-kappaB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF-kappaB and IkappaBalpha kinase (IKK), which is needed for NF-kappaB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF-kappaB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX-2 and MMP-9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF-kappaB by cell-permeable p65-based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK-mediated NF-kappaB activation and of NF-kappaB-regulated gene expression.
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PMID:Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling. 1525 36

It has been reported that two inducible prostaglandin synthetic enzymes, cylooxygenase-2 (COX-2) and microsomal PGE synthase, are over-expressed in non-small cell lung cancer (NSCLC). Using quantitative reverse transcription-polymerase chain reaction, we analyzed RNA levels of the key prostaglandin catabolic enzyme, NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH), in 19 pairs of NSCLC tumors and adjacent non-malignant tissue from the same patient. We found that 100% of tumor-tissue pairs showed at least a 2-fold decrease and 61% showed a 10-fold decrease. This suggests that the increased expression of COX-2 and PGE synthase in tumors may work in concert with the decreased expression of 15-PGDH to amplify an increase in tissue levels of proliferative PGE2. To further explore if 15-PGDH is related to tumorigenesis, athymic nude mice were injected with control A549 cells or cells transiently over-expressing wild-type or mutant 15-PGDH (Y151F). It was found that mice injected with control A549 cells or with cells expressing mutant enzyme produced tumors normally. However, mice injected with A549 cells expressing wild-type 15-PGDH had a significant decrease in tumor growth. Examining the effects of 15-PGDH expression on cellular changes in A549 cells, we found that over-expression of 15-PGDH induced apoptosis of A549 cells as evidenced by fragmentation of DNA, activation of pro-caspase 3, cleavage of poly(ADP-ribose) polymerase and decreased expression of Bcl-2. We also found that the expression of 15-PGDH was negatively related to that of pro-adhesive and invasive CD44. Furthermore, the expression of 15-PGDH was found to be stimulated by hyaluronidase. These results suggest that 15-PGDH may decrease the level of proliferative PGE2, induce apoptosis and function like a tumor suppressor.
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PMID:NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. 1535 36

The present study was designed to select the effective dosage range of Z24 [3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one], a novel synthetic indolin-2-ketone small-molecule compound, against tumorigenesis and angiogenesis in vitro and in vivo and to investigate the primary action mechanism of Z24 on the angiogenesis by comparing with SU5416 [3-[(2,4-dimethylpyrrol-5-yl)methyllidenyl]-indolin-2-one] in the selective effects on vascular endothelial growth factor (VEGF)/basic fibroblast growth factor (bFGF) signaling and Bcl-2-related cell vitality because Z24 is a potential inhibitor of the Bcl-2 that inhibits growth of multiple tumor types in vivo in our previous study. Per os Z24 inhibited dose-dependently the mouse S180 xenograft tumor growth and angiogenesis in mouse subcutaneous (s.c.) Matrigel plugs in vivo. The maximum growth inhibitory rate was 56.1% by 80 mg/kg/day on S180 mouse sarcoma cells; however, the maximum inhibitory potency on angiogenesis in C57BL/6 mouse subcutaneous Matrigel plug model was 50 mg/kg/day. Z24 inhibited angiogenesis in chicken chorioallantoic membrane (CAM) and invasion and inhibited tube formation of endothelial cells in a dose-dependent manner. Compared with SU5416, the IC50 (50% inhibition concentration) of Z24 on the proliferation of ECV-304 carcinoma cells induced by VEGF or bFGF was 24.4 and 17.99 microM, respectively, which is higher or lower, respectively, than that of SU5416 (14.2 microM for VEGF and 22.7 microM for bFGF). Furthermore, the IC50 of Z24 on the proliferation of Bcl-2 over-expressing HeLa cells and non-Bcl-2-expressing (wild-type) HeLa cells are 11.9 and 24.8 microM, respectively. SU5416 did not exert such a selective inhibiting effect on Bcl-2 over-expressing HeLa cells. These results suggest that Z24 per os has dose-dependent antitumor and antiangiogenesis pharmacological activity. The higher selectivity of Z24 on Bcl-2 protein and on bFGF other than VEGF signaling path may contribute to its efficiency against tumor and tumor-associated angiogenesis.
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PMID:Antitumor activities of a novel indolin-2-ketone compound, Z24: more potent inhibition on bFGF-induced angiogenesis and bcl-2 over-expressing cancer cells. 1546 84

Angiogenesis is a critical event in tumor growth and metastasis, which can be inhibited by conventional anticancer drugs such as the microtubule-damaging agent paclitaxel (Taxol). In this study, we investigate the mechanism of action of paclitaxel on human endothelial cells. We characterize two distinct effects of paclitaxel on human umbilical vein endothelial cell and human microvascular endothelial cell-1 proliferation according to drug concentration: a cytostatic effect at low concentrations and a cytotoxic effect at concentrations > or =10 nmol/L. The cytotoxic effect involves signaling pathways similar to those described in tumor cells (i.e., microtubule network disturbance, G(2)-M arrest, increase in Bax/Bcl-2 ratio, and mitochondria permeabilization) that result in apoptosis. In sharp contrast, the cytostatic effect involves an inhibition of endothelial cell proliferation without apoptosis induction and without any structural modification of the microtubule network. This cytostatic effect is due to a slowing of the cell cycle rather than to an arrest in a specific phase of the cell cycle. In addition, paclitaxel, at cytostatic concentrations, early initiates an apoptotic signaling pathway associated with increases in the mitochondrial reducing potential, mitochondrial membrane potential, p53 expression, and Bax/Bcl-2 ratio. However, this apoptotic pathway is stopped upstream of mitochondria permeabilization and it does not lead to endothelial cell death. Finally, we found that paclitaxel inhibits endothelial cell morphogenesis on Matrigel at all tested concentrations. In conclusion, we describe the mechanism of action of low concentrations of paclitaxel related to the antiangiogenic properties of this drug.
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PMID:Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway. 1548 97

Genistein has multiple anticancer properties. However, its mechanisms of action and its molecular targets on human colon cells remain to be further elucidated. Here, we demonstrated that genistein reduced proliferation and induced G2/M phase arrest and apoptotic death in colon cancer HT-29 cells. We then investigated the effects of genistein on molecules that regulate apoptosis and cell cycle progress. Genistein increased expression of Bax and p21WAF1 and slightly decreased Bcl-2 level. Our results demonstrated that genistein inhibited the viability of human colon cancer HT-29 cell via induction of apoptosis mainly through regulation of p21WAF1 and Bax/Bcl-2 expression. These data suggested a role of genistein in prevention of colon tumor and might reduce colon tumor growth.
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PMID:Inhibition of proliferation and induction of apoptosis by genistein in colon cancer HT-29 cells. 1548 34

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family and a potent inducer of apoptosis. TRAIL has been shown to effectively limit tumor growth in vivo without detectable cytotoxic side-effects. Interferon (IFN)-gamma often modulates the anticancer activities of TNF family members including TRAIL. However, little is known about the mechanism. To explore the mechanism, A549, HeLa, LNCaP, Hep3B and HepG2 cells were pretreated with IFN-gamma, and then exposed to TRAIL. IFN-gamma pretreatment augmented TRAIL-induced apoptosis in all these cell lines. A549 cells were selected and further characterized for IFN-gamma action in TRAIL-induced apoptosis. Western blotting analyses revealed that IFN-gamma dramatically increased the protein levels of interferon regulatory factor (IRF)-1, but not TRAIL receptors (DR4 and DR5) and pro-apoptotic (FADD and Bax) and anti-apoptotic factors (Bcl-2, Bcl-XL, cIAP-1, cIAP-2 and XIAP). To elucidate the functional role of IRF-1 in IFN-gamma-enhanced TRAIL-induced apoptosis, IRF-1 was first overexpressed by using an adenoviral vector AdIRF-1. IRF-1 overexpression minimally increased apoptotic cell death, but significantly enhanced apoptotic cell death induced by TRAIL when infected cells were treated with TRAIL. In further experiments using an antisense oligonucleotide, a specific repression of IRF-1 expression abolished enhancer activity of IFN-gamma for TRAIL-induced apoptosis. Therefore, our data indicate that IFN-gamma enhances TRAIL-induced apoptosis through IRF-1.
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PMID:IFN-gamma enhances TRAIL-induced apoptosis through IRF-1. 1551 Dec 28


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