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

Chan Su is a traditional Chinese medicine prepared from the dried white secretion of the auricular and skin glands of toads, and has been used as an Oriental drug. However, little is known about the effect of Chan Su on the growth of human cancer cells. This study was undertaken to investigate the underlying mechanism of Chan Su-induced apoptosis in a human bladder carcinoma cell line, T24. The effects of this compound were also tested on cyclooxygenase (COX) activity. Treatment of T24 cells with Chan Su resulted in the inhibition of viability and induction of apoptosis in a concentration-dependent manner, which was proved by trypan blue counts, DAPI staining, agarose gel electrophoresis and flow cytometric analysis. Apoptosis of T24 cells by Chan Su was associated with a down-regulation of anti-apoptotic Bcl-2 and Bcl-X(S/L) expression and an up-regulation of pro-apoptotic Bax expression. Chan Su treatment induced the proteolytic activation of caspase-3 and caspase-9, and a concomitant degradation of poly(ADP-ribose)-polymerase and beta-catenin protein. Furthermore, Chan Su decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with an inhibition in prostaglandin E(2) synthesis. Taken together, these findings partially provide novel insights into the possible molecular mechanisms of the anti-cancer activity of Chan Su.
 ...
PMID:Induction of apoptosis by Chan Su, a traditional Chinese medicine, in human bladder carcinoma T24 cells. 1601 33

Interleukin-1beta (IL-1beta) is a pivotal proinflammatory cytokine. To investigate the mechanism of IL-1beta-induced cell death in human malignant melanoma A375-S2 cells, MTT assay, photomicroscopical observation, DNA agarose gel electrophoresis, radioimmunoassay and Western blot analysis were carried out. IL-1beta did not only induce nuclear condensation and DNA fragmentation, but also increased degradation of two substrates of caspase-3, poly ADP-ribose polymerase (PARP) and inhibitor of caspase-activated DNase (ICAD). Simultaneously, release of precursor of IL-1beta (pro-IL-1beta) and endogenous IL-1beta production were involved in the apoptotic process. IL-1beta enhanced the ratio of Bax/Bcl-2 and Bax/Bcl-xL expression and up-regulated apoptosis inducing factor (AIF) expression, which required the activation of downstream caspases. These results suggest that IL-1beta induces endogenous IL-1beta production, enhances cleavage of caspase downstream substrates and promotes mitochondria mediated apoptosis in A375-S2 cells.
 ...
PMID:IL-1beta acts in synergy with endogenous IL-1beta in A375-S2 human melanoma cell apoptosis through mitochondrial pathway. 1610 Apr 43

Gadd45a, gadd45b and gadd45g (Gadd45/MyD118/CR6) are genes that are rapidly induced by genotoxic stress. However, the exact function of Gadd45 proteins in the response of mammalian cells to genotoxic stress is unclear. Here, advantage was taken of gadd45a- and gadd45b-deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. BM cells from gadd45a- and gadd45b-deficient mice were observed to be more sensitive to ultraviolet radiation chemotherapy (UVC), VP-16 and daunorubicin (DNR)-induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a- and gadd45b-deficient cells was evident also by enhanced activation of caspase-3 and poly-ADP-ribose polymerase cleavage and decreased expression of c-inhibitor of apoptotic protein-1, Bcl-2, Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45-deficient BM cells restored the wt apoptotic phenotype. Both gadd45a- and gadd45b-deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Taken together, these findings identify gadd45a and gadd45b as anti-apoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs.
 ...
PMID:Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis. 1617 Mar 81

Berberine, a main component of Coptidis Rhizoma, is a plant alkaloid with a long history of medicinal use in Chinese medicine. Berberine has indicated significant antimicrobial activity against a variety of organisms including bacteria, viruses, fungi. The mechanism by which berberine initiates apoptosis remains poorly understood. In the present study, we demonstrated that berberine exhibited significant cytotoxicity in hepatoma HepG2 cells but is ineffective in Chang liver cells. Herein we investigated cytotoxicity mechanism of berberine in HepG2 cells. The results showed that HepG2 cells underwent internucleosomal DNA fragmentation after 24-h treatment with berberine (50 microM). Moreover, berberine induced the activation of caspase-8 and -3, and caused the cleavage of poly ADP-ribose polymerase (PARP) and the cytochrome c release, whereas the expression of Bid and anti-apoptosis factor Bcl-XL were decreased markedly. The loss of mitochondrial membrane potential (Delta psim) at 24 h and activation of Fas at 12 h were also seen in the berberine-treated HepG2 cells. These findings supported the fact that the inhibitors of caspases, DEVD-FMK, IETD-FMK and VAD-FMK, prevented apoptosis and restored the expression of Bcl-XL, Bcl-2 and Bid. These results indicated that the potential of anti-hepatoma activity of berberine may be mediated through a caspases-mitochondria-dependent pathway.
 ...
PMID:Berberine induces apoptosis through a mitochondria/caspases pathway in human hepatoma cells. 1618 62

While significant advances in the treatment of cancer occured during the last half of the twentieth century, parallel decreases in overall cancer death rates were not observed. Cancer therapy remains an area of significant unmet medical need. Abbott's oncology research programs are focused on pioneering trageted, less toxic therapies, aimed at different aspects of tumor growth and development. Oncology drugs in development at Abbott target several mechanisms of cancer progression by interfering with multiple processes necessary for tumor growth: recruitment of a blood supply, cell proliferation, and the development of metastases. They include a selective endothelin A-receptor antagonist (atrasentan/Xinlay), 3 angiogenesis inhibitors (ABT 510, a thrombospondin mimetic: ABT-869, a multitargeted receptor tyrosine kinase inhibitor; and ABT 828, recombinant human plasminogen kringle 5), a cell proliferation inhibitor (ABT-751, an antimitotic agent), an apoptosis inducer (ABT 737, a Bcl-2 family inhibitor), and a poly(ADP-ribose)polymerase inhibitor.
 ...
PMID:Targeting the unmet medical need: the Abbott Laboratories oncology approach. 1622 44

TRPM2 is a Ca(2+)-permeable channel activated by oxidative stress or TNF-alpha, and TRPM2 activation confers susceptibility to cell death. The mechanisms were examined here in human monocytic U937-ecoR cells. This cell line expresses full-length TRPM2 (TRPM2-L) and several isoforms including a short splice variant lacking the Ca(2+)-permeable pore region (TRPM2-S), which functions as a dominant negative. Treatment with H(2)O(2), a model of oxidative stress, or TNF-alpha results in reduced cell viability. Expression of TRPM2-L and TRPM2-S was modulated by retroviral infection. U937-ecoR cells expressing increased levels of TRPM2-L were treated with H(2)O(2) or TNF-alpha, and these cells exhibited significantly increased intracellular calcium concentration ([Ca(2+)](i)), decreased viability, and increased apoptosis. A dramatic increase in cleavage of caspases-8, -9, -3, and -7 and poly(ADP-ribose)polymerase (PARP) was observed, demonstrating a downstream mechanism through which cell death is mediated. Bcl-2 levels were unchanged. Inhibition of the [Ca(2+)](i) rise with the intracellular Ca(2+) chelator BAPTA blocked caspase/PARP cleavage and cell death induced after activation of TRPM2-L, demonstrating the critical role of [Ca(2+)](i) in mediating these effects. Downregulation of endogenous TRPM2 by RNA interference or increased expression of TRPM2-S inhibited the rise in [Ca(2+)](i), enhanced cell viability, and reduced numbers of apoptotic cells after exposure to oxidative stress or TNF-alpha, demonstrating the physiological importance of TRPM2. Our data show that one mechanism through which oxidative stress or TNF-alpha mediates cell death is activation of TRPM2, resulting in increased [Ca(2+)](i), followed by caspase activation and PARP cleavage. Inhibition of TRPM2-L function by reduction in TRPM2 levels, interaction with TRPM2-S, or Ca(2+) chelation antagonizes this important cell death pathway.
 ...
PMID:TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage. 1630 29

We tested the hypothesis that the expression levels of p53 and the pro-apoptotic mediators from the Bcl-2 family are higher in cytotrophoblasts, when compared to cultures with abundant syncytiotrophoblasts. Cytotrophoblasts isolated from normal term human placentas were cultured in Dulbecco's Modified Eagle medium (DMEM) for 24 h, when the cytotrophoblast phenotype predominates, in DMEM for 72 h, when the syncytiotrophoblast phenotype predominates, or in Ham's-Waymouth medium or DMEM with 1.5% dimethylsulfoxide, each of which maintains the cytotrophoblast phenotype through 72 h of culture. Apoptosis was assessed by detection of cleavage products of poly-ADP-ribose polymerase, by expression of cleaved cytokeratin 18 intermediate filaments, and by assessment of caspase-3 activity. Independent of time in culture, cytotrophoblasts showed higher levels of apoptosis compared to syncytiotrophoblasts. Cytotrophoblasts also expressed a 2-fold higher level of p53, a 2-fold lower level of 60 kDa Mdm-2 protein, a 2-fold higher level of Bak, but no differences in the expression of 90 kDa Mdm-2, Bcl-2, Bcl-X(L), Mcl-1, Bax, Bad, and Bad phosphorylated at the serine(112), serine(136), or serine(155) sites, compared to the syncytiotrophoblasts. Using co-immunoprecipitation, we demonstrated a greater degree of Bak-p53 interaction in cytotrophoblasts than in syncytiotrophoblasts. We also detected Bak-Mcl-1 interaction that was no different between the two phenotypes. Among the proteins studied, enhanced p53 activity, differential Bak expression, and Bak-p53 interactions may contribute to the higher level of constitutive apoptosis in cultures of cytotrophoblasts compared to syncytiotrophoblasts.
 ...
PMID:Enhanced basal apoptosis in cultured term human cytotrophoblasts is associated with a higher expression and physical interaction of p53 and Bak. 1637 85

Extracts of Artemisia asiatica Nakai (Asteraceae) possess anti-inflammatory and antioxidative activities. Eupatilin (5,7-dihydroxy-3',4', 6-trimethoxyflavone), one of the pharmacologically active ingredients derived from A. asiatica was shown to induce apoptosis in human promyelocytic leukemia (HL-60) cells. In the present study, we examined the ability of eupatilin to induce apoptosis in human gastric cancer (AGS) cells. Eupatilin induced the apoptosis of AGS cells as revealed by a decrease in the ratio of pro-apoptotic Bax and anti-apoptotic Bcl-2, as well as the cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP). The pro-apoptotic effects of eupatilin were further verified by its perturbation of the mitochondrial transmembrane potential (DeltaPsim). In addition, eupatilin treatment led to an elevated expression of p53 and p21. Eupatilin inhibited the activation of ERK1/2 and Akt, which are important components of cell-survival pathways.
 ...
PMID:Eupatilin, a pharmacologically active flavone derived from Artemisia plants, induces apoptosis in human gastric cancer (AGS) cells. 1639 20

Oridonin, an active component isolated from Rabdosia rubescences, has been reported to have antitumor effects. In this study, we compared the signal transduction pathways between TNFalpha-and oridonin-induced L929 cell death. Oridonin and TNFalpha initiated apoptotic morphologic changes, but DNA fragmentation was found in TNFalpha-treated L929 cells but not in oridonin-treated ones. The pan-caspase inhibitor (z-VAD-fmk), caspase-8 inhibitor (z-IETD-fmk) and caspase-3 inhibitor (z-DEVD-fmk) augmented oridonin-and TNFalpha-induced cell death. However, the caspase-9 inhibitor (z-LEHD-fmk) only increased oridonin-induced L929 cell death. Moreover, poly (ADPribose) polymerase (PARP) was cleaved in oridonin-treated L929 cells but not in the TNFalpha-treated groups, and the caspase-3 inhibitor (z-DEVD-fmk) failed to inhibit PARP cleavage. These results showed that only oridonin-induced L929 cell death required PARP degradation in a caspase-3 independent manner. In addition, oridonin increased the ratio of Bax/Bcl-2 protein expression, but TNFalpha did not. TNFalpha induced p38 and ERK activation, whereas oridonin triggered only ERK activation. We also investigated the effect of oridonin on intracellular TNFalpha expression, and found that oridonin augmented endogenous pro-TNFalpha expression and its upstream protein IkB phosphorylation. These results indicated that although oridonin promoted endogenous pro-TNFalpha expression, a great difference existed between the signal pathways through which TNFalpha-and oridonin-induced cell death.
 ...
PMID:A comparison of the signal pathways between the TNF alpha- and oridonin-induced murine L929 fibrosarcoma cell death. 1641 69

We investigated the possible mechanisms by which petrotetrayndiol A, a polyacetylene from the sponge Petrosia sp., exerts its anti-proliferative activity in cultured SK-MEL-2 human melanoma cells. Petrotetrayndiol A-treated SK-MEL-2 cells showed growth inhibition and induction of apoptosis in a dose-dependent manner as measured by MTT assay, fluorescent microscopy and flow cytometric analysis. Flow cytometric analysis revealed that petrotetrayndiol A resulted in G2/M arrest in the cell cycle progression which was associated with a marked decrease in the protein expression of cyclin B1 and its activating partner Cdc2 with concomitant inductions of p21WAF1/CIP1. The increase in apoptosis was associated with a dose-dependent up-regulation of cytosolic factor, such as Bax and release of cytochrome c, and down-regulation of Bcl-2. We also observed activation of caspase-9 and caspase-3, DNA ladder formation, proteolytic degradation of poly(ADP-ribose)-polymerase (PARP), and selective down-regulation of cIAP-1. The apoptotic manifestations, such as PARP cleavage and DNA fragmentation, were abolished in the presence of the tripeptide caspase inhibitor z-VAD-fmk and a caspase-3-specific inhibitor Ac-DEVD-cho. Our data thus demonstrate that petrotetrayndiol A-induced apoptosis and growth inhibition of SK-MEL-2 cells is dependent on caspase activation.
 ...
PMID:Petrotetrayndiol A induces cell cycle arrest and apoptosis in SK-MEL-2 human melanoma cells through cytochrome c-mediated activation of caspases. 1645 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>