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)

Most anticancer agents mediate their effects through common pathways which induce apoptosis or in some cases necrosis of cancer cells. The apoptotic pathways are regulated by Bcl-2 family proteins, which include both pro- and anti-apoptotic members. Much is known about the interactions of these proteins involved in apoptosis and this information is being utilized in the development of new reagents that may be used to treat patients with cancers. The inhibitor of apoptosis family of proteins constitute a second group of proteins which inhibit the effector caspases. Reagents that inhibit their activity are also under development. Resistance of cancer cells to treatment can in many instances be attributed to activation of intracellular signal pathways involved in survival, such as the Ras-Raf-MEK-ERK1/2 or the P13K-Akt pathway. Again, much has been learned about the control of these pathways and their activation of resistance mechanisms. Inhibitors of such pathways are being evaluated in preclinical and clinical studies and are showing promise as a new class of anticancer agents. Much of the progress in future studies will likely depend on the ability to target these new treatments to particular subgroups of patients with tumor characteristics that make them responsive to the agents in question.
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PMID:Current strategies in overcoming resistance of cancer cells to apoptosis melanoma as a model. 1693 79

Gliomas remain to be an unresolved medical problem. Better understanding of complex regulation and key molecules involved in glioma pathology are needed for designing new and effective treatment modalities. Activation of mitogen-activated protein kinase/extracellular signal regulated kinase (ERK) pathway is known to be having a critical role in cell proliferation and differentiation during the invasion and metastasis of the tumor cells. In the present study, N-ethyl N-nitrosourea induced glioma rat model was used to understand the role of ERK1/2 and Akt pathways in the progression of tumor malignancy. Twenty-four glioma rat brains of early (P90) and progressive (P180) stages were used for histological and immunoblot analysis. Results have shown increased levels of activated ERK1/2, activated Akt or protein kinase B, Bcl-2 and pBad in the glioma rats. This study may indicate increased cell proliferation and angiogenesis, mediated through activation of both ERK and Akt pathways along with increased levels of pBad. Further, pAkt and Bcl-2 levels in the progressive stage glioma rats may indicate existence of sustained tumor cell survival signals. Moreover, enhanced pBad levels in tumor may indicate that there are anti-apoptotic mechanisms, further making the malignant cells resistant to apoptosis.
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PMID:pERK, pAkt and pBad: a possible role in cell proliferation and sustained cellular survival during tumorigenesis and tumor progression in ENU induced transplacental glioma rat model. 1694 16

Nitric oxide (NO) produced by NO synthases causes nitration and nitrosylation of cellular factors. We have shown previously that endogenously produced or exogenously added NO induces expression of BNIP3 (Bcl-2/adenovirus E1B 19 kDa-interacting protein 3), leading to death of macrophages (Yook, Y.-H., Kang, K.-H., Maeng, O., Kim, T.-R., Lee, J.-O., Kang, K.-i., Kim, Y.-S., Paik, S.-G., and Lee, H. (2004) Biochem. Biophys. Res. Commun. 321, 298-305). We now provide evidence that Ras mediates NO-induced BNIP3 expression via the MEK/ERK/hypoxia-inducible factor (HIF)-1 pathway. (a) ras-Q61L, a constitutively active form of Ras, up-regulated BNIP3 protein expression by enhancing Bnip3 promoter activity, and ras-S17N, a dominant-negative form, and ras-C118S, an S-nitrosylation mutant, blocked NO-induced BNIP3 expression, suggesting that Ras acts downstream of NO and that NO activates Ras by nitrosylation. (b) U0126, a specific MEK inhibitor, completely abolished BNIP3 expression and the stimulation of promoter activity by NO and Ras, whereas 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, SB203580, and wortmannin, specific inhibitors of soluble guanylyl cyclase, p38 MAPK, and phosphatidylinositol 3-kinase, respectively, had no effect. Ras, MEK1/2, and ERK1/2 were sequentially activated by NO treatment of macrophages. (c) Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction, and HIF-1alpha was strongly induced by NO. (d) Transient expression of activated Ras promoted macrophage death, as did NO, and this Ras-mediated cell death was inhibited by silencing BNIP3 expression. These results suggest that NO-induced death of macrophages is mediated, at least in part, by BNIP3 induction.
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PMID:Activation of Ras up-regulates pro-apoptotic BNIP3 in nitric oxide-induced cell death. 1695 13

Exposure to sublethal stress can trigger endogenous protection against subsequent, higher levels of stress. We tested for this preconditioning phenomenon in a model of Parkinson's disease by applying 6-hydroxydopamine to the dopaminergic MN9D cell line. Exposure to sublethal concentrations of 6-hydroxydopamine (5-10 microM) protected against the toxic effects of a subsequent exposure to a higher concentration (50 microM), as measured by the Hoechst assay for nuclear viability. This was accompanied by little or no protection against 6-hydroxydopamine-induced lactate dehydrogenase release, decline in ATP, or reduction in (3)H-dopamine uptake. The antioxidant, N-acetyl cysteine (20 mM), when applied during preconditioning, abolished protection, as did the protein synthesis inhibitor, cycloheximide (0.2 microM). Preconditioning did not affect superoxide dismutase or glutathione peroxidase enzymes, or levels of heat shock protein-72. However, Bcl-2 protein levels rose with preconditioning. Preconditioning rapidly increased phosphorylation of kinases ERK1/2, Akt and JNK, and was abolished by pharmacological inhibitors of their activity. Finally, sublethal 6-hydroxydopamine preconditioned against the toxicity of proteasome inhibitor, MG-132 (1 microM). Thus, exposure of a dopaminergic cell line to sublethal oxidative stress can protect against additional oxidative stress due to translational and post-translational modifications, as well as confer 'cross-tolerance' against a different insult, proteasome inhibition.
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PMID:Effect of sublethal 6-hydroxydopamine on the response to subsequent oxidative stress in dopaminergic cells: evidence for preconditioning. 1695 75

Advanced ovarian cancer (OC) is not curable by surgery alone and chemotherapy is essential for its treatment. Isothiocyanates have been shown to inhibit carcinogen-induced tumorigenesis in animal models, yet no efforts have been made to determine their therapeutic potential in OC. In the present study, we investigated the mechanism of the anti-proliferative and apoptotic activity of benzyl isothiocyanate (BITC) in OC. BITC inhibited the proliferation of OC cells and induced apoptosis in OC cells. Apoptosis was induced by a strong activation of caspase-3 and -9, and cleavage of PARP-1. However, caspase-8 was not activated by BITC. Cytotoxic effects of BITC were reversed by the inhibition caspase-3 and -9 specific inhibitors. BITC showed a concentration dependent decrease in the levels of Bcl-2 with a concomitant increase in Bax levels. In addition, BITC activated proapoptotic signaling by phosphorylation JNK1/2 and p38 while simultaneously inhibiting survival signaling mediated by ERK1/2 and Akt phosphorylation in a dose-dependent manner. While JNK inhibitor SP600125 and p38 inhibitor SB203580, abolished the cytotoxic effect of BITC, MEK inhibitor, PD98059 and PI3 kinase inhibitor, LY294002 failed to show such reversal indicating a critical role played by JNK1/2 and p38 signaling in apoptosis induced by BITC. In summary, our studies demonstrate that BITC inhibits proliferation of OC cells and induces apoptosis via caspase-9 and -3 pathways. BITC inhibits ERK1/2 and Akt survival signaling while simultaneously activating pro-apoptotic p38 and JNK1/2. Therefore, BITC can be potentially developed as a therapeutic agent to treat OC.
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PMID:Benzyl isothiocyanate (BITC) induces apoptosis in ovarian cancer cells in vitro. 1755 57

Cyclic GMP-dependent protein kinases protein kinase G (PKG) Ialpha and PKGIbeta are major mediators of cGMP signaling in the cardiovascular system. PKGIalpha is present in the heart, although its role in protection against ischemia/reperfusion injury is not known. We investigated the direct effect of PKGIalpha against necrosis and apoptosis following simulated ischemia (SI) and reoxygenation (RO) in cardiomyocytes. Adult rat cardiomyocytes were infected with adenoviral vectors containing hPKGIalpha or catalytically inactive mutant hPKGIalphaK390A. After 24 h, the cells were subjected to 90 min of SI and 2 h RO for necrosis (trypan blue exclusion and lactate dehydrogenase release) or 18 h RO for apoptosis studies. To evaluate the role of K(ATP) channels, subgroups of cells were treated with 5-hydroxydecanoate (100 microm), HMR1098 (30 microm), or glibenclamide (50 microm), the respective blockers of mitochondrial, sarcolemmal, or both types of K(ATP) channels prior to SI. The necrosis observed in 33.7 +/- 1.6% of total myocytes in the SI-RO control group was reduced to 18.6 +/- 0.8% by PKGIalpha (mean +/- S.E., n = 7, p < 0.001). The apoptosis observed in 17.9 +/- 1.3% of total myocytes in the SI-RO control group was reduced to 6.0 +/- 0.6% by PKGIalpha (mean +/- S.E., n = 7, p < 0.001). In addition, PKGIalpha inhibited the activation of caspase-3 after SI-RO in myocytes. Myocytes infected with the inactive PKGIalphaK390A mutant showed no protection. PKGIalpha enhanced phosphorylation of Akt, ERK1/2, and JNK, increased Bcl-2, inducible nitric-oxide synthase, endothelial nitric-oxide synthase, and decreased Bax expression. 5-Hydroxydecanoate and glibenclamide abolished PKGIalpha-mediated protection against necrosis and apoptosis. However, HMR1098, had no effect. A scavenger of reactive oxygen species, as well as inhibitors of phosphatidylinositol 3-kinase, ERK, JNK1, and NOS, also blocked PKGIalpha-mediated protection against necrosis and apoptosis. These results show that opening of mitochondrial K(ATP) channels and generation of reactive oxygen species, in association with phosphorylation of Akt, ERK, and JNK, and increased expression of NOS and Bcl-2, play an essential role in the protective effect of PKGIalpha.
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PMID:Cyclic GMP-dependent protein kinase Ialpha attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocyte. 1703 26

Glutamate treatment depletes hippocampal HT22 cells of glutathione, which renders the cells incapable to reduce reactive oxygen species and ultimately cumulates in cell death by oxidative stress. HT22 cells resistant to glutamate displayed increased phosphorylation of cAMP-response-element binding (CREB) and decreased ERK1/2 suggestive of differences in signal transmission. We investigated the amount of candidate G-protein-coupled receptors involved in this resistance and found an increase in mRNA for receptors activated by the vasoactive intestinal peptide VIP (VPAC2, 12.6-fold) and glutamate like the metabotropic glutamate receptor mGlu1 (5.3-fold). Treating cells with VIP and glutamate led to the same changes in protein phosphorylation observed in resistant cells and induced the proto-oncogene Bcl-2. Bcl-2 overexpression protected by increasing the amount of intracellular glutathione and Bcl-2 knockdown by small interfering RNAs (siRNA) increased glutamate susceptibility of resistant cells. Other receptors upregulated in this paradigm might represent useful targets in the treatment of neurological diseases associated with oxidative stress.
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PMID:Induction of Bcl-2 by functional regulation of G-protein coupled receptors protects from oxidative glutamate toxicity by increasing glutathione. 1705 Jan 65

Ghrelin is an endogenous ligand for the GH secretagogue receptor, produced and secreted mainly from the stomach. Ghrelin stimulates GH release and induces positive energy balances. Previous studies have reported that ghrelin inhibits apoptosis in several cell types, but its antiapoptotic effect in neuronal cells is unknown. Therefore, we investigated the role of ghrelin in ischemic neuronal injury using primary hypothalamic neurons exposed to oxygen-glucose deprivation (OGD). Here we report that treatment of hypothalamic neurons with ghrelin inhibited OGD-induced cell death and apoptosis. Exposure of neurons to ghrelin caused rapid activation of ERK1/2. Ghrelin-induced activation of ERK1/2 and the antiapoptotic effect of ghrelin were blocked by chemical inhibition of MAPK, phosphatidylinositol 3 kinase, protein kinase C, and protein kinase A. Ghrelin attenuated OGD-induced activation of c-Jun NH2-terminal kinase and p-38 but not ERK1/2. We also investigated ghrelin regulation of apoptosis at the mitochondrial level. Ghrelin protected cells from OGD insult by inhibiting reactive oxygen species generation and stabilizing mitochondrial transmembrane potential. In addition, ghrelin-treated cells showed an increased Bcl-2/Bax ratio, prevention of cytochrome c release, and inhibition of caspase-3 activation. Finally, in vivo administration of ghrelin significantly reduced infarct volume in an animal model of ischemia. Our data indicate that ghrelin may act as a survival factor that preserves mitochondrial integrity and inhibits apoptotic pathways.
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PMID:Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation. 1705 24

We recently showed that the histone deacetylase inhibitor D1 induced apoptosis in the t(8;21) Kasumi 1 acute myeloid leukaemia (AML) cell line and activated caspase 9. The present study characterised the effects of the combined administration of D1 with PD98059, SB203580 or SP600125, specific inhibitors of mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 or Jun N-terminal kinase (JNK), respectively. Among these inhibitors, SP600125 was the only one to markedly induce apoptosis and decrease cell proliferation. These experiments showed that SP600125 activated caspase 8 and confirmed that D1 activated the intrinsic pathway of apoptosis, as caspase 8 was not affected while Bcl-2 was down-regulated following D1 administration. The combination of the two drugs enhanced caspase-8 activation and induced apoptosis in an additive fashion. JNK was constitutively activated in the Kasumi 1, NB4, HL60 and THP-1 human AML cell lines, as well as in primary blasts from a t(8;21) AML patient. In all these cells, the pro-apoptotic effect of the two drugs alone was increased when they were combined. On this basis, the combined administration of D1 with SP600125 seems to be very promising as a potential anti-leukaemic tool in AML.
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PMID:The c-Jun-N-terminal-Kinase inhibitor SP600125 enhances the butyrate derivative D1-induced apoptosis via caspase 8 activation in Kasumi 1 t(8;21) acute myeloid leukaemia cells. 1705 27

We have recently shown that the expression levels of both cannabinoid receptors CB(1) and CB(2) are higher in human prostate cancer cells than in normal prostate epithelial cells, and treatment of LNCaP cells with WIN-55,212-2 (a mixed CB(1)/CB(2) agonist) resulted in inhibition of cell growth and induction of apoptosis (Sarfaraz, S., Afaq, F., Adhami, V. M., and Mukhtar, H. (2005) Cancer Res. 65, 1635-1641). This study was conducted to understand the mechanistic basis of these effects. Treatment of LNCaP cells with WIN-55,212-2 (1-10 microm; 24 h) resulted in: (i) an arrest of the cells in the G(0)/G(1) phase of the cell cycle; (ii) an induction of p53 and p27/KIP1; (iii) down-regulation of cyclins D1, D2, E; (iii) decrease in the expression of cdk-2, -4, and -6; (iv) decrease in protein expression of pRb; (v) down-regulation of E2F (1-4); and (vi) decrease in the protein expression of DP1 and DP2. Similar effects were also observed when androgen-independent PC3 cells were treated with WIN-55,212-2 (5-30 microm). We further observed sustained up-regulation of ERK1/2 and inhibition of PI3k/Akt pathways in WIN-55,212-2-treated cells. Inhibition of ERK1/2 abrogated WIN-55,212-2-indued cell death suggesting that sustained activation of ERK1/2 leads to cell cycle dysregulation and arrest of cells in G(0)/G(1) phase subsequently leading to an induction of apoptosis. Further, WIN-55,212-2 treatment of cells resulted in a dose-dependent increase in Bax/Bcl-2 ratio in such a way that favors apoptosis. The induction of apoptosis proceeded through down-regulation of caspases 3, 6, 7, and 9 and cleavage of poly (ADP-ribose) polymerases. Based on these data we suggest that cannabinoid receptor agonists should be considered as novel agents for the management of prostate cancer.
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PMID:Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest. 1706 43


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