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)

Lithium is a monovalent cation that was introduced in 1949 by John Cade for the treatment of bipolar disorder. Clinical reports and subsequent studies confirmed this application and the beneficial effects of this compound. However, over the last 15 years, various authors have also demonstrated the neuroprotective effects of lithium against several neurotoxic paradigms. Thus, experimental studies in neuronal cell cultures and animal models of Alzheimer disease and others pathologies have provided strong evidence for the potential benefits of lithium. The main mechanism underlying its neuroprotective effects is thought to be inhibition of glycogen synthase kinase-3 (GSK-3), although other biochemical pathways in the brain could also be affected. In this review, the main mechanisms of lithium action are summarized, including the modulation of glutamate receptors, effects on arachidonic acid metabolism, its role with respect to AKT, and other potential mechanisms. In addition, its effects on neuroprotective proteins such as Bcl-2 and p53 are also discussed. Although the cellular and molecular biological effects of lithium may constitute an effective therapeutic strategy for Alzheimer disease, further clinical and experimental studies with this drug and specific GSK-3 inhibitors are necessary to confirm the use of lithium in therapeutic approaches to neurodegenerative diseases.
 ...
PMID:Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium. 1988 30

Polyamidoamine (PAMAM) dendrimer and Tat peptides were conjugated to bacterial magnetic nanoparticles (BMPs) for the construction of an efficient and targeted gene delivery system with transmembrane ability for the gene therapy of brain tumors. Tat-BMPs-PAMAM was complexed with small interfering RNA expression plasmid (psiRNA) corresponding to the open reading frame of the human epidermal growth factor receptor gene (psiRNA-EGFR) to downregulate the EGFR gene by electrostatic interaction. The antitumor effect of psiRNA-EGFR delivered via Tat-BMPs-PAMAM was assessed both in human glioblastoma U251-MG cells and in nude mouse models. Compared with control groups, Tat-BMPs-PAMAM/psiRNA-EGFR resulted in better suppression of EGFR expression and a more obviously arrested effect on the proliferation and invasion ability of U251 cells in vitro. In addition, the growth rate of tumor in the U251 subcutaneous nude mouse model treated with Tat-BMPs-PAMAM/psiRNA-EGFR was slower than in those treated with phosphate-buffered saline or Lipofectamine 2000/psiRNA-Scr. Also, compared with control groups, the expression of oncoproteins (EGFR, p-AKT, MMP2/9, PCNA, VEGF, Bcl-2, and cyclin D1) was obviously downregulated and the number of apoptotic cells was clearly increased in the Tat-BMPs-PAMAM/psiRNA-EGFR treatment groups. In addition, there was no significant difference between the results in vitro and in vivo for the Tat-BMPs-PAMAM/psiRNA-EGFR treatment groups and those of the Lipofectamine 2000/psiRNA-EGFR treatment groups. These results show that Tat-BMPs-PAMAM, with its targeted delivery and transmembrane ability, may be a novel gene delivery system with potential applications in the targeted gene therapy of brain tumors.
 ...
PMID:Tat-BMPs-PAMAM conjugates enhance therapeutic effect of small interference RNA on U251 glioma cells in vitro and in vivo. 1989 55

Hormone refractory prostate cancer poses a huge problem and standard of care chemotherapy has not been very successful. We used a novel strategy to combine properties of 2 well-studied class of compounds (selenium and COX-2 inhibitor) and examined the resulting effectiveness against prostate cancer. Bearing in mind that sulfonamide moiety and pyrazole ring is important for the proapoptotic activity of Celecoxib, we synthesized a selenium derivative, Selenocoxib-1, by modifying Celecoxib at position 3 of the pyrazole ring. The PAIII cells derived from a metastatic prostate tumor that arose spontaneously in a Lobund-Wistar (LW) rat were used to examine the efficacy of Selenocoxib-1 in vitro. In addition, human metastatic prostate cancer cells, PC-3M, were tested for antitumor effect of Selenocoxib-1 in vitro. The IC(50) in PAIII and PC-3M cells for Selenocoxib-1 was about 5 microM, while for Celecoxib it was more than 20 microM. Selenocoxib-1 induced apoptosis in a dose-dependent manner in the PAIII cells. COX-2 expression in PAIII cells was downregulated by Celecoxib and Selenocoxib-1 at 20 and 5 microM, respectively; the COX-2 activity was, however, not affected by Selenocoxib-1. Following treatment with Selenocoxib-1, PAIII cells resulted in dose-dependent decrease in HIF-1alpha, p-AKT and Bcl-2 levels. A reduction in weights was observed in subcutaneous tumors produced by PAIII cells pretreated with Selenocoxib-1 as compared to Celecoxib in LW rats. Further, following 1 week Selenocoxib-1 treatment of PAIII tumors resulted in significant reduction of tumor weights. This study demonstrates that Selenocoxib-1 is more effective against prostate cancer than Celecoxib.
 ...
PMID:Synthesis and antitumor properties of selenocoxib-1 against rat prostate adenocarcinoma cells. 1991 50

Cyclooxygenase-2 (COX-2) and Protein kinase B (PKB/Akt) play a crucial role in the formation of many malignant tumors and have been shown to be the important therapeutic targets. In the present study, we examined immunohistochemical expression of phosphorylated Akt (p-Akt) and COX-2 in 45 gastric adenocarcinomas with different tumor grades. Then, adenovirus-mediated small hairpin RNA (shRNA) expression vectors rAd5-Akt1+COX-2 (rAd5-A+C) that target sequences of human COX-2 and Akt1 were used to examine the inhibitory effects on cell proliferation, invasion and apoptosis in SGC7901 gastric adenocarcinoma and U251 glioma cells. Cell growth was inhibited by over 70%, as indicated by a MTT assay, and was accompanied by G1/G0 phase arrest in the rAd5-A+C treated group, indicating poor cell growth activities. The number of cells invading through the matrigel in the rAd5-A+C treated group was significantly decreased (36.2+/-3.1) compared with that of the control group SGC7901 (105.0+/-4.0) and the nonsense sequence group rAd5-HK (102.5+/-6.4). In addition, the tumor volumes in the SGC7901 subcutaneous nude mouse model treated with rAd5-A+C was significantly smaller than those of the control group and nonsense sequence group rAd5-HK. When COX-2 and Akt1 were dramatically downregulated, Ki-67, CyclinD1, MMP-2, MMP-9 and Bcl-2 were also downregulated. Our results demonstrated that p-Akt and COX-2 were overexpressed in gastric adenocarcinomas and their expression levels were elevated with the ascending order of tumor malignancy; rAd5-A+C targeting COX-2 and Akt1 downregulated their expression significantly in a sequence-specific manner, exerting inhibitory effects on SGC7901 and U251 cell proliferation, invasion and apoptosis. In conclusion, our data suggest a novel mechanism for the regulation of malignant tumor cell growth and provide evidence for combined gene therapy for malignant tumors.
 ...
PMID:Expression of p-Akt and COX-2 in gastric adenocarcinomas and adenovirus mediated Akt1 and COX-2 ShRNA suppresses SGC-7901 gastric adenocarcinoma and U251 glioma cell growth in vitro and in vivo. 1992 30

Recently more evidences support baicalein (Bai) is neuroprotective in models of ischemic stroke. This study was conducted to determine the molecular mechanisms involved in this effect. Either permanent or transient (2 h) middle cerebral artery occlusion (MCAO) was induced in rats in this study. Permanent MCAO led to larger infarct volumes in contrast to transient MCAO. Only in transient MCAO, Bai administration significantly reduced infarct size. Baicalein also markedly reduced apoptosis in the penumbra of transient MCAO rats. Additionally, oxygen and glucose deprivation (OGD) was used to mimic ischemic insult in primary cultured cortical neurons. A rapid increase in the intracellular reactive oxygen species level and nitrotyrosine formation induced by OGD was counteracted by Bai, which is parallel with attenuated cell injury. The reduction of phosphorylation Akt and glycogen synthase kinase-3beta (GSK3beta) induced by OGD was restored by Bai, which was associated with preserved levels of phosphorylation of PTEN, the phophatase that negatively regulates Akt. As a consequence, Bcl-2/Bcl-xL-associated death protein phosphorylation was increased and the protein level of Bcl-2 in motochondria was maintained, which subsequently antagonize cytochrome c released in cytosol. LY294002 blocked the increase in phospho-AKT evoked by Bai and abolished the associated protective effect. Together, these findings provide evidence that Bai protects neurons against ischemia injury and this neuroprotective effect involves PI3K/Akt and PTEN pathway.
 ...
PMID:Neuroprotection by baicalein in ischemic brain injury involves PTEN/AKT pathway. 2005 Sep 73

BNIP3 is a hypoxia-inducible BH3-only member of the Bcl-2 family of proteins that regulate apoptosis and autophagy. However the role of BNIP3 in the hypoxia response has proved difficult to define and remains controversial. In this study we show that in cancer cells, knockdown or forced expression of BNIP3 fails to modulate cell survival under hypoxic or normoxic conditions. However, we demonstrate that BNIP3 is regulated post-translationally, existing as multiple monomeric and dimeric phosphorylated forms. Upon treatment with microtubule inhibitors, but not other classes of chemotherapeutics, BNIP3 becomes hyperphosphorylated. We demonstrate that the phosphorylation of BNIP3 occurs in synchrony with phosphorylation of its binding partners Bcl-2 and Bcl-xL. Microtubule inhibitor-induced phosphorylation of these proteins occurs independently of the AKT/mTor and JNK kinase pathways and requires Mps1 mitotic checkpoint kinase activity. Inhibition of mitotic arrest in the presence of paclitaxel blocks the phosphorylation of BNIP3, Bcl-2 and Bcl-xL, demonstrating that these proteins are phosphorylated by a mitochondrially active mitotic kinase. We show that phosphorylation increases the stability of BNIP3 and that BNIP3 predominantly interacts with the phosphorylated form of Bcl-2. This study provides new insight into the post-translational functional control of these Bcl-2 family members.
 ...
PMID:Synchronised phosphorylation of BNIP3, Bcl-2 and Bcl-xL in response to microtubule-active drugs is JNK-independent and requires a mitotic kinase. 2010 Apr 68

NSAIDs and COX-2 inhibitors show anti-cancer activities in many cancer cells. In this study, we investigated the effects of NSAIDs (aspirin or indomethacin) and COX-2 inhibitor (NS-398) on growth of YD-8 human oral squamous carcinoma cells. Interestingly, among drugs tested, aspirin showed strongest inhibitory effects on viability and survival of YD-8 cells. Profoundly, aspirin treatment resulted in severe cell shrinkage and nuclear DNA fragmentation in YD-8 cells, suggesting the aspirin-induced apoptosis in YD-8 cells. Data of Western blot further demonstrated that aspirin treatment caused activation of caspases, down-regulation of Mcl-1 protein, dephosphorylation of ERK-1/2 and AKT, and also IkappaB-alpha proteolysis-dependent NF-kappaB activation in YD-8 cells. Aspirin, however, had no effect on expressions of Bcl-2, XIAP, and HIAP-1 in YD-8 cells. Importantly, pretreatment with z-VAD-fmk, a pan-caspase inhibitor blocked the aspirin-induced apoptosis and Mcl-1 down-regulation in YD-8 cells. These findings collectively suggest that aspirin induces apoptosis in YD-8 cells and the induction may be correlated to activation of caspases, caspase-dependent Mcl-1 proteolysis, inactivation of ERK-1/2 and AKT, and activation of NF-kappaB. It is suggested that aspirin may be applied a potential anti-cancer drug against human oral squamous carcinoma.
 ...
PMID:Aspirin induces apoptosis in YD-8 human oral squamous carcinoma cells through activation of caspases, down-regulation of Mcl-1, and inactivation of ERK-1/2 and AKT. 2011 23

In this article, we demonstrate that the synthetic cannabinoid R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)-(1-naphthalenyl) methanone mesylate (WIN 55,212-2) sensitizes human hepatocellular carcinoma (HCC) cells to apoptosis mediated by tumor necrosis-related apoptosis inducing ligand (TRAIL). The apoptotic mechanism induced by treatment with WIN/TRAIL combination involved the loss of the mitochondrial transmembrane potential and led to the activation of caspases. In HCC cells, WIN treatment induced the up-regulation of TRAIL death receptor DR5, an effect that seemed to be related to the increase in the level of p8 and CHOP, two factors implicated in cellular stress response and apoptosis. This relationship was suggested by the observation that the down-regulation of p8 or CHOP by specific small interfering RNAs attenuated both WIN-mediated DR5 up-regulation and the cytotoxicity induced by WIN/TRAIL cotreatment. Moreover, WIN induced a significant decrease in the levels of some survival factors (survivin, c-inhibitor of apoptosis protein 2, and Bcl-2) and in particular in that of the active phosphorylated form of AKT. This event seemed to be dependent on the transcription factor peroxisome proliferator-activated receptor-gamma whose level significantly increased after WIN treatment. Therefore, both the induction of DR5 via p8 and CHOP and the down-regulation of survival factors seem to be crucial for the marked synergistic effects induced by the two drugs in HCC cells. Taken together, the results reported in this article indicate that WIN/TRAIL combination could represent a novel important tool for the treatment of HCC.
 ...
PMID:The synthetic cannabinoid WIN 55,212-2 sensitizes hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating p8/CCAAT/enhancer binding protein homologous protein (CHOP)/death receptor 5 (DR5) axis. 2015 39

Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death of men in the United States. To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer to more invasive forms. In this study, we identified Saussurea involucrata Kar. et Kir., a rare traditional Chinese medicinal herb, as a potential agent for androgen-independent prostate cancer patients and investigated its biological mechanism as an antineoplastic agent. S. involucrata caused a concentration- and time-dependent inhibition of cell proliferation in human hormone-resistant prostate cancer PC-3 cells. Moreover, in vitro studies in a panel of several types of human cancer cell lines revealed that S. involucrata inhibited cell proliferation with high potency. To evaluate the bioactive compounds, we successively extracted the S. involucrata with fractions of methanol (SI-1), ethyl acetate (SI-2), n-butanol (SI-3), and water (SI-4). Among these extracts, SI-2 contains the most effective bioactivity. SI-2 treatment resulted in significant time-dependent growth inhibition together with G1 phase cell cycle arrest and apoptosis in PC3 cells. In addition, SI-2 treatment strongly induced p21WAF1/CIP and p27KIP1 expression, independent of the p53 pathway, and downregulated expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4). SI-2 treatment increased levels of Bax, cytochrome c, activated caspase-3, and active caspase-9 and decreased Bcl-2 expression level. One of the major targets for the therapy in prostate cancer can be epidermal growth factor receptor (EGFR). SI-2 markedly reduced phosphorylation of EGFR and inhibited activation of AKT and STAT3. Moreover, p.o. administration of SI-2 induced a dose-dependent inhibition of PC-3 tumor growth in vivo. In summary, our study identifies S. involucrata as an effective inhibitor of EGFR signaling in human hormone-resistant prostate cancer PC-3 cells. We suggest that S. involucrata could be developed as an agent for the management of EGFR-positive human cancers.
 ...
PMID:Inhibition of epidermal growth factor receptor signaling by Saussurea involucrata, a rare traditional Chinese medicinal herb, in human hormone-resistant prostate cancer PC-3 cells. 2016 59

Local release of TGF-beta during times of high bone turnover leads to elevated levels within the bone microenvironment, and we have shown that TGF-beta suppresses osteoclast apoptosis. Therefore, understanding the influences of TGF-beta on bone resorbing osteoclasts is critical to the design of therapies to reduce excess bone loss. Here we investigated the mechanisms by which TGF-beta sustains suppression of osteoclast apoptosis. We found TGF-beta rapidly increased leukemia inhibitory factor (LIF) expression and secretion by phosphorylated mothers against decapentaplegic-dependent and -independent signaling pathways. TGF-beta also induced suppressor of cytokine signaling 3 (SOCS3) expression, which was required for TGF-beta or LIF to promote osteoclast survival by. Blocking LIF or SOCS3 blocked TGF-beta promotion of osteoclast survival, confirming that LIF and SOCS3 expression are necessary for TGF-beta-mediated suppression of osteoclast apoptosis. Investigation of the mechanisms by which LIF promotes osteoclast survival revealed that LIF-induced expression of Bcl-X(L) and repressed Bcl-2 interacting domain expression by activating MAPK kinase, AKT, and nuclear factor-kappaB pathways. Suppression of Janus kinase/signal transducer and activator of transcription signaling further increased Bcl-X(L) expression and enhanced osteoclast survival, supporting that this pathway is not involved in prosurvival effects of TGF-beta and LIF. These data show that TGF-beta coordinately induces LIF and SOCS3 to promote prosurvival signaling. This alters the ratio of prosurvival Bcl2 family member Bcl-X(L) to proapoptotic family member Bcl-2 interacting domain, leading to prolonged osteoclast survival.
 ...
PMID:Transforming growth factor-{beta} coordinately induces suppressor of cytokine signaling 3 and leukemia inhibitory factor to suppress osteoclast apoptosis. 2018


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