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)

Microtubules are long-standing targets in cancer chemotherapy. Previously, we reported that marchantin C triggers apoptosis of human tumor cells. We show here that marchantin C induced cell cycle arrest at G(2)/M phase in A172 and HeLa cells. In addition, marchantin C decreased the quantity of microtubules in a time- and dose-dependent manner in these cells. Exposure of purified bovine brain tubulin to marchantin C inhibited polymerization of gross tubulin in vitro. Moreover, marchantin C potently suppressed the growth of human cervical carcinoma xenografts in nude mice. Marchantin C-treated xenografts showed decreased microtubules, Bcl-2 and increased cyclin B1, Bax, caspase-3, indicating that marchantin C possess the same ability to induce microtubules depolymerization and tumor cell apoptosis in tumor-bearing mice as in vitro. In conclusion, marchantin C is a novel microtubule inhibitor that induces mitotic arrest of tumor cells and suppresses tumor cell growth, exhibiting promising antitumor therapeutic potential.
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PMID:Marchantin C, a novel microtubule inhibitor from liverwort with anti-tumor activity both in vivo and in vitro. 1909 49

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Vascular endothelial growth factor, platelet derived growth factor and the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, invasiveness and metastatic potential of HCC. In this study, we investigated the in vivo antitumour activity and mechanisms of action of sorafenib tosylate on four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth suppression and apoptosis were associated with inhibition of angiogenesis, down-regulation of phospho-platelet-derived growth factor receptor beta Tyr1021, phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, p27 and p21. Expression of IGF-1Rbeta and phosphorylation of c-Raf Ser338, MEK1/2 Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in sorafenib-less-sensitive 10-0505 xenograft. Sorafenib-induced phosphorylation of c-met, p70S6K and 4EBP1 was significantly reduced when 10-0505 cells were co-treated with anti-human anti-HGF antibody, suggesting that treatment with sorafenib leads to increased HGF secretion and activation of c-met and mTOR targets. Treatment of 10-0505 tumours with sorafenib plus rapamycin resulted in growth inhibition, inhibition of vascular endothelial growth factor receptor-2 phosphorylation, increased apoptosis and completely blocked sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression. These data also provide a strong rationale for clinical investigation of sorafenib in combination with mTOR inhibitors in patients with HCC.
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PMID:Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. 1922 May 80

Pyrogallol, a catechin compound, is an active component of Emblica officinalis extracts and has an anti-proliferative effect on some human cancer cell lines. In our preliminary study, pyrogallol had highly cytotoxic effect on human lung cancer cell lines and less effect on human bronchial epithelium cell line. This study was performed to investigate the beneficial effect of pyrogallol on human lung cancer cell lines - H441 (lung adenocarcinoma) and H520 (lung squamous cell carcinoma). The MTT (cytotoxic) data showed the inhibition growth of lung cancer cells followed pyrogallol treatment. The cell cycle of lung cancer cells was arrested in G2/M phase using flow cytometry. Using Western blot analysis, the cell cycle related proteins - cyclin B1 and Cdc25c were decreased in a time-dependent manner and the phosphorylated Cdc2 (Thr14) was increased within 4h pyrogallol treatment. Moreover, the higher cleavage of poly (ADP)-ribose polymerase (PARP), the increased of Bax concurrent with the decreased of Bcl-2 indicated that pyrogallol treatment resulted in apoptosis of lung cancer cells. The cell apoptosis was also directly demonstrated using Annexin V-FITC and TUNEL stain. Additionally, the tumoricidal effect of pyrogallol was measured using a xenograft nude mice model. After 5 weeks of pyrogallol treatment could cause the regression of tumor. Taken in vitro and in vivo studies together, these results suggest that pyrogallol can be developed as a promising anti-lung cancer drug particular for the non-small cell lung cancer (NSCLC).
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PMID:Pyrogallol induces G2-M arrest in human lung cancer cells and inhibits tumor growth in an animal model. 1923 5

The objectives of this study were to determine the antiproliferation effect of prostate cancer cell lines LNCaP and PC-3 as affected by 4 isoflavone fractions prepared from soybean cake and isoflavone standards genistein and daidzein. With the MTT test, most treatments were effective in inhibiting prostate cancer cell growth at a low dose of 5 and 10 mug/mL. In cell cycle analysis, the fractions of aglycon, a mixture of acetylglucoside and aglycon, as well as genistein and a combination of genistein and daidzein standards exhibited a high G2/M ratio for LNCaP, as did the acetylglucoside, genistein and a combination of genistein and daidzein standards for PC-3. Results of Western blotting revealed an increase in p53 protein expression of LNCaP following treatments of the aglycon fraction, genistein and a combination of genistein and daidzein standards. However, all the treatments did not affect Bcl-2 protein expression significantly in both LNCaP and PC-3 cells. A decline in cyclin B1 expression of LNCaP was observed for all the treatments, with the mixture of acetylglucoside and aglycon possessing the most pronounced effect. But for PC-3, a decrease in cyclin B1 expression was shown for all the isoflavones, with the exception of malonylglucoside, glucoside and acetylglucoside fractions. The outcome of this study may provide a basis for possible production of functional food in the future with soybean cake as raw material.
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PMID:Antiproliferation effect and mechanism of prostate cancer cell lines as affected by isoflavones from soybean cake. 1929 64

Emodin was isolated from Rheum palmatum L. and exhibits an anticancer effect on human cancer cell lines, however, the molecular mechanisms of emodin-mediated apoptosis in human tongue cancer cells have not been fully investigated. In this study, treatment of human tongue cancer SCC-4 cells with various concentrations of emodin led to G2/M arrest through promoted p21 and Chk2 expression but inhibited cyclin B1 and cdc2; it also induced apoptosis through the pronounced release of cytochrome c from mitochondria and activations of caspase-9 and caspase-3. These events were accompanied by the generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (delta psi(m)) and a decrease in the ratio of mitochondrial Bcl-2 and Bax content; emodin also promoted the levels of GADD153 and GRP78. The free radical scavenger N-acetylcysteine and caspase inhibitors markedly blocked emodin-induced apoptosis. Taken together, these findings suggest that emodin mediated oxidative injury (DNA damage) based on ROS production and ER stress based on the levels of GADD153 and GRP78 that acts as an early and upstream change in the cell death cascade to caspase- and mitochondria-dependent signaling pathways, triggers mitochondrial dysfunction from Bcl-2 and Bax modulation, mitochondrial cytochrome c release and caspase activation, consequently leading to apoptosis in SCC-4 cells.
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PMID:Emodin induces apoptosis of human tongue squamous cancer SCC-4 cells through reactive oxygen species and mitochondria-dependent pathways. 1933 Nov 69

Regulator of Cullins-1 (ROC1) or Ring Box Protein-1 (RBX1) is a RING component of SCF (Skp-1, cullins, F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting a variety of substrates for degradation. However, little is known about the role of ROC1 in human cancer. Here, we report that ROC1 is ubiquitously overexpressed in primary human tumor tissues and human cancer cell lines. ROC1 silencing by siRNA significantly inhibited the growth of multiple human cancer cell lines via induction of senescence and apoptosis as well as G(2)-M arrest. Senescence induction is coupled with DNA damage in p53/p21- and p16/pRB-independent manners. Apoptosis is associated with accumulation of Puma and reduction of Bcl-2, Mcl-1, and survivin; and G(2)-M arrest is associated with accumulation of 14-3-3sigma and elimination of cyclin B1 and Cdc2. In U87 glioblastoma cells, these phenotypic changes occur sequentially upon ROC1 silencing, starting with G(2)-M arrest, followed by apoptosis and senescence. Thus, ROC1 silencing triggers multiple death and growth arrest pathways to effectively suppress tumor cell growth, suggesting that ROC1 may serve as a potential anticancer target.
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PMID:ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence. 1950 29

New chemotherapeutic strategy should be investigated to enhance clinical management in salivary gland adenoid cystic carcinoma (ACC). Recently, sulforaphane (SFN), as a natural compound from cruciferous vegetables exhibits a potent anti-cancer activity in various tumor cells, but remains uncertain in ACC cells. The present study examined whether SFN suppresses proliferation and in ACC cells, if so, the possible molecular targets would be further investigated. Cell survives, apoptosis, cell cycle progression and molecular targets were identified by multiple detecting techniques, including trypan blue dye exclusion assay, electron microscopy, AO/EB staining, flow cytometry and immunoblotting in human lung high metastasis cell line of salivary gland adenoid cystic carcinoma (ACC-M). The results showed that 5-20 microM SFN suppressed proliferation and induced apoptosis of ACC-M cells in dose- and time-dependent manners. Cell cycle analysis demonstrated treatment of ACC-M cells with 20 microM SFN resulted in G(2)/M cell cycle arrest, which was associated with a marked decline in protein levels of G(2)/M regulatory proteins including cyclin B1 and cyclin-dependent kinase 1 (Cdk1). In terms of apoptosis, SFN increased the expression of Bax and decreased the level of Bcl-2 and subsequently triggered release of cytochrome c from mitochondria and activation of caspase-3, but Fas level and caspase-8 activity remained unchanged at all time points. Furthermore, levels of nuclear factor-kappaB (NF-kappaB) p65 in both of the cytoplasm and the nucleus have also been markedly suppressed by SFN in a time-dependent manner. Taken together, these results suggest SFN inhibits cell growth via inducing G(2)/M cell arrest and apoptosis in ACC-M cells. These events have been associated with SFN-regulated multiple targets involved in ACC-M cell proliferation. The present study provides an evidence for testing SFN efficacy in vivo and warranting future investigations to exam the clinical potential of SFN in ACC chemotherapy.
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PMID:Sulforaphane induces G2-M arrest and apoptosis in high metastasis cell line of salivary gland adenoid cystic carcinoma. 1958 18

Betuletol 3-methyl ether (BME) is a natural phenylbenzo-gamma-pyrone that inhibits cell proliferation in human tumor cell lines and induces apoptotic cell death in HL-60 cells. Here we show that BME displays strong cytotoxic properties in several human leukemia cell lines (U937, K-562, THP-1, Jurkat, and Molt-3) and in cells that over-express two anti-apoptotic proteins, namely Bcl-2 and Bcl-x(L). BME arrested HL-60 cells at G(2)-M phase of the cell cycle, which was associated with the accumulation of cyclin B1 and p21(Cip1). Fluorescence microscopy experiments suggest that BME blocked the cell cycle in mitosis. The in vivo tubulin polymerization assay shows that BME inhibits tubulin polymerization and causes similar changes of cellular microtubule network as colchicine. Our results demonstrate that BME-induced cell death is (i) triggered in human myeloid leukemia cell that over-express Bcl-2 and Bcl-x(L), and (ii) associated with loss of inner mitochondrial membrane potential (DeltaPsim) and an increase in reactive oxygen species (ROS). Although ROS increased in response to BME, this did not seem to play a pivotal role in the apoptotic process since the anti-oxidant trolox was unable to provide cell protection. The treatment of HL-60 cells with BME induces the activation of mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases, p38 mitogen-activated protein kinases and extracellular signal-regulated kinases (ERK)1/2 and stimulates the acid sphingomyelinase with concomitant ceramide generation. The findings of this study suggest that BME could be useful in the development of novel anticancer agents.
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PMID:Betuletol 3-methyl ether induces G(2)-M phase arrest and activates the sphingomyelin and MAPK pathways in human leukemia cells. 1967 4

BCL2L12, a newly identified member of Bcl-2 family, and its transcript variant BCL2L12A have been found to be associated with favorable prognosis in breast cancer patients while correlated with tumorigenesis of glioblastoma and colon cancer. However, the biological functions of BCL2L12 and especially those of BCL2L12A are largely unknown. Here, we report that, unlike other Bcl-2 family proteins, BCL2L12 and its transcript variant BCL2L12A are nuclear proteins. Interestingly, BCL2L12 forms speckle patterns in the nuclei and potently induces apoptosis in CHO cells. BCL2L12A had a diffuse distribution in the nuclei and inhibits cell growth by inducing cell cycle arrested at G2/M transition in CHO cells. More importantly, BCL2L12A-induced G2/M arrest was associated with a slight up-regulation of cyclin B1 and significant down-regulation of an active form of cyclin B1 phosphorylated at Ser147. Taken together, our study suggests that both BCL2L12 and BCL2L12A have negative effects on CHO cell growths, and that BCL2L12A is a potential cell cycle regulator that interferes with G2-M transition.
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PMID:BCL2L12A localizes to the cell nucleus and induces growth inhibition through G2/M arrest in CHO cells. 1976 95

Identification of agents that are nontoxic but can delay onset and/or progression of breast cancer, which is the main leading cause of cancer-related deaths among women, is highly desirable. Garlic-derived organosulfur compounds (OSCs) have highly effective antitumor effects, but the mechanism has yet to be investigated. The aim of the present study was undertaken to examine the effect of diallyl trisulfide (DATS), a promising cancer chemopreventive constituent of garlic, on growth of two cell lines respectively, MCF-7 human breast cancer cells and nontumorigenic MCF-12a mammary epithelial cells. The effects of DATS were examined by MTT assay, clonogenic survival assay, ELISA based apoptotic assay, TUNEL assay, immunofluoresence staining, flow Cytometry, RT-PCR and western blot analysis. Garlic constituent diallyl trisulfide (DATS) suppresses viability of cultured MCF-7 and MCF-12a cells respectively by decreasing the percent of cells in G(2)/M and inducing apoptotic cell death. DATS-induced apoptosis was markedly elevated in MCF-7 cells compared with MCF-12a cells and this was correlated with elevated levels of cyclin B1. The results from semi-quantitative and real-time RT-PCR indicated that DATS-enhanced the expression levels of FAS and cyclin D1, but in contrast, downregulated the expression levels of Akt and Bcl-2. Furthermore, the DATS-induced apoptosis was correlated with induction of pro-apoptotic Bax protein and p53 protein expression was upregulated and translocation to nucleus in MCF-7 cells. Together, the results of the present study show, for the first time, that DATS administration might offer a novel strategy for the treatment of human breast cancer.
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PMID:Garlic constituent diallyl trisulfide induced apoptosis in MCF7 human breast cancer cells. 1982 37


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