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)

Her-2/neu (ErbB2) oncogene, the second member of the epidermal growth factor receptor (EGFR) family, encodes a transmembrane tyrosine kinase receptor in Her-2-positive tumors. Accumulating evidences demonstrate that signaling networks activated by EGFR and transcription factor NF-kappaB are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF-kappaB activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominant-negative mutant IkappaB (MCF-7/ErbB2/mIkappaB) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF-kappaB activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF-kappaB regulation, basal and IR-induced Akt, a kinase downstream of ErbB2, was activated in MCF-7/ErbB2 cells and inhibited by Herceptin. To identify specific genes affected by ErbB2-mediated NF-kappaB activation, a group of IR-responsive elements Cyclin B1, Cyclin D1, Bcl-2, Bcl/XL, BAD and BAX were evaluated. Basal levels of prosurvival elements Cyclin B1, Cyclin D1, Bcl-2 and Bcl/XL but not apoptotic BAD and BAX were upregulated in MCF-7/ErbB2 cells with striking enhancements in Bcl-2 and Bcl/XL. IR further induced Cyclin B1 and Cyclin D1 expression that was reduced by Herceptin. Bcl-2 kept a high steady level after Herceptin+IR treatment and, in contrast to control MCF-7/Vector cells, Bcl/XL was inhibited in MCF-7/ErbB2 cells by Herceptin+IR treatment. However, all four prosurvival proteins were downregulated by inhibition of NF-kappaB in MCF-7/ErbB2/mIkappaB cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF-kappaB response to IR, and that a specific prosurvival network downstream of NF-kappaB is triggered by treatments using anti-ErbB2 antibody combined with radiation.
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PMID:Expression of ErbB2 enhances radiation-induced NF-kappaB activation. 1472 81

In the present studies, the role of oxidative stress in radiosensitization by a combination of 2-DG and 6-aminonicotinamide (6-AN) was examined in a human glioma cell line (BMG-1: wild type p53). Presence of 2-DG or 6-AN for 4 hr after irradiation (gamma ray 2.5 Gy) significantly enhanced the radiation-induced cell death by 18% and the combination (2-DG + 6-AN) enhanced the cell death by 35%. Neither 2-DG nor 6-AN had any further significant effect on the glutathione levels in irradiated cells. However, the combination (2-DG + 6-AN) caused a significant decrease in GSH content, increase in GSSG levels, and enhanced the superoxide radical generation under these conditions. The enhanced cell death caused by the combination (2-DG + 6-AN) mainly resulted by the process of apoptosis as revealed by annexin V binding and was associated with elevated levels of Cyclin B1. However, no significant change was observed in the levels of Bcl-2. Thus, for the first time, our results have demonstrated that the radiosensitizing effects of these modifiers could also be mediated through alterations in the oxidative stress besides energy limited inhibition of repair and recovery processes.
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PMID:Contribution of oxidative stress to radiosensitization by a combination of 2-DG and 6-AN in human cancer cell line. 1532 Apr 90

Recent studies have shown that Cyclin B1 is overexpressed in various tumor types but present at low levels in normal tissues. To explore the possibility of employing Cyclin B1 as an anticancer target, we knocked down Cyclin B1 in an HeLa cell line using RNA interference (RNAi). Subsequently, we monitored cell cycle-related molecules by Western blot together with immunofluorescence and determined cell cycle distribution by flow cytometry. XTT and soft agar colony growth experiments were performed to detect cell viability and proliferation. Furthermore, we analyzed cell apoptosis by measuring Bcl-2 and Bax protein level and DNA-ladder assay. After performing Cyclin B1 RNAi, Cyclin B1, Cyclin A and Cdk2 protein levels were found to be markedly downregulated, whereas Cdc2 was almost unaffected; S-phase fraction increased significantly; HeLa cell viability and cell colony forming ability were markedly diminished after the RNAi; Bcl-2 was noticeably attenuated but Bax was hardly changed; and HeLa cells displayed typical DNA ladder. The loss of Cyclin B1 resulted in the downregulation of Cyclin A and Cdk2, S-phase delay and eventually led to cell apoptosis and the decrease of cell viability and proliferation. Our studies suggest that Cyclin B1 may be a promising anticancer target.
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PMID:Loss of Cyclin B1 followed by downregulation of Cyclin A/Cdk2, apoptosis and antiproliferation in Hela cell line. 1581 17

Carboxyamido-triazole (CAI), a voltage-independent calcium channel inhibitor, has been shown to be able to induce growth inhibition and apoptosis in cancer cells. In the present study, we demonstrate that CAI significantly inhibits proliferation of cultured MCF-7 human breast cancer cells in a dose-dependent manner with an IC(50) of approximately 26 microM. Reduced proliferation of MCF-7 cells in the presence of CAI correlated with accumulation of cells in G(2)/M phase and induction of apoptosis. A treatment of MCF-7 cells with 30 microM CAI caused a time-dependent decrease in the levels of proteins that regulate G(2)/M progression, including Cdk1, Cyclin B1, and Cdc25C. A simultaneous increase in the expression of p21 protein was observed. We also demonstrated a concurrent decrease of the mitochondrial membrane potential (DeltaPsi(m)), and down-regulation of anti-apoptotic protein Bcl-2. In conclusion, it seems reasonable to hypothesize that the antitumor effect of CAI in MCF-7 cells is based on G(2)/M cell cycle arrest and inducing apoptosis.
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PMID:Carboxyamido-triazole inhibits proliferation of human breast cancer cells via G(2)/M cell cycle arrest and apoptosis. 1669 67

We demonstrated here for the first time that zerumbone (ZER), a natural cyclic sesquiterpene, significantly suppressed the proliferation of promyelocytic leukemia NB4 cells among several leukemia cell lines, but not human umbilical vein endothelial cells (HUVECs), by inducing G2/M cell cycle arrest followed by apoptosis with 10 microM of IC50. Treatment of NB4 cells with growth-suppressive concentrations of ZER resulted in G2/M cell cycle arrest that was associated with a decline of Cyclin B1 protein, but with the phosphorylation of ATM/ Chk1/Chk2. In addition, ZER induced the phosphorylation of Cdc25C at the Thr48 residue and Cdc2 at the Thr14/Tyr15 residues. Furthermore, ZER-induced apoptosis in NB4 cells was initiated by the expression of Fas (CD95)/Fas Ligand (CD95L), concomitant with the activation of caspase-8. ZER was also found to induce the cleavage of Bid, a mediator that is known to connect the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. ZER also induced the cleavage of Bax and Mcl-1 proteins, but not Bcl-2 or Bcl-XL. ZER-induced apoptosis took place in association with a loss of the mitochondrial transmembrane potential as well as the activation of caspase-3 and -9, resulting in the degradation of the proteolytic poly (ADP-ribose) polymerase (PARP). ZER also triggered a release of cytochrome c into the cytoplasm. Both antagonistic anti-Fas antibody ZB4 and pan-caspase inhibitor Z-VAD inhibited ZER-induced apoptosis in NB4 cells. Taken together, ZER is an inducer of apoptosis in leukemic cells that specifically triggers the Fas/CD95- and mitochondria-mediated apoptotic signaling pathway.
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PMID:Zerumbone, a bioactive sesquiterpene, induces G2/M cell cycle arrest and apoptosis in leukemia cells via a Fas- and mitochondria-mediated pathway. 1712 59

The aim of the present study is to investigate the effect of genistein on human neuroblastoma SK-N-MC cells. MTT proliferation assay, LDH cytotoxicity assay, flow cytometric analysis, real-time quantitative RT-PCR and western blotting were used to investigate the effect of genistein on cell survival, cellular toxicity, cell cycle progression, and mRNA and protein alterations of selected DNA damage-, cell cycle- and apoptosis-related genes in SK-N-MC cells. Genistein suppressed cell proliferation, increased LDH release and modulated cell cycle distribution through accumulation of cells at G2/M- and S-phase and sub-G0 (cell death) with a concurrent decrease of cells at G0/G1 phase. Genistein increased the MDC1 (Mediator of DNA damage Checkpoint protein 1), p53, p21(waf1/cip1), Cdc2 and Bax mRNA levels in a dose-dependent manner. However, PLK1 (Polo-Like Kinase 1) and Cyclin B1 mRNAs were down-regulated after genistein treatment. Furthermore, Genistein did not alter Chk2 (Checkpoint Kinase 2), Bcl-2 and Cdc25C mRNA levels. On western blotting analyses; genistein increased the protein level of MDC1, p53, p21(waf1/cip1), and Bax in a dose-dependent manner. Genistein also increased the phosphorylation of Chk2 and Cdc25C at Thr-68 and Ser-216, respectively. In addition, consistently with PLK1 down-regulation, the phosphorylation of Cdc25C at Ser-198 was markedly decreased after genistein treatment. Additionally, Chk2, Cdc25C, Cyclin B1, p-Cyclin B1 (Ser-147), and Cdc2 as well as Bcl-2 proteins were down-regulated after genistein treatment. Altogether, these results suggest for the first time the involvement of MDC1 up-regulation after genistein treatment in DNA damage-induced Chk2 activation- and PLK1 down-regulation-mediated apoptosis and cell cycle checkpoint pathways.
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PMID:Genistein-induced neuronal apoptosis and G2/M cell cycle arrest is associated with MDC1 up-regulation and PLK1 down-regulation. 1770 63

Kaempferol-7-O-beta-D-glucoside (KG), a flavonoid glycoside, isolated from Smilax china L. rhizome, displayed marked anticancer activity on a panel of established cancer cells, of which, HeLa human cervix carcinoma cells were the most sensitive. Meanwhile, the cytotoxic effects of KG on normal human cells (HEK293 embryonic kidney cells and L-02 embryonic liver cells) were much smaller than on cancer cells. This work studied the molecular mechanisms underlying KG induced growth inhibition in HeLa cells. The results showed that KG induced G2/M phase growth arrest correlated with Cyclin B1 and Cdk1 decrease in a p53-independent manner, and also caused an increase in apoptosis, which was confirmed by characteristic morphological changes, evident DNA fragmentation, increased apoptotic sub-G1 population. Furthermore, inhibition of NF-kappaB nuclear translocation, up-regulation of Bax and down-regulation of Bcl-2, were observed in HeLa cells treated with KG, which indicated that the mitochondrial pathway was involved in the apoptosis signal pathway. In summary, KG displayed a significant anti-tumor effect through cell cycle arrest and apoptotic induction in HeLa cells, which suggested that KG might have therapeutic potential against cervix carcinoma.
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PMID:Kaempferol-7-O-beta-D-glucoside (KG) isolated from Smilax china L. rhizome induces G2/M phase arrest and apoptosis on HeLa cells in a p53-independent manner. 1834 26

To investigate the anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer, gastric cancer AGS cells were treated with luteolin and/or other chemotherapeutic agents. Cell growth was assessed by MTT assay, cell cycle and apoptosis were assessed by flow-cytometric analysis, and the expression of major proteins regulating cell cycle and apoptosis was also detected. The results showed that luteolin inhibited the growth of gastric cancer cells in a dose- and time-dependent manner. Flow cytometry revealed that the percentage of cells at G2/M phase increased dose-dependently. The protein levels of Cdc2, Cyclin B1 and Cdc25C were reduced and p21/cip1 was up-regulated after the treatment with luteolin. Furthermore, luteolin induced apoptosis in gastric cancer AGS cells. Western blotting showed that luteolin treatment significantly increased the levels of pro-apoptotic proteins, including Caspase-3, 6, 9, Bax, and p53, and decreased the levels of anti-apoptotic protein Bcl-2, thus shifting the Bax/Bcl ratio in favor of apoptosis. It was also demonstrated that a combinational treatment of cisplatin and luteolin induced more effectively cell growth inhibition, compared to cisplatin treatment alone. These findings indicate the anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer AGS cells and luteolin may be a promising candidate agent used in the treatment of gastric cancer.
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PMID:Anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer AGS cell line. 1839 71

Flavonoids are polyphenolic compounds and capable of inhibiting the growth of human cancer cells. Protoapigenone, a novel flavonoid, was isolated from the whole plant Thelypteris torresiana (Gaud), a native fern in Taiwan. In the present study, we explored the cytotoxic effects of protoapigenone on ovarian cancer cells and the immortalized ovarian epithelial cells by XTT assay. The effects of protoapigenone on cell cycle progression and apoptosis were also analyzed by FACS analysis, immunofluorescence study and immunoblotting analysis. The anti-ovarian cancer effect of protoapigenone was further examined using nude mice xenograft assay and immunohistochemistry. Our results showed that protoapigenone had a significant cytotoxicity on human ovarian cancer cells MDAH-2774 and SKOV3 but not on the immortalized non-cancer ovarian epithelial cells HOSE 6-3 and HOSE 11-12. Protoapigenone arrested MDAH-2774 and SKOV3 cells at S and G2/M phases via decreasing the expression of p-Cdk2, Cdk2, p-Cyclin B1 and Cyclin B1, as well as increasing the expression of inactive p-Cdc25C. Besides, protoapigenone had an enhanced cytotoxicity on SKOV3 cells enriched at S and G2/M phases, and ability to induce apoptosis through decreasing the protein levels of Bcl-xL and Bcl-2 and increasing the cleaved PARP by activating caspase-3. In nude mice study, protoapigenone treatment significantly suppressed the tumor growth, without major side effects. Taken together, protoapigenone showed a significant anti-ovarian cancer activity with low toxicity, suggesting its potential to be developed as a chemotherapeutic agent.
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PMID:Protoapigenone, a novel flavonoid, inhibits ovarian cancer cell growth in vitro and in vivo. 1843 May 9

Amonafide, a naphthalimide derivative, although selected for exploratory clinical trials for its potent anticancer activity, has long been challenged by its unpredictable side effects. In the present study, a novel amonafide analogue, M(2)-A 2-(2-(dimethylamino)ethyl)-6-(thiophene-2-ylmethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione was ascribed to its potent effects on topoisomerase IIalpha. Moreover, our investigation indicates that M(2)-A induces G(2)/M phase growth arrest through inhibiting PI3K/Akt pathway. M(2)-A inhibits proliferation of HeLa, HL60, HCT-8, A375, MCF-7 and MRC-5 cells, especially inhibits proliferation of HL60 with an IC(50) value of 18.86 microM. M(2)-A can not only induce DNA fragmentation, but also enhance Annexin V-FITC binding of the cells. On the one hand the expression levels of protein Cyclin B1, Cdk1 changed in response to M(2)-A treatment in HL60 cells. On the other hand we observed the inhibition of NF-kappaB nuclear translocation, up-regulation of Bax and down-regulation of Bcl-2, the caspase -3, -9 activity increase in HL60 cells after treated with M(2)-A, which indicated that the mitochondrial pathway was involved in the apoptosis signal pathway. Our results showed that the phosphorylation of p85/PI3K and Akt decreased following M(2)-A treatment. In summary, M(2)-A displayed a significant anti-tumor effect through cell cycle arrest and apoptotic induction in HL60 cells, which suggested that M(2)-A might have therapeutic potential against leukaemia.
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PMID:M(2)-A induces apoptosis and G(2)-M arrest via inhibiting PI3K/Akt pathway in HL60 cells. 1943 48


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