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)

The purpose of this study is to investigate in vitro and ex vivo effects of matrine on the growth of human lung cancer and hepatoma cells and the cancer cell migration as well as the expressions of related proteins in the cancer cells. Matrine significantly inhibited the in vitro and ex vivo growth of human non-small cell lung cancer A549 and hepatoma SMMC-7721 cells. Matrine induced the apoptosis in A549 and SMMC-7721 cells. Western blot analysis indicated that matrine dose-dependently down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro-apoptotic protein bax, eventually leading the reduction of ratios of Bcl-2/Bax proteins in A549 and SMMC-7721 cells. Furthermore, matrine significantly suppressed the A549 cell migration without reducing the cell viability. In addition, matrine dramatically reduced the secretion of vascular endothelial growth factor A in A549 cells. More importantly, matrine markedly enhanced the anticancer activity of anticancer agent trichostatin A (the histone deacetylase inhibitor) by strongly reducing the viability and/or the ratio of Bcl-2/Bax protein in A549 cells. Our findings suggest that matrine may have the broad therapeutic and/or adjuvant therapeutic application in the treatment of human non-small cell lung cancer and hepatoma.
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PMID:Effects of matrine against the growth of human lung cancer and hepatoma cells as well as lung cancer cell migration. 1964 19

Lovastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. Its inhibitory action on HMG-CoA reductase leads to depletion of isoprenoids, which inhibits post-translational modification of RAS. In this study, we investigated the effect of combining lovastatin with gefitinib on gefitinib-resistant human non-small cell lung cancer (NSCLC) cell lines with K-Ras mutations. Antitumor effects were measured by growth inhibition and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Effects on apoptosis were determined by flow cytometry, DNA fragmentation, and immunoblots. Protein levels of RAS, AKT/pAKT, and RAF/ERK1/2 in cancer cells were analyzed by immunoblot. Compared with gefitinib alone, a combination of gefitinib with lovastatin showed significantly enhanced cell growth inhibition and cytotoxicity in gefitinib-resistant A549 and NCI-H460 human NSCLC cells. In addition, lovastatin combination treatment significantly increased gefitinib-related apoptosis, as determined by fluorescence microscopy and flow cytometric analysis. These effects correlated with up-regulation of cleaved caspase-3, poly (ADP-ribose) polymerase (PARP), and Bax and down-regulation of Bcl-2. The combination of lovastatin and gefitinib effectively down-regulated RAS protein and suppressed the phosphorylation of RAF, ERK1/2, AKT, and EGFR in both cell lines. Taken together, these results suggest lovastatin can overcome gefitinib resistance, in NSCLC cells with K-Ras mutations, by down regulation of RAS protein, which leads to inhibition of both RAF/ERK and AKT pathways.
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PMID:Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-Ras mutations. 1976 Jan 59

The function of the epidermal growth factor receptor (EGFR) is dysregulated in various types of malignancy as a result of gene amplification, mutations, or abnormally increased ligand production. Therefore, the tyrosine kinase activity of the EGFR is a promising therapeutic target. EGFR tyrosine kinase inhibitors, such as gefitinib (Iressa), show evident anticancer effects in patients with non-small cell lung cancer. The induction of apoptosis has been considered to be the major mechanism for these gefitinib-mediated anticancer effects. Lung cancer cells harboring mutant EGFRs become dependent on them for their survival and, consequently, undergo apoptosis following the inhibition of EGFR tyrosine kinase by gefitinib. Gefitinib has been shown to inhibit cell survival and growth signaling pathways such as the extracellular signal-regulated kinase 1/2 pathway and the Akt pathway, as a consequence of the inactivation of EGFR. However, the precise downstream signaling molecules of extracellular signal-regulated kinase 1/2 and Akt have not yet been elucidated. In this minireview we have highlighted the effect of tyrosine kinase inhibitors on members of the Bcl-2 family of proteins, which are downstream signaling molecules and serve as the determinants that control apoptosis. We also discuss tyrosine kinase inhibitor-induced apoptosis via c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase.
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PMID:EGF receptor in relation to tumor development: molecular basis of responsiveness of cancer cells to EGFR-targeting tyrosine kinase inhibitors. 1992 67

The purpose of this study is to investigate the effects of berbamine (BER), a naturally occurring small-molecule compound from Traditional Chinese Medicine (TCM) Berberis amurensis, on the growth and migration of human lung cancer A549 cell line. This cell line is the non-small cell lung cancer (NSCLC) which constitutes 80% of lung cancer cases and remains an aggressive lung cancer associated with a poor patient survival. Our present results have shown that BER significantly suppressed the in vitro and ex vivo growth of A549 cells in dose- and time-dependent manners. Furthermore, Western blot analysis confirmed that BER dose-dependently down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro-apoptotic protein Bax, eventually leading the reduction of Bcl-2/Bax protein ratio in A549 cells. In addition, BER significantly inhibited the A549 cell migration at the low concentrations without restraining the cell growth. More importantly, BER significantly enhanced the anticancer activity of anticancer agents such as trichostatin A (the histone deacetylase inhibitor) and celecoxib (the inhibitor of cyclooxygenase-2) by strongly reducing the viability and/or the Bcl-2/Bax protein ratio in A549 cells. Our findings suggest that BER may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human NSCLC.
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PMID:Suppression of human lung cancer cell growth and migration by berbamine. 1996 2

Non-small cell lung cancer (NSCLC) is a common and often fatal malignancy, diagnosed at an advanced stage in more than half of the cases. Chemo-resistance remains a major problem in the treatment of NSCLC patients with conventional chemotherapeutic agents. Therefore main research efforts are focused on the development of novel targeted agents. In this review we provide an overview on the use of TNF-related apoptosis-inducing ligand (TRAIL) receptor targeting agents in NSCLC models and in early clinical studies. Different TRAIL receptor targeting agents are available which have been tested in NSCLC models and some were tested in the clinic. The efficacy of these drugs as single agents in NSCLC models is discussed as well as different mechanisms of resistance that are found in NSCLC cell lines. In order to maximize sensitivity to TRAIL receptor targeting drugs, combined use with other drugs is of interest. The current status of tested combinations of TRAIL receptor targeting agents with other therapeutics, such as classical cytotoxics, Bcl-2 family targeting agents, proteasome inhibitors, EGFR inhibitors, histone deacetylase inhibitors and COX-2 inhibitors as well as their mechanisms in preclinical studies are discussed. Clinical studies on TRAIL targeted therapies in which NSCLC patients were included are discussed and future perspectives are considered.
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PMID:TRAIL receptor targeting therapies for non-small cell lung cancer: current status and perspectives. 2003 2

Tanshinone IIA (Tan-IIA) is extracted from Danshen and known to inhibit proliferation and induce apoptosis in many cancer cells. We aimed to elucidate its anticancer activity and molecular mechanism in human lung cancer A549 cells. The cytotoxicity of Tan-IIA in A549 cells were measured by the MTT assay. The effects of Tan-IIA on the cell cycle, mitochondrial membrane potential (MMP), calcium and reactive oxygen species (ROS) released in A549 cells were detected by flow cytometry. The protein expressions of p53, Bax, Bcl-2 and beta-actin in A549 cells were tested by Western blotting. The proliferative rates of A549 cells were obviously inhibited by Tan-IIA in a dose- and time-dependent manner. The results of FACS showed that the sub-G1 phase was increased when A549 cells were cultured with various concentrations of Tan-IIA (control, 2.5, 5 and 10 microg/ml) for 48 h. Tan-IIA induced the production of ROS, Ca+2 and decreased MMP. The outcome of Western blotting showed that protein expressions of p53 and bax were increased, but proto-oncogene bcl-2 was notably decreased, after culturing with Tan-IIA (5 microg/ml) for 6, 12 and 24 h. Tan-IIA inhibited the proliferation of non-small cell lung cancer A549 cells, possibly by decreasing the MMP and inducing apoptosis due to the induction of a higher ratio of Bax/Bcl-2.
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PMID:Tanshinone IIA induces apoptosis in human lung cancer A549 cells through the induction of reactive oxygen species and decreasing the mitochondrial membrane potential. 2004 32

The effects of norcantharidin (NCTD), an anticancer drug in China, on the growth and migration in human lung cancer cells were investigated by in vitro and ex vivo assays. NCTD significantly inhibited the in vitro and ex vivo growth of human non-small cell lung cancer A549 cells in dose- and time-dependent manners. Western blot analysis indicated that NCTD dose-dependently down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro-apoptotic protein Bax, eventually leading the reduction of ratio of Bcl-2/Bax proteins in A549 cells. Moreover, NCTD significantly suppressed the A549 cell migration in the case of without reducing the cell viability. More importantly, NCTD significantly enhanced the anticancer activity of anticancer agents such as trichostatin A (the histone deacetylase inhibitor), celecoxib (the inhibitor of cyclooxygenase-2) and lovastatin (the inhibitor of HMG-CoA reductase) by strongly reducing the viability and/or the ratio of Bcl-2/Bax protein in A549 cells. Our findings suggest that NCTD may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human lung cancer.
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PMID:Inhibitory effects of norcantharidin against human lung cancer cell growth and migration. 2008 54

Abnormalities in gene expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including breast. Consequently, the dual kinase inhibitor of EGFR and VEGFR ZD6474 represents a promising biologically-based treatment that is currently undergoing clinical trials for non-small cell lung cancer. Patients suffering from breast cancers have a poor prognosis because of the lack of effective agents and treatment strategies. We hypothesized that inhibition of phosphorylation of the EGFR and VEGFR by ZD6474 would inhibit breast cancer cell proliferation and induce apoptosis. This hypothesis was tested using human breast cancer cell lines. ZD6474 inhibited cell proliferation in a dose-dependent manner, by blocking cell progression at the G(0)-G(1) stage, through downregulation of expression of cyclin D1 and cyclin E. In vitro, ZD6474 inhibited growth factor-induced phosphorylation of EGFR, VEGFR-2, MAPK and Akt. ZD6474 also downregulated anti-apoptotic markers including Bcl-2, upregulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3, and induction of poly (ADP-ribose) polymerase during apoptosis. ZD6474 inhibited anchorage independent colony formation using soft agar assays, and invasion of breast cancer cells in vitro using Boyden chamber assays. In a xenograft model using human MDA-MB-231 breast cancer cells, ZD6474 inhibited tumor growth and induced cancer-specific apoptosis. Collectively, these data imply that ZD6474 a dual kinase inhibitor has potential for the targeted therapy of breast cancer.
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PMID:ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells. 2016 Apr 95

Epithelial and endothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase) plays an important role in apoptosis of epithelial cells. The goal of this study was to investigate whether Etk is involved in apoptosis of small cell lung cancer (SCLC) cells and correlated with the expression levels of apoptosis-associated proteins such as Bcl-2, Bcl-X(L) and p53. One hundred and seventy-one cases of lung cancer specimens including seventy-one SCLCs and one hundred NSCLCs were immunostained for Etk, Bcl-2, Bcl-X(L) and p53. Parental SCLC H446 cell line, and its subline (H446-Etk) that overexpresses Etk, were used to study the role of Etk in apoptosis induced by doxorubicin. It was found that high expression of Etk occurs in 74.6% of SCLC cases, but only in 40% of NSCLC cases, and there is marked difference in the expression levels of Bcl-2, Bcl-X(L) and p53 between Etk-positive and Etk-negative SCLC cases. Furthermore, the levels of Bcl-2 and Bcl-X(L) significantly increased in H446-Etk cells than that in H446 cells after doxorubicin treatment, and were positively associated with Etk expression. However, p53 did not correspond with Etk expression although its expression decreased greatly with apoptosis both in H446-Etk and H446 cells. After doxorubicin treatment, the cell viability was significantly higher in H446-Etk cells than in parental H446 cells. Downregulation of Etk by Etk siRNA sensitized H446 cells to doxorubicin. Our results indicate that upregulation of tyrosine kinase Etk may be a new mechanism involved in protection of SCLC cells from apoptosis. Bcl-2 and Bcl-X(L) but not p53 may contribute to doxorubicin-induced apoptosis through Etk pathway.
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PMID:Non-receptor tyrosine kinase Etk is involved in the apoptosis of small cell lung cancer cells. 2020 22

Mitocans are drugs selectively killing cancer cells by destabilizing mitochondria and many induce apoptosis via generation of reactive oxygen species (ROS). However, the molecular events by which ROS production leads to apoptosis has not been clearly defined. In this study with the mitocan alpha-tocopheryl succinate (alpha-TOS) the role of the Bcl-2 family proteins in the mechanism of malignant cell apoptosis has been determined. Exposure of several different cancer cell lines to alpha-TOS increased expression of the Noxa protein, but none of the other proteins of the Bcl-2 family, an event that was independent of the cellular p53 status. alpha-TOS caused a profound conformational change in the pro-apoptotic protein, Bak, involving oligomerization in all cell types, and this also applied to the Bax protein, but only in non-small cell lung cancer cells. Immunoprecipitation studies indicated that alpha-TOS activates the two BH1-3 proteins, Bak or Bax, to form high molecular weight complexes in the mitochondria. RNAi knockdown revealed that Noxa and Bak are required for alpha-TOS-induced apoptosis, and the role of Bak was confirmed using Bak- and/or Bax-deficient cells. We conclude that the major events induced by alpha-TOS in cancer cells downstream of ROS production leading to mitochondrial apoptosis involve the Noxa-Bak axis. It is proposed that this represents a common mechanism for mitochondrial destabilization activated by a variety of mitocans that induce accumulation of ROS in the early phases of apoptosis.
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PMID:alpha-Tocopheryl succinate causes mitochondrial permeabilization by preferential formation of Bak channels. 2021 35


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