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)

Small cell lung cancer (SCLC) cell growth is sustained by multiple autocrine and paracrine growth loops involving neuropeptides. The bombesin family of peptides are autocrine growth factors in H345 SCLC cells and provide a paradigm for the study of growth factors and mitogenic signaling in SCLC cells. We show that bombesin (and other neuropeptides) stimulates protein tyrosine phosphorylation (particularly focal adhesion kinase) and protein tyrosine kinase (PTK) activity in intact SCLC cells. Furthermore, the broad spectrum neuropeptide receptor antagonist [D-Arg, D = Phe, D-Trp, Leu11]substance P inhibits all neuropeptide-mediated signals (including PTK activation), SCLC cell growth in vivo and in vitro, and also increases the natural rate of apoptosis seen in growing SCLC cell lines. Hence the effect of selective PTK inhibition on SCLC cell growth and apoptosis was examined. We show that selective inhibition of PTK activity, with genistein and (3,4,5-tri-hydroxyphenyl)-methylene(-propanedinitrile) tyrphostin-25 inhibits basal and neuropeptide-stimulated SCLC cell growth. Genistein and tyrphostin-25 also stimulate apoptosis in SCLC cells. Inhibition of proliferation in these cells is intimately linke to apoptosis, because these changes occurred without any effect on SCLC cell cycle kinetics, suggesting that apoptosis occurs independently of the cell cycle and that failure to progress through the cell cycle results in apoptosis. Because tyrphostin-25 fails to influence p53 or Bcl-2 expression in these cells, this mode of programmed cell death appears to be via a p53- and Bcl-2-independent mechanism. These results provide evidence that tyrosine phosphorylation is a mitogenic signal in SCLC cells and suggest that regulation of the level of protein tyrosine phosphorylation represents a critical determinant of whether SCLC cells survive and proliferate or die by apoptosis. Thus PTK inhibition may provide a novel therapeutic option in SCLC that has become resistant to conventional chemotherapeutic agents.
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PMID:Inhibition of neuropeptide-stimulated tyrosine phosphorylation and tyrosine kinase activity stimulates apoptosis in small cell lung cancer cells. 879 1

Cell adhesion to the extracellular matrix (ECM) has been implicated in apoptosis in anchorage-dependent cell types. We recently found that a peptide derived from fibronectin (termed III14-2) inhibits the integrin-mediated cell adhesion to ECM. Using this antiadhesive peptide and a variety of ECM proteins, we show here a critical role of the integrin-ECM protein interaction in apoptotic regulation of human umbilical vein endothelial cells (HUVEC). HUVEC in suspension underwent apoptosis under the serum-free conditions, as judged by nuclear and DNA fragmentations. This apoptosis was suppressed to varying degrees when alpha 5 beta 1, alpha v beta 3, and alpha 2 beta 1 integrins were occupied with either soluble or immobilized ECM proteins such as fibronectin, vitronectin, and type I collagen, respectively. Peptide III14-2, which had no effect by itself on the HUVEC apoptosis, disrupted the ligation of alpha 5 beta 1 and alpha v beta 3 but no alpha 2 beta 1 and ultimately led the cells to apoptosis, indicating that this antiadhesive peptide indirectly induces apoptosis by blocking cell survival signal delivered from alpha 5 beta 1 and alpha v beta 3 integrins. Genistein, a protein tyrosine kinase inhibitor, slightly reduced the rescuing effect of fibronectin, whereas sodium orthovanadate and bombesin, which increase in the level of protein tyrosine phosphorylation, made HUVEC less susceptible to apoptosis and blocked the effect of peptide III14-2. HUVEC adhesion to fibronectin substrate raised the tyrosine phosphorylation level of focal adhesion kinase and the expression of cytoprotective Bcl-2 protein, both of which were reversed by the antiadhesive effect of peptide III14-2. Thus, the opposing effects of ECM proteins, including fibronectin and vitronectin, and peptide III14-2 on HUVEC apoptosis appear to be due to the opposing effects of these factors on the signaling pathway which includes tyrosine phosphorylation of FAK and Bcl-2 expression.
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PMID:Modulation of apoptotic cell death by extracellular matrix proteins and a fibronectin-derived antiadhesive peptide. 966 6

Breast cancer is the most common cancer among American women, whereas Asian women, who consume a traditional diet high in soy products, have a relatively low incidence. Genistein is a prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We investigated the effects of genistein on cell growth and apoptosis-related gene expression in breast cancer cells MDA-MB-231. We found up-regulation of Bax and p21WAF1 expressions and down-regulation of Bcl-2 and p53 expression in genistein-treated cells. Furthermore, DNA ladder formation, CPP32 activation, and PARP cleavage were observed after treatment with genistein, indicating apoptotic cell deaths. Flow cytometry with 7-amino actinomycin D staining showed that the number of apoptotic cells increased with longer treatment of genistein. From these results, we conclude that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. The up-regulation of Bax and p21WAF1 may be the molecular mechanisms by which genistein induces apoptosis, however, further definitive studies are needed. These results suggest that genistein may be a potentially effective chemopreventive or therapeutic agent against breast cancer.
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PMID:Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. 1034 Mar 89

Breast cancer is the most common cancer and second leading cause of cancer related deaths in women in the United States. Genistein is a protein tyrosine kinase inhibitor and prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We have previously shown that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. In this study, we investigated these effects of genistein in the breast cancer cell line MDA-MB-435 and 435.eB cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. We also investigated the effect of genistein on matrix metalloproteinase (MMP) secretion previously shown to be effected by erbB-2 transfection. Genistein was found to inhibit MDA-MB-435 and 435.eB cell growth. Induction of apoptosis was also observed in these cell lines when treated with genistein, as measured by DNA laddering, poly(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. We also found an up-regulation of Bax and p21WAF1 expression and down-regulation of Bcl-2 and c-erbB-2 in genistein-treated cells. Gelatin zymography showed that genistein inhibits the secretion of MMP in the breast cancer cells. From these results, we conclude that genistein inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and may inhibit invasion and metastasis of breast cancer cells. These findings suggest that genistein may be a potentially effective chemopreventive or therapeutic agent against breast cancer.
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PMID:Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. 1042 35

Genistein is a potent plant-derived isoflavone displaying estrogenic activity at low (nanomolar) concentrations and antiproliferative and antiangiogenic properties at higher concentrations (above 10-50 microM). The antiproliferative potential of genistein has made it an interesting candidate for cancer chemotherapy at high concentrations; however, the potential for genistein toxicity in neurons at such concentrations has not been previously addressed. We show that genistein is toxic to rat primary cortical neurons at a concentration of 50 microM, whereas daidzein, a structural analog, shows no toxicity at similar concentrations. The dying cells display an apoptotic morphology that is characterized by fragmented nuclei, appearance of apoptotic bodies, DNA laddering, and caspase-dependent poly(ADP-ribose) polymerase cleavage. This cell death is partially dependent on caspase activity, independent of estrogen receptors, and does not result in a significant loss of Bcl-2 or Bcl-X(L) protein. Genistein exposure induces delayed and prolonged activation of p42/44 mitogen-activated protein kinase (MAPK) and p38 MAPK but not c-Jun NH2-terminal kinase. The specific p42/44 MAPK kinase inhibitor PD98059 (50 microM) partially blocks genistein-induced apoptosis, whereas the p38 MAPK inhibitor SB202190 (10 microM) has no effect. Genistein elevates intracellular calcium and both 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (1 microM) and dantrolene (10 microM) inhibit genistein-induced apoptosis, suggesting a link between genistein-induced intracellular calcium release and apoptosis. The combination of dantrolene and PD98059 block genistein-induced apoptosis in an additive manner compared with either compound alone. These findings provide evidence for a proapoptotic function of p42/44 MAPK and raise caution about potential side effects in the nervous system with genistein use as a high-dose therapeutic agent.
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PMID:Neuronal apoptosis resulting from high doses of the isoflavone genistein: role for calcium and p42/44 mitogen-activated protein kinase. 1156 Oct 64

Genistein (4,5,7-trihydroxyisoflavone) has been reported to induce cell cycle arrest and apoptosis in different cancer cell lines in vitro and to show antitumor activity against a variety of tumors in animal models. We have previously reported (S. A. Alhasan et al., Nutr. Cancer, 34:12-19, 1999; S. A. Alhasan et al., Int. J. Oncol., 16: 333-338, 2000) that genistein induces cell cycle arrest and apoptosis by up-regulating p21(WAF1) and Bax, and down-regulating cyclin B1 and Bcl-2 in a head and neck cancer cell line. However, the precise molecular mechanism(s) by which genistein elicits its effects on head and neck cancer cells still remains to be elucidated. In the present study, we report that genistein induces several specific molecular changes in head and neck cancer cells, such as down-regulation of c-erbB-2 expression, down-regulation of MMP-2 and MMP-9 secretion, inhibition of tumor cell invasion and down-regulation of nuclear factor-kappaB DNA binding activity. In addition, genistein inhibited the levels of phosphorylated Akt and the expression of 14-3-3 protein. Moreover, genistein induces telomere shortening in treated cells without affecting telomerase activity in vitro. We also observed that genistein inhibits the translocation of telomerase catalytic subunit [human telomerase reverse transcriptase (hTERT)] to the nucleus, which may result in telomere shortening, although the activity of telomerase is unaffected, along with the inhibition of metaphase spread of chromosomes. From these results, together with our previously published reports, (S. A. Alhasan et al., Nutr. Cancer, 34: 12-19, 1999; S. A. Alhasan et al., Int. J. Oncol., 16: 333-338, 2000) we conclude that genistein elicits pleiotropic molecular changes that resulting in the inhibition of cell growth and the induction of apoptotic cell death of head and neck cancer cells, which suggests that genistein may be useful as a chemotherapeutic and/or chemopreventive agent for head and neck cancer.
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PMID:Genistein elicits pleiotropic molecular effects on head and neck cancer cells. 1175 18

Although genistein has been demonstrated to induce apoptosis of various cells, there is no report of its effect on mast cell proliferation. Here we show that genistein reduced the viability of mast cell tumor cell lines, p815 and RBL-2H, but not of a human mast cell line, HMC-1. Further investigation on its growth-inhibitory mechanism was undertaken on p815 mastocytoma cells. Genistein induced G2/M arrest and subsequent apoptotic death. p815 cells undergoing apoptosis showed many apoptotic manifestations, such as reduction of mitochondrial membrane potential, release of cytochrome c to cytosol, translocation of apoptosis-inducing factor to nucleus, activation of caspase-3, nuclear condensation, and generation of DNA fragmentation. Genistein treatment resulted in the increase of Bax expression and its translocation into mitochondria, whereas expression levels of Bcl-2 remained unchanged. Proteasome activity decreased at the early time points after genistein treatment, but thereafter it fluctuated at increased levels. A proteasome inhibitor, lactacystin, potentiated the induction of apoptosis. Taken together, genistein-induced apoptosis of p815 mastocytoma cells is at least in part mediated by proteasome, Bax, apoptosis-inducing factor, and caspase and augmented by cotreatment with a proteasome inhibitor, lactacystin.
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PMID:Genistein-induced apoptosis of p815 mastocytoma cells is mediated by Bax and augmented by a proteasome inhibitor, lactacystin. 1241 67

Genistein, biochanin-A, and daidzein, the predominant soy isoflavones, have been reported to lower the risk of cancer, but it is not known whether they protect against human hepatoma cancer. This study was designed to investigate their effects on cell growth, the cell cycle, and apoptosis induction in the human hepatoma cell lines, HepG2, Hep3B, Huh7, PLC, and HA22T. Genistein, biochanin-A, and daidzein inhibited growth of all five lines in a dose-dependent manner. DNA fragmentation studies and the TUNEL assay demonstrated that isoflavones caused tumor cell death by induction of apoptosis. Activation of caspase-3 and cleavage of the caspase-3 substrate, poly(ADP-ribose)polymerase, was seen in hepatoma cells after 24 hours' exposure to isoflavones. In addition, isoflavone cytotoxicity correlated with downregulation of Bcl-2 and Bcl-XL expression. Synergistic effects of the three isoflavones were observed on cell growth inhibition, apoptosis induction, and anti-apoptotic protein expression. Flow cytometry showed that genistein, but not biochanin-A or daidzein, induced progressive and sustained accumulation of hepatoma cancer cells in the G2/M phase as a result of inhibition of Cdc2 kinase activity. Coapplication of caffeine prevented this cell cycle arrest, but not apoptosis, showing that cell cycle arrest was not necessary for apoptosis. Furthermore, the isoflavones combination also had a significant tumor-suppressive effect in nude mice. These results suggest that isoflavones might be promising agents for the treatment of human hepatoma.
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PMID:Effects of soy isoflavones on apoptosis induction and G2-M arrest in human hepatoma cells involvement of caspase-3 activation, Bcl-2 and Bcl-XL downregulation, and Cdc2 kinase activity. 1279 11

The incidence of non-Hodgkin's lymphoma (NHL) has been increasing and is now the leading cause of death in males aged 15-54. Diffuse large cell lymphoma (DLCL) is the most common subtype of NHL. These cells are notable for the high expression of the transcription factor nuclear factor kappa beta (NF-kappaB), raising the possibility that constitutive activation of the NF-kappaB pathway may contribute to the poor prognosis of DLCL patients. Soy isoflavone genistein promotes apoptosis by decreasing NF-kappaB activity. The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remains the standard therapy for DLCL with a cure rate of approximately 40%. The WSU-DLCL(2) cell line and its severe combined immunodeficient (SCID) xenograft have constitutively active NF-kappaB which provides us with an excellent model in which to study NF-kappaB modulation and CHOP sensitization by genistein. The antitumor activity of CHOP with or without a genistein was evaluated in our WSU-DLCL(2) model. In vivo, WSU-DLCL(2)-bearing SCID mice received genistein alone (800 micro g kg(-1) day(-1), p.o. as gavages for 5 days), CHOP alone ("C", 40 mg/kg, i.v.; "H", 3.3 mg/kg, i.v.; "O", 0.5 mg/kg, i.v.; and "P", 0.2 mg/kg, every day for 5 days, p.o.), or genistein for 5 days followed by CHOP. Tumor growth inhibition (T/C), tumor growth delay (T - C), and log(10) kill for genistein, CHOP, and genistein followed by CHOP were 33.6%, 19.2%, and 5.2%; 7, 8, and 17 days; and 1.0, 1.2, and 2.6, respectively. To begin elucidating the mechanism of genistein-induced sensitization of WSU-DLCL(2) cells to CHOP chemotherapy in this xenograft mouse model, we studied the in vitro effect of genistein on WSU-DLCL(2) growth inhibition, cell cycle, Bax:Bcl-2 ratio, NF-kappaB DNA binding, and apoptosis in vitro. At 30 micro M, genistein inhibited the growth significantly, induced G(2)-M arrest, increased Bax:Bcl-2 ratio, decreased NF-kappaB DNA binding, and induced apoptosis. Genistein also inhibited NF-kappaB DNA binding in vivo, whereas CHOP enhanced it. Our results show that genistein has growth modulatory effects on WSU-DLCL(2) cells and enhances the antitumor activity of CHOP. Because soy isoflavone genistein is a widely available nutritional supplement, its use in combination with CHOP chemotherapy should be further explored in a clinical trial in patients with NHL.
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PMID:Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. 1470 77

Recently, cancer chemoprevention with strategies using foods and medicinal herbs has been regarded as one of the most visible fields for cancer control. Genistein in soy, American ginseng, and resveratrol are well-known to have antiproliferative properties in human breast cancer. Licorice root is a botanical, a shrub native to southern Europe and Asia, which primarily has desirable qualities in sweetening and herbal medicine. In this study, licorice (Glycyrrhiza uralensis Fisch) root also inhibits cell proliferation in human breast cancer cell. The cell proliferation study demonstrated that licorice root reduced the proliferation of MCF-7 cells in a dose- and time-dependent manner. The extracts were fractionated in CHCl(3), EtOAc, C(6)H(14), and CH(3)OH-H(2)O (70:30), and these extracts of licorice root (50 microg/mL) induced DNA fragmentation demonstrated by Hoechst 33258 staining. Apoptosis also determined the sub-G1 accumulation by flow cytometry analysis. These results were consistent with specific cleavage of PARP and antiapoptotic protein Bcl-2 and up-regulation of proapoptotic protein Bax demonstrated by Western blotting. Our findings suggest that licorice root may have chemopreventive effects against human breast cancer through the modulation of the expression of the Bcl-2/Bax family of apoptotic regulatory factors.
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PMID:Modulations of the Bcl-2/Bax family were involved in the chemopreventive effects of licorice root (Glycyrrhiza uralensis Fisch) in MCF-7 human breast cancer cell. 1503 Feb 35


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