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)

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are 'cancer-specific', which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase platelet-derived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.
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PMID:Novel anticancer drug discovery. 1041 54

A novel bioactive polyacetylene compound, 1,2-dihydroxy-5(E)-tridecene-7,9,11-triyne (compound 1), was identified from the Bidens pilosa extract using an ex vivo primary human umbilical vein endothelium cell (HUVEC) bioassay-guided fractionation protocol. Our results demonstrate that compound 1 (at 2.5 microg/mL) possessed significant anti-angiogenic effects, as manifested by an inhibition of HUVEC proliferation, migration, and the formation of tube-like structures in collagen gel. Moreover, compound 1 induced HUVECs to undergo cell death in a concentration- and time-dependent manner. The mechanisms underlying these pharmacological effects include reduced expression of cell cycle mediators such as CDK4, cyclins D1 and A, retinoblastoma (Rb) and vascular endothelial growth factor receptor 1 (VEGFR-1), and promotion of caspase-mediated activation of CDK inhibitors p21(Cip1) and p27(Kip). Moreover, apoptotic induction in HUVECs mediated by compound 1 was found to be in part through overexpression of FasL protein, down-regulation of anti-apoptotic Bcl-2, and activation of caspase-7 and poly(ADP-ribose) polymerase. This study demonstrates the potent anti-angiogenic and apoptotic activities of compound 1, suggesting that phytocompounds such as polyacetylenes deserve more attention regarding their potential as candidates for anti-angiogenic therapeutics.
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PMID:A novel polyacetylene significantly inhibits angiogenesis and promotes apoptosis in human endothelial cells through activation of the CDK inhibitors and caspase-7. 1755 25

ZD6474 is a vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study was undertaken to investigate the direct antiproliferative effect of ZD6474 on human nasopharyngeal carcinoma (NPC) in vitro and the antitumor activity on NPC xenografts in vivo. Results indicated that ZD6474 treatment inhibited EGFR phosphorylation and led to a dose- and time-dependent decrease in NPC cell (CNE-1, CNE-2 and C666-1) proliferation. Further investigation demonstrated G0/G1 cell cycle arrest in all 3 cell lines, which was associated with an upregulation of p21 and/or p27, and downregulation of CDK4, CDK6 and CDK2. ZD6474 treatment also induced apoptosis in CNE-1 and CNE-2 cells. The apoptosis mechanisms involved reduction of Bcl-2 and/or Bcl-XL, induction of Bak and/or Bax, and activation of caspases-3, -9 and/or -8. The in vivo antitumor activity was evaluated in CNE-2 and C666-1 xenografted nude mice. Administration of ZD6474 (25-100 mg/kg/day, once-daily, p.o.) produced a dose-dependent inhibition of tumor growth and prolonged survival in both models. This study suggests that ZD6474 exerts direct antiproliferative effects on NPC cell lines in vitro by inducing G0/G1 arrest and apoptosis, and potent antitumor effects on NPC xenografts in vivo. It indicates that ZD6474 may offer a new and effective treatment for human NPC.
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PMID:Induction of cell cycle arrest and apoptosis in human nasopharyngeal carcinoma cells by ZD6474, an inhibitor of VEGFR tyrosine kinase with additional activity against EGFR tyrosine kinase. 1763 46

We have investigated the mechanism of antiapoptotic and cell renewal effects of lansoprazole, a proton pump inhibitor, to protect and heal gastric mucosal injury in vivo induced by indomethacin, a non-steroidal anti-inflammatory drug (NSAID). Lansoprazole prevents indomethacin-induced gastric damage by blocking activation of mitochondrial and Fas pathways of apoptosis. Lansoprazole prevents indomethacin-induced up-regulation of proapoptotic Bax and Bak and down-regulation of antiapoptotic Bcl-2 and Bcl(xL) to maintain the normal proapoptotic/antiapoptotic ratio and thereby arrests indomethacin-induced mitochondrial translocation of Bax and collapse of mitochondrial membrane potential followed by cytochrome c release and caspase-9 activation. Lansoprazole also inhibits indomethacin-induced Fas-mediated mucosal cell death by down-regulating Fas or FasL expression and inhibiting caspase-8 activation. Lansoprazole favors mucosal cell renewal simultaneously by stimulating gene expression of prosurvival proliferating cell nuclear antigen, survivin, epidermal growth factor, and basic fibroblast growth factor. The up-regulation of Flt-1 further indicates that lansoprazole activates vascular epidermal growth factor-mediated controlled angiogenesis to repair gastric mucosa. Lansoprazole also stimulates the healing of already formed ulcers induced by indomethacin. Time course study of healing indicates that it switches off the mitochondrial death pathway completely but not the Fas pathway. However, lansoprazole heals mucosal lesions almost completely after overcoming the persisting Fas pathway, probably by favoring the prosurvival genes expression. This study thus provides the detailed mechanism of antiapoptotic and prosurvival effects of lansoprazole for offering gastroprotection against indomethacin-induced gastropathy.
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PMID:Lansoprazole protects and heals gastric mucosa from non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy by inhibiting mitochondrial as well as Fas-mediated death pathways with concurrent induction of mucosal cell renewal. 3188 21

Human neutrophilic polymorphonuclear leukocytes (PMNs) are central to innate immunity and are responsible for clearance of pathogens. PMNs undergo a tightly regulated apoptosis program that allows for timely clearance of PMNs without extravasation of toxic intracellular contents. We investigated the rate of spontaneous apoptosis of human peripheral blood PMNs cultured at basal (37 degrees C) and febrile-range (39.5 degrees C) temperatures (FRT). We found that PMN apoptosis is accelerated at FRT, reaching approximately 90% completion by 8 h at 39.5 degrees C vs 18 h at 37 degrees C based on morphologic criteria. Caspase-8 activation peaked within 15 min of PMN exposure to FRT, and subsequent activation of caspase-3 and -9, cleavage of the BH3 (Bcl-2 homology domain 3) only protein Bid, and mitochondrial release of cytochrome c were also greater in FRT-exposed PMNs. Inhibition of caspase-3, -8, and -9 conferred comparable protection from apoptosis in FRT-exposed PMNs. These results demonstrate that exposure to FRT enhances caspase-8 activation and subsequent mitochondrial-dependent and mitochondrial-independent apoptosis pathways. The PMN survival factors G-CSF, GM-CSF, and IL-8 each prolonged PMN survival at 37 degrees C and 39.5 degrees C, but did not reduce the difference in survival at the two temperatures. In a mouse model of intratracheal endotoxin-induced alveolitis, coexposure to FRT (core temperature approximately 39.5 degrees C) doubled the proportion of bronchoalveolar PMNs undergoing apoptosis compared with euthermic mice. This process may play an important role in limiting inflammation and tissue injury during febrile illnesses.
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PMID:Febrile-range hyperthermia accelerates caspase-dependent apoptosis in human neutrophils. 1868 54

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

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

The present study was to evaluate the effects of Ardipusilloside I isolated from Ardisia pusilla on the growth, vascular endothelial growth factor receptor (VEGFR) expression and apoptosis of NCI-H460 cell line by MTT, ELISA and flow cytometer, respectively. The docking assay between Ardipusilloside I and VEGFR was studied by Sybyl/Sketch module. The change of microstructure was observed by transmission electron microscope (TEM). DNA fragmentation was visualized by agarose gel electrophoresis. The protein expression of Bax and Bcl-2 was detected by immunohistochemistry (IHC). A series of changes were observed in NCI-H460 cell treated by Ardipusilloside I, including microstructure, DNA fragmentation, protein expression of VEGFR, Bax and Bcl-2. The results showed Ardipusilloside I had a good docking with VEGFR and could inhibit growth and induce apoptosis of NCI-H460 cell in a dose-dependent manner. Cell cycle was significantly stopped at the G(1) phase. Under electronic microscope, the morphology of NCI-H460 cell treated with Ardipusilloside I showed nuclear karyopycnosis, chromatin agglutination and typical apoptotic body. VEGFR and Bcl-2 expression were decreased and Bax expression was increased. In conclusion, all these results demonstrate that Ardipusilloside I has a good docking with VEGFR and has an inhibitory effect on growth of NCI-H460 cell and can induce its apoptosis.
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PMID:Ardipusilloside I purified from Ardisia pusilla competitively binds VEGFR and induces apoptosis in NCI-H460 cells. 2014 13

A large literature demonstrates the multifunctional nature of vascular endothelial growth factor (VEGF). Though initially characterized as an endothelial cell-specific factor, recent studies reveal that VEGF has numerous effects on diverse cell types in the brain including neurons. The objective of this study is to examine the effects of VEGF in cultured cortical neurons on survival, p38 mitogen-activated protein kinase (p38 MAP kinase) activity, pro- and anti-apoptotic protein expression and on release of neurotrophic and neurotoxic factors. The results show that VEGF dose-dependently enhances the survival of neurons in culture. VEGF decreases active caspase 3 levels and increases expression of the anti-apoptotic protein Bcl-2. VEGF decreases phosphorylated p38 MAP kinase level and activity in cortical neurons. In addition to modulating survival/death pathways in cortical neurons, VEGF also regulates release of proteins that affect neuronal viability. VEGF causes a dose-dependent release of the neurotrophic protein pigment epithelial-derived factor (PEDF), while significantly decreasing release of the neurotoxic protein amyloid beta. The VEGF-mediated decrease in amyloid beta is dependent on a functional Flt-1 receptor and is inhibited by dicoumarol, a multifunctional inhibitor of stress-activated protein kinase (SAPK)/JNK and NFkappaB pathways. Taken together, these data demonstrate that the neurotrophic effects of VEGF are likely mediated directly by increasing survival and decreasing apoptotic proteins and signals as well as indirectly by modulating release of proteins that affect neuronal viability.
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PMID:Multiple neurotrophic effects of VEGF on cultured neurons. 2043 Apr 42

We compared the differences in a number of angiogenesis-related immunohistochemical parameters, including microvascular density (MVD) and tumor cell activity, between multiple myeloma (MM) and solitary plasmacytoma (SP). Tissue sections from tumors of MM and SP were immunohistochemically stained and analyzed using ImageJ image analysis software for the expression of vascular endothelial growth factor (VEGF), VEGF receptors (Flt-1 and Flk-1), inducible nitric oxide (iNOS), and anti-apoptotic (Bcl-2) protein. Tumor tissues were cytologically graded as high-, intermediate-, or low-grade. Two pathologists determined the MVD of each section independently by recording the average number of CD34+ blood vessels in 500 unit fields. The arithmetic means for MVD were statistically analyzed using the Student's t-test and the significance level was calculated at P-value <0.001. The results indicate a direct correlation between upregulation of iNOS/VEGF in high-grade tumors. For MM, an increase in MVD is also correlated with a high-grade. Tumor survival signaling by Bcl-2 in both SP and MM emphasizes the fact that VEGF has a bimodal role that is mainly angiogenic in MM and tumorigenic, promoting tumor cell survival in SP.
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PMID:Biological impact of vascular endothelial growth factor on vessel density and survival in multiple myeloma and plasmacytoma. 2070 63


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