Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metronomic dosing of cytotoxic drugs such as cyclophosphamide has shown anti-angiogenic activity, most likely by inducing hypoxia in tumors. Hypoxia leads to activation of escape mechanisms allowing tumor cell survival. This potentially limits the activity of anti-angiogenic strategies. We hypothesized that mTORC1 inhibition by everolimus (RAD001) leads to suppression of HIF-1alpha and VEGF resulting in synergistic anti-tumor activity in combination with anti-angiogenically dosed cyclophosphamide. In vitro, effects of everolimus on mTORC1 signaling, proliferation, cell cycle, HIF-1alpha expression and VEGF secretion were evaluated in two gastric cancer cell lines. In vivo, anti-tumor activity of everolimus in combination with metronomic cyclophosphamide was studied in a NCI-N87 human gastric cancer SCID mouse xenograft model. Expression of Ki-67 and HIF-1alpha, activated caspase 3, microvascular density (MVD) and tumor necrotic area assessed. Everolimus decreased proliferation and attenuated production of HIF-1alpha as well as VEGF in gastric cancer cells in vitro. In vivo, everolimus significantly inhibited tumor growth. This anti-tumor activity was linked to a significant increase in tumor necrotic area (p < 0.02) and trends for decreased proliferation, increased apoptosis, decreased HIF-1alpha and lower tumor MVD (p = n.s.). The combination of everolimus and cyclophosphamide resulted in a striking and highly significant long-term tumor growth control compared to monotherapy (p < 0.001), which was associated with a sharp increase in central tumor necrosis (p < 0.001). In conclusion, the combination of everolimus and metronomic cyclophosphamide showed synergistic anti-tumor activity. Depriving cancer cells by everolimus of factors necessary for their survival under hypoxia induced by anti-angiogenic chemotherapy appears to be a promising approach for treatment of gastric cancer.
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PMID:Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. 1876 27

Gastric cancer is an aggressive cancer with poor prognosis. Identification of precise prognostic marker and effective therapeutic target is important in the treatment of gastric cancer. TIP30, a newly identified tumor suppressor, appears to be involved in multiple functions including tumorigenic suppression, apoptosis induction and diminishing angiogenic properties. Here, the level of TIP30 expression was determined in gastric cancer, and the impact of its alteration on cancer biology and clinical outcome was investigated. We found that TIP30 protein was absent or reduced in gastric cancer cell lines. There was also a loss or substantial decrease of TIP30 expression in 106 cases of gastric tumors as compared with that in normal gastric mucosa (p<0.05), which was significantly associated with inferior survival duration. In a Cox proportional hazards model, TIP30 expression independently predicted better survival (p<0.05). We also restored TIP30 protein expression in human gastric cancer-derived cells AGS and MKN28 lacking endogenous TIP30 protein to study the effects of TIP30 expression on cell proliferation, cell kinetics, tumorigenicity and metastasis in BALB/c nude mice and found that adenoviral-mediated restoration of TIP30 expression led to downregulation of cyclin D1, Bcl-2, Bcl-xl, but to upregulation of p27, Bax, p53, caspase 3 and 9 expression, cell cycle G0/G1 arrest and apoptosis in vitro, and dramatic attenuation of tumor growth and abrogation of metastasis in animal models. Taken together, the present work revealed a novel function of TIP30, which can possibly be used as an independent prognostic factor and a potential therapeutic target for gastric cancer.
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PMID:Reduction of TIP30 correlates with poor prognosis of gastric cancer patients and its restoration drastically inhibits tumor growth and metastasis. 1897 34

Bufalin is the active ingredient of the Chinese medicine Chan Su, and it has been reported that bufalin induces apoptosis in some human leukemia and solid cancer cell lines. The exact mechanism of bufalin-induced apoptosis is, however, still not clear. In this study, we demonstrated that bufalin inhibited the proliferation of gastric cancer MGC803 cells in a dose-dependent and time-dependent manner. At a low concentration (20 nmol/l), bufalin induced M-phase cell cycle arrest, whereas at a high concentration (80 nmol/l) it induced apoptosis in MGC803 cells. Bufalin increased the Bax/Bcl-2 ratio and activated caspase-3 during the apoptotic process of MGC803 cells. It should be noted that bufalin transiently activated the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and then inhibited it completely, and upregulated the Casitas B-lineage lymphoma (Cbl) family of ubiquitin ligases, upstream modulators of PI3K. A combination of bufalin and LY294002, a PI3K-specific inhibitor, enhanced apoptosis, but PD98059, an extracellular-regulated protein kinase-specific inhibitor, had no significant effect on bufalin-induced apoptosis. These results suggested that the PI3K/Akt pathway might play a key role in bufalin-induced apoptosis in gastric cancer MGC803 cells.
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PMID:PI3K/Akt is involved in bufalin-induced apoptosis in gastric cancer cells. 1934 1

Orally applicable Delta9-tetrahydrocannabinol and its synthetic derivatives have been used as antiemetic drugs during chemotherapy in cancer patients. However, it is not well known how cannabinoids influence the effects of chemotherapeutic agents on malignant tumors. In this study, we investigated how the endogenous cannabinoid anandamide (AEA) changes the effect of paclitaxel on gastric cancer cell lines. In the human gastric cancer cell line, HGC-27, which express cannabinoid receptor 1 (CB1), AEA stimulated proliferation at concentrations under 1 microM, while it strongly suppressed proliferation through the induction of apoptosis at 10 microM. This bimodal effect was reproduced by a selective CB1 agonist, arachidonyl-2-chloroethylamide, although the effects were less marked. When AEA was used with paclitaxel, AEA at 10 microM synergistically enhanced the cytotoxic effect of paclitaxel, whereas it showed no significant effect at lower concentrations. Flow cytometric analysis revealed that addition of 10 microM AEA synergistically enhanced paclitaxel-induced apoptosis, possibly through the activation of caspase-3, -8, and -9. Our results suggest that cannabinoids could be a good palliative agent for cancer patients receiving paclitaxel.
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PMID:Pharmacological synergism between cannabinoids and paclitaxel in gastric cancer cell lines. 1996 33

Beta-sitosterol is an important phytosterol found in plant food. It has been shown to have antiproliferative effects on cancers of the colon, breast, and prostate, but its effect on stomach cancer cells in vitro is unknown. Proliferation, cytotoxicity, and apoptosis in SGC-7901 human stomach cancer cells were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, clone formation, lactate dehydrogenase (LDH) leakage assay, acridine orange (AO)/ethidium bromide (EB) double staining, 4',6-diamidine-2'-phenylindole dihydrochloride (DAPI) staining, comet assay, and Western blotting. The results showed that beta-sitosterol suppresses the proliferation and induces the cell cytotoxicity of SGC-7901 stomach cancer cells in a time- and dose-dependent manner. Cells treated with different concentrations of beta-sitosterol also showed changes typical of apoptosis: morphological changes, DNA damage, increased expression of pro-caspase-3 and bax (p < 0.05), and activation of pro-caspase-3 and suppression of bcl-2 expression (p < 0.05). This study therefore revealed that beta-sitosterol significantly inhibits the growth and induces the apoptosis of SGC-7901 human stomach cancer cells in vitro. The decrease of the bcl-2/bax ratio and DNA damage may be the critical mechanisms of apoptosis induced by beta-sitosterol in SGC-7901 human stomach cancer cells.
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PMID:Beta-sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells. 1945 33

Closely located at the tumor suppressor locus 16q22.1, CKLF-like MARVEL transmembrane domain-containing member 3 and 4 (CMTM3 and CMTM4) encode two CMTM family proteins, which link chemokines and the transmembrane-4 superfamily. In contrast to the broad expression of both CMTM3 and CMTM4 in normal human adult tissues, only CMTM3 is silenced or down-regulated in common carcinoma (gastric, breast, nasopharyngeal, esophageal, and colon) cell lines and primary tumors. CMTM3 methylation was not detected in normal epithelial cell lines and tissues, with weak methylation present in only 5 of 35 (14%) gastric cancer adjacent normal tissues. Furthermore, immunohistochemistry showed that CMTM3 protein was absent in 12 of 35 (34%) gastric and 1 of 2 colorectal tumors, which was well correlated with its methylation status. The silencing of CMTM3 is due to aberrant promoter CpG methylation that could be reversed by pharmacologic demethylation. Ectopic expression of CMTM3 strongly suppressed the colony formation of carcinoma cell lines. In addition, CMTM3 inhibited tumor cell growth and induced apoptosis with caspase-3 activation. Thus, CMTM3 exerts tumor-suppressive functions in tumor cells, with frequent epigenetic inactivation by promoter CpG methylation in common carcinomas.
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PMID:CMTM3, located at the critical tumor suppressor locus 16q22.1, is silenced by CpG methylation in carcinomas and inhibits tumor cell growth through inducing apoptosis. 1950 37

Peritoneal dissemination of gastric cancer is a refractory disease. This paper focuses on the efficacy of actin-binding marine macrolide latrunculin A, which quickly inhibits actin polymerization and disrupts the function of the actin cytoskeleton. The effects of latrunculin A on cell viability in vitro were evaluated by treatment of MKN45 or NUGC-4 cell cultures. An in vitro viability assay demonstrated an anticancer effect of latrunculin A in a dose-dependent manner. Latrunculin A induced acute cell injury and programmed cell death through activating the caspase-3/7 pathway. In vivo, MKN45 or NUGC-4 cells were intraperitoneally inoculated into nude mice, as a model of peritoneal dissemination. Intraperitoneal (i.p.) injection of latrunculin A significantly improved survival rate in mice without any major side-effects. Data indicated that latrunculin A has strong anticancer effects, and it may be a new candidate i.p. drug against peritoneal dissemination of gastric cancer in humans.
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PMID:Latrunculin a has a strong anticancer effect in a peritoneal dissemination model of human gastric cancer in mice. 1952 69

The radiosensitizing effects of luteolin were studied in the gastric cancer cell line SGC-7901. SGC-7901 cells were treated with luteolin or/and irradiation, and radiosensitizing effects were assessed by colony-forming assay with cells and nude mice. In order to study the underlying mechanism, the levels of apoptosis-related proteins, the activities of caspase-3 and -9, and the production of PGE2 were measured. The results showed that luteolin could enhance irradiation-induced colonogenic inhibition and the activities of Caspase-3 and -9. The remarkable down-regulation of Bcl-2 and release of cytochrome C were also observed. In addition, significantly reduced production of PGE(2) was observed in luteolin plus radiation treatment by ELISA, as well as decreased expression levels of VEGF and HIF-1 alpha. Finally, luteolin significantly enhances the radioresponse of human tumors transplanted into nude mice. Our results indicate that luteolin may be a promising radiosensitizer for use in the treatment of gastric cancer.
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PMID:Radiosensitization effect of luteolin on human gastric cancer SGC-7901 cells. 1958 87

We investigated the effects of a water-soluble extract of Maitake (Grifola frondosa), a Japanese edible mushroom, on the proliferation and cell death of four human gastric cancer cell lines (TMK-1, MKN28, MKN45 and MKN74). The Maitake extract (ME) inhibited the proliferation of all four cell lines in a time-dependent manner. The inhibition was most pronounced in TMK-1 cells, which exhibited up to 90% inhibition after treatment with 10% ME for 3 days. Staining of ME-treated TMK-1 cells with Hoechst 33258 revealed increased numbers of nuclear condensations and apoptotic bodies. Induction of apoptosis was confirmed by fluorescence-activated cell sorting analyses. Western blot analyses of TMK-1 cells after ME treatment revealed increases in intracytoplasmic cytochrome c and cleavage of caspase-3 and poly(ADP-ribose) polymerase, but no expression of p21 or Bax. The caspase-3 protease activities in lysates of TMK-1 cells treated with 1% or 10% ME were about three times higher than those in control cells. The proliferation of TMK-1 cells was hardly affected by the caspase-3 inhibitor z-DEVD-fmk. Taken together, these results suggest that ME induces apoptosis of TMK-1 cells by caspase-3-dependent and -independent pathways, resulting in potential antitumor effects on gastric cancer.
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PMID:Antitumor effects of a water-soluble extract from Maitake (Grifola frondosa) on human gastric cancer cell lines. 1963 12

Histone deacetylase inhibitors (HDACIs) are potent anticancer drugs, and suberoylanilide hydroxamic acid is used for the treatment of cutaneous T-cell lymphoma patients. We synthesized a novel hydroxamate-based HDACI, CG0006, and assessed its antiproliferative effects on the NCI-60 cancer cell panel and cell lines from liver and stomach cancers that are common in Korea. Micromolar levels of CG0006 induced cell death in several breast, central nervous system, colon, hematopoietic, lung, melanoma, ovarian, prostatic, renal, and stomach cancer cell lines. We further analyzed cell death mechanisms activated by CG0006 in HCT116 (colon cancer) and K562 (leukemia) cells. First, to test the activity of CG0006, we analyzed acetylation of substrates of HDACs and effect on gene expression. CG0006 increased acetylation of histone 3, histone 4, and tubulin in a time-dependent and dose-dependent manner in both HCT116 and K562 cells. Moreover, CG0006 increased the mRNA level of p21 and decreased that of Bcl-xl efficiently in HCT116 cells. Cell cycle analysis showed G2-M arrest, and increased apoptosis in populations of HCT116 and K562 cells treated with CG0006. Western blot analysis showed that CG0006 increased levels of p21 in HCT116 cells and of p21 and p27 in K562 cells. In addition, CG0006 activated caspase-9, caspase-3, and caspase-8. These results indicate that CG0006 induces death in HCT116 and K562 cells through both intrinsic and extrinsic apoptotic pathways. The HDACI CG0006 may be a potent anticancer drug for solid tumors and leukemia.
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PMID:A novel histone deacetylase inhibitor, CG0006, induces cell death through both extrinsic and intrinsic apoptotic pathways. 1964 55


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