Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antimycin A (AMA) inhibits mitochondrial electron transport between cytochrome b and c. We evaluated the effects of AMA on the growth of human lung cancer cell line, Calu-6. AMA inhibited the growth of Calu-6 cells. AMA induced a G1 phase arrest of the cell cycle in these cells at 72h. AMA increased a cyclin-dependent kinase inhibitor (CDKI), p27 and decreased CDK2, CDK4, and CDK6, as well as cyclin D1 and cyclin E in Calu-6 cells. AMA also induced apoptosis in Calu-6 cells. The apoptotic process in AMA-treated Calu-6 cells was accompanied by the up-regulation of Bax, the loss of mitochondrial membrane potential (DeltaPsi(m)), and the activation of caspase-3 and -8. All of the tested caspase inhibitors, especially pan-caspase inhibitor (Z-VAD), markedly rescued Calu-6 cells from AMA-induced Calu-6 cell death. Inhibitors of pan-caspase and caspase-8 also prevented the loss of mitochondrial membrane potential (DeltaPsi(m)). AMA decreased the intracellular ROS levels but increased the O(2)(*-) levels in Calu-6 cells. In conclusion, AMA as a mitochondrial electron transport inhibitor decreased the growth of lung cancer Calu-6 cell via inducing a G1 arrest of the cell cycle and apoptosis.
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PMID:Growth inhibition in antimycin A treated-lung cancer Calu-6 cells via inducing a G1 phase arrest and apoptosis. 1911 65

Liver fibrosis due to hepatic stellate cell (HSC) activation represents a common response to chronic liver injury. PTK787/ZK222584 (PTK/ZK) is a pan-VEGFR tyrosine kinase inhibitor. The aim of this study was to examine the effect of PTK/ZK in liver fibrosis. In primary HSCs, PTK/ZK inhibited the expression of alpha-smooth muscle actin (alpha-SMA), collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as cell proliferation, migration and actin filament formation. PTK/ZK-induced apoptosis of HSCs, which was correlated with increased caspase-3 activation and suppressed Bcl-2 expression. PTK/ZK also induced cell cycle arrest, accompanied by increasing the expression of p27(Kip1) and downregulation of cyclin D1 and cyclin E. PTK/ZK significantly inhibited vascular endothelial growth factor (VEGF) expression, as well as VEGF-simulated cell proliferation and phosphorylation of Akt in activated HSCs. In a murine fibrotic liver, PTK/ZK attenuated collagen deposition and alpha-SMA expression in carbon tetrachloride-induced fibrosis in both a 'prevention' and 'treatment' dosing scheme. These beneficial effects were associated with reduced phosphorylation of Akt and suppressed mRNA expression of procollagen-(I), TIMP-1, matrix metalloproteinase-9 and CD31. These findings provide novel insights into the potential value of blocking VEGF signaling by a small molecule tyrosine kinase inhibitor in treating hepatic fibrosis.
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PMID:PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling. 1911 84

Honokiol is a naturally occurring neolignan abundant in Magnoliae Cortex and has showed anti-proliferative and pro-apoptotic effects in a wide range of human cancer cells. However, the molecular mechanisms on the anti-proliferative activity in cancer cells have been poorly elucidated. In this study, we evaluated the growth inhibitory activity of honokiol in cultured estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Honokiol exerted anti-proliferative activity with the cell cycle arrest at the G0/G1 phase and sequential induction of apoptotic cell death in a concentration-dependent manner. The honokiol-induced cell cycle arrest was well correlated with the suppressive expression of CDK4, cyclin D1, CDK2, cyclin E, c-Myc, and phosphorylated retinoblastoma protein (pRb) at Ser780. Apoptosis caused by honokiol was also concomitant with the cleavage of caspases (caspase-3, -8, and -9) and Bid along with the suppressive expression of Bcl-2, but it was independent on the expression of Bax and p53. In addition, honokiol-treated cells exhibited the cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. In the analysis of signal transduction pathway, honokiol down-regulated the expression and phosphorylation of c-Src, epidermal growth factor receptor (EGFR), and Akt, and consequently led to the inactivation of mTOR and its downstream signal molecules including 4E-binding protein (4E-BP) and p70 S6 kinase. These findings suggest that honokiol-mediated inhibitory activity of cancer cell growth might be related with the cell cycle arrest and induction of apoptosis via modulating signal transduction pathways.
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PMID:Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells. 1913 78

Berberine, an alkaloid, has anti-tumor properties in some cancer cells, but action mechanisms are not clear yet. We here investigated the anticancer activity of berberine and possible mechanisms in human neuroblastoma SK-N-SH and SK-N-MC cells. The p53-expressing cells, SK-N-SH (IC50=37 microM) were more susceptible to berberine than the p53-deficient cells, SK-N-MC (IC50 > or =100 microM) without cytotoxic effect on the cortical neuronal cells. Berberine caused cell cycle arrest in G0/G1 phase and apoptotic cell death, and these effects were much greater in SK-N-SH cells than those in SK-N-MC cells. Berberine much greatly decreased G0/G1 phase-associated cyclin and cyclin-dependent kinase (cyclin D1, cyclin E, Cdk2, and Cdk4) expression, and increased apoptotic gene expression and activation of caspase-3 in SK-N-SH cells. Exploration of p53 siRNA or pifithrin-alpha (PFT-alpha), a p53 inhibitor, in the SK-N-SH cells resulted in increase of IC50 values for cell viability, and decreased apoptotic cell death, expression of p53 and activation of caspase-3. Therefore, these results showed that berberine causes p53-dependent apoptotic death of neuroblastoma cells, and suggested that berberine may be useful as an anticancer agent for neuroblastoma.
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PMID:Berberine inhibits human neuroblastoma cell growth through induction of p53-dependent apoptosis. 1918 64

The lack of effective anti-tumor therapy for renal cell carcinoma (RCC) has stimulated the search for novel target whose inhibition could block tumorigenesis. Recently, reduced DLC-1 has been shown to be associated with aggressive and highly metastatic renal cell carcinoma. In this study, the biological role of DLC-1 on cell growth, migration and cell cycle progression in RCC cells was investigated. Over-expression of DLC-1 was associated with a marked inhibition of cell growth (P<0.01). The inhibitory effect was partly due to the induction of apoptosis and cell cycle arrest in G(0)/G(1) accompanied by up-regulation of the intracellular signal proteins of p27 and down-regulation of cyclin D1 and cyclin E. Furthermore, DLC-1 induced FAK dephosphorylation of focal adhesion proteins inhibited cell migration (P<0.05). Decreased DLC-1 expression strongly correlated with proliferative activity, as indicated by the elevated levels of Ki67. Restoration of DLC-1 expression in RCC cells led to Bcl-2 and caspase-3 mediated apoptosis as well as attenuated the ability of the cells to form RCC tumors in athymic nude mice (P<0.05). Taken together, these results suggest that DLC-1 plays a crucial role in signal transduction pathway regulating the cell proliferation, migration, and carcinogenesis of human RCC.
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PMID:Overexpression of DLC-1 induces cell apoptosis and proliferation inhibition in the renal cell carcinoma. 1938 Jan 90

We examined the effect of apogossypolone (ApoG2), a new derivative from gossypol on cell cycle regulation in U937 human leukemic monocyte lymphoma cells in vitro. ApoG2 decreased the viability of U937 cells by inducing G1 arrest followed by apoptosis in a dose-dependent manner. The G0/G1 phase of the cell cycle is regulated by cyclin-dependent kinases (Cdk), cyclins and cyclin-dependent kinase inhibitors (Cdki). We show by western blot analysis, that the ApoG2-induced G1 arrest was mediated through the increased expression of Cdki proteins (p21cip1/waf1) with a simultaneous decrease in cdk2, cdk4, cyclin D1 and cyclin E expression. The induction of apoptosis after treatment with ApoG2 for 12, 24 and 48 h was demonstrated by flow cytometry analysis. ApoG2 also induced cytochrome c release and activation of caspase-3. To our knowledge, this is the first time that ApoG2 has been reported to potently inhibit the proliferation of human monocytic lymphoma U937 cells through G1 arrest. These findings suggest that ApoG2 may be a potential chemotherapeutic agent for the treatment of cancer.
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PMID:Apogossypolone inhibits cell growth by inducing cell cycle arrest in U937 cells. 1951 23

The mammalian target of rapamycin (mTOR) kinase is a key regulator of cell growth and proliferation. Overexpression of the mTOR signaling pathway has been described in several tumor cells, including the majority of acute myeloid leukemia (AML) cases. The anti-tumor efficacy of mTOR inhibitors was shown in several preclinical and clinical studies. In AML, however, the potential antineoplastic effect of mTOR inhibitors has received little attention thus far. In this in-vitro study of the human AML cell line, HL-60, we aimed to assess the antileukemic activity of rapamycin (RAPA), an mTOR inhibitor, alone and in combination with cytarabine (Ara-C). The study showed that RAPA in concentrations of 1-10 nmol/l arrested the cell cycle progression of Hl-60 cells in the G1 phase, without evident cytotoxic effect. This effect was associated with significant inhibition of cyclin E expression. At concentrations higher than 10 nmol/l, RAPA exerted a significant proapoptotic effect, with the collapse of mitochondrial potential and caspase-3 activation. The most prominent proapoptotic effect was observed for a combination of 1 nmol/l of RAPA and 50 nmol/l of Ara-C, especially when Ara-C was added at a 24-h interval after RAPA. In conclusion, these data indicate that RAPA might be effective in the treatment of acute leukemia patients, especially in combination with Ara-C, the drug routinely used in AML treatment. On the basis of these results, attempts to combine classical induction chemotherapy with an inhibitor of the mTOR kinase in AML treatment could be warranted.
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PMID:Rapamycin, the mTOR kinase inhibitor, sensitizes acute myeloid leukemia cells, HL-60 cells, to the cytotoxic effect of arabinozide cytarabine. 1958 9

Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine) is an anticancer nucleoside analogue active against a wide variety of solid tumors. However, following intravenous administration, this drug is rapidly inactivated by enzymatic deamination and displays a short biological half-life necessitating the administration of high doses leading also to unwanted side effects. To overcome these drawbacks and to improve the therapeutic index of gemcitabine, we have recently developed the concept of squalenoylation which consisted in the bioconjugation of gemcitabine with squalene, a natural lipid. In our preliminary studies, we have shown that this bioconjugate (SQgem) self-organized in water as nanoassemblies with considerable resistance to deamination and significantly higher anticancer activity compared with gemcitabine in an intravenously grafted tumor model in mice. To further establish the candidature of this nanomedicine for clinical trials, in this communication we have tested the preclinical efficacy of squalenoyl gemcitabine nanomedicine on several human tumor cell lines and on the subcutaneously grafted experimental L1210 murine tumor in mice. SQgem nanomedicine displayed an efficient cytotoxicity against a variety of human tumor cell lines in the 60 human tumor cell panel. In vivo, following intravenous administration, SQgem nanomedicine displayed a superior anticancer activity against subcutaneous L1210 tumor, comparatively to gemcitabine. The molecular mechanism behind the anticancer efficacy of SQgem has been investigated by flow cytometry analysis and protein expression profiling of L1210 wt cells treated in vitro with the squalenoyl gemcitabine bioconjugate. It was found that this nanomedicine arrested the cell cycle in G2/M, characterized by an increased cyclin A and cyclin E expression, and activation of caspase-3 and the cleavage of poly(ADP-ribose) polymerase with an increase of cytochrome C level. Taken together, these results suggest that the cell kill by this nanomedicine occurred through mitochondrial apoptotic triggered pathway, similarly to that of gemcitabine free.
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PMID:Anticancer efficacy of squalenoyl gemcitabine nanomedicine on 60 human tumor cell panel and on experimental tumor. 1963 15

Head and neck cancer is the sixth most common cancer worldwide and laryngeal cancer represents the largest subgroup. However, the molecular mechanism underlying its malignant behavior and progression is not clarified. Accumulating evidence has shown that Notch1 signaling pathway plays a central role in carcinogenesis, but its potential role in regulating the development of laryngeal carcinoma, has not been characterized. Here, we identified that Notch1 signaling pathway was activated in laryngeal carcinoma accompanied with up-regulation of Notch1 and Hes1 expression. Overexpression of Notch1 in laryngeal carcinoma cell line Hep-2 led to suppression of tumor cellular proliferation and arrested cell cycle in the G0/G1 phase and induced cell apoptosis, which were coupled with the down-regulation of cyclin D1, cyclin E, cdk2 and bcl-2 and up-regulation of caspase-3, caspase-9 and p53. Most importantly, up-regulation of Notch1 expression also reduced the migration of Hep-2 cells, which was closely associated with down-regulation of MMP-2 and MMP-9. The finding may lay a foundation for further investigations into the Notch1 signaling pathway as a potential target for laryngeal carcinoma.
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PMID:Potential role of Notch1 signaling pathway in laryngeal squamous cell carcinoma cell line Hep-2 involving proliferation inhibition, cell cycle arrest, cell apoptosis, and cell migration. 1972 60

We isolated two phytochemical lignans, schisandrin and schisandrin C, from Schizandra chinensis Baill and investigated their anti-cancer effects in human leukemia U937 cells. Schisandrin C inhibited cell growth in a dose-dependent manner, which was associated with the induction of G1 arrest of the cell cycle and apoptosis; schisandrin did not inhibit growth. Schisandrin C induced G1 arrest was correlated with down-regulation of cyclin D1, cyclin E, cyclin-dependent kinase (Cdk) 4 and E2Fs expression, inhibition of phosphorylation of retinoblastoma protein (pRB), and up-regulation of the Cdk inhibitor p21(WAF1/CIP1). In addition, schisandrin C-induced apoptosis was associated with down-regulation of expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, proteolytic activation of caspase-3 and -9, and a concomitant degradation of poly(ADP-ribose) polymerase (PARP). Furthermore, schisandrin C-induced apoptosis was significantly inhibited by a caspase-3 specific inhibitor z-DEVD-fmk, indicating an important role for caspase-3 in the schisandrin C mechanism. In summary, growth inhibition by schisandrin C is related to cell cycle arrest at G1 and induction of caspase-3-dependent apoptosis in U937 cells; these findings suggest that schisandrin C may be a useful chemotherapeutic agent.
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PMID:Induction of G1 arrest and apoptosis by schisandrin C isolated from Schizandra chinensis Baill in human leukemia U937 cells. 1972 90


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