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

Vitis amurensis Rupr. (Vitaceae) has long been used in Chinese/Oriental herbal medicine for the treatment of cancer, but its active compounds and mechanisms of action have not been well studied. To this end, we isolated from its root heyneanol A (HA), which is a tetramer of resveratrol (RES), and established the in vivo antitumor activity of HA using the mouse Lewis lung carcinoma (LLC) model. We administered HA and RES by daily intraperitonial injection to C57BL/6 mice that were subcutaneously inoculated with LLC cells. HA dose-dependently decreased tumor growth without any adverse effect on body weight and seemed more potent than RES. The tumor inhibitory effects were accompanied by a marked increase in tumor cell apoptosis detected by cleaved caspase-3 and TUNEL assays and decreased tumor cell proliferation index and tumor microvessel density, supporting the involvement of apoptotic and anti-angiogenic activities in the anticancer effects. We next investigated the cellular and molecular processes that mediate the apoptosis and anti-angiogenesis effects using cell culture models. Mechanistically, treatment of LLC cells in vitro with HA or RES significantly increased apoptotic cells. Both HA- and RES-induced cleavage of caspase-9 and caspase-3 and PARP were completely blocked by a pan caspase inhibitor, Z-VAD-FMK. In addition, HA and RES suppressed the basic fibroblast growth factor (bFGF)-induced proliferation and capillary differentiation of human umbilical vein endothelial cells, and inhibited the binding of bFGF to its receptor in a test tube assay and the bFGF-induced vascularization of Matrigel plugs in vivo. Remarkably, HA was fairly stable in cell culture medium and did not undergo intracellular conversion to RES. Therefore, HA is an active anticancer compound that induces caspase-mediated cancer cell apoptosis and inhibits angiogenesis rivaling the potency of RES and merits further evaluation for cancer chemoprevention.
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PMID:Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. 1667 71

In the treatment of lung cancers, a local cryotherapy can be proposed as a palliative option for bronchial clearance. But this therapy can also be used as an adjuvant treatment, for instance in association with chemotherapy. We have already demonstrated differential biological effects of these therapies and the benefit to combine them. The aim of this study was to determine if this benefit observed at a molecular level was correlated with tumour growth. As vascular changes occur after cryotherapy, intratumoral angiogenesis was also studied. Cells from the A549 cell line were inoculated into SCID mice. Tumours were treated by cryotherapy (nitrous oxide cryoprobe), chemotherapy (injection of Vinorelbine) or both. Tumour growth was studied in each group and the T/C ratios were compared. Tumours treated by cryochemotherapy presented a significantly reduced volume and the lower T/C ratio, confirming the benefit of a combined treatment. Angiogenesis was assessed at variable time points after cryotherapy by immunohistochemical staining of VEGF and western blot analysis. A late cryo-induced angiogenesis was observed 8-15 days after treatment (expression of VEGF increased from 13% in untreated tumours to 77 and 70%, respectively). To determine if this hypervascularization could enhance the efficiency of chemotherapy, the drug was injected 15 days after cryotherapy and the induction of cell death was investigated (morphological study, immunohistochemical staining of cleaved caspase-3, TUNEL). Necrosis was increased but not apoptosis, suggesting that though a crucial parameter, intratumoral microvessel density is not the only factor to consider to reach an optimal efficiency of a combined treatment.
Lung Cancer 2006 Oct
PMID:Benefit of a combined treatment of cryotherapy and chemotherapy on tumour growth and late cryo-induced angiogenesis in a non-small-cell lung cancer model. 1688 70

Low molecular weight nitroxides are widely used as electron paramagnetic resonance (EPR)-detectable spin labels in the biological and pathological areas. A novel nitroxide derivative, 4-ferrocenecarboxyl-2,2,6,6-tetramethyl piperidine-1-oxyl (FC-TEMPO), was synthesized for evaluating the effects of spin label compounds on tumor cells and firstly its biological effects on tumor and normal cells were evaluated. The cytotoxicity of FC-TEMPO in the high metastatic lung carcinoma cells (95-D) showed that it markedly inhibited the viability of cancer cells in a dose-dependent manner, while it was less toxic to a normal human cell line. Further studies found that FC-TEMPO suppressed the growth of tumor cells by induced apoptosis through activating caspase-3 but not caspase-8 which was proved by caspase inhibitors, and the cell cycle arrest at G1 phase. Moreover, the concomitant increase of superoxide dismutase (SOD) and catalase (CAT) activity was observed. Taken together, these results might provide a base for further anticancer investigations of nitroxides and their potential pharmacological applications.
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PMID:Cytotoxicity of a newly synthesized nitroxide derivative of 4-ferrocenecarboxyl-2,2,6,6-tetramethylpiperidine-1-oxyl in high metastatic lung tumor cells. 1728 62

Cells typically die by either apoptosis or necrosis. However, the consequences of apoptosis and necrosis are quite different for a whole organism. In the case of apoptosis, the cell content remains packed in the apoptotic bodies that are removed by macrophages, and thereby inflammation does not occur; during necrosis, the cell membrane is ruptured, and the cytosolic constituents are released into the extracellular space provoking inflammation. Recently, inflammation and necrosis have been suggested to promote tumor growth. We investigated the molecular mechanism underlying cell death in response to glucose depletion (GD), a common characteristic of the tumor microenvironment. GD induced necrosis through production of reactive oxygen species (ROS) in A549 lung carcinoma cells. Inhibition of ROS production by N-acetyl-L-cysteine and catalase prevented necrosis and switched the cell death mode to apoptosis that depends on mitochondrial death pathway involving caspase-9 and caspase-3 activation, indicating a critical role of ROS in determination of GD-induced cell death mode. We demonstrate that protein kinase C-dependent extracellular regulated kinase 1/2 (ERK1/2) activation also switched GD-induced necrosis to apoptosis through inhibition of ROS production possibly by inducing manganese superoxide dismutase (SOD) expression and by preventing GD-induced degradation of copper zinc SOD. Thus, these results suggest that GD-induced cell death mode is determined by the protein kinase C/ERK1/2 signal pathway that regulates MnSOD and CuZnSOD and that these antioxidants may exert their known tumor suppressive activities by inducing necrosis-to-apoptosis switch.
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PMID:Protein kinase C-ERK1/2 signal pathway switches glucose depletion-induced necrosis to apoptosis by regulating superoxide dismutases and suppressing reactive oxygen species production in A549 lung cancer cells. 1730 78

Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractive targets for the development of anticancer therapeutics. Based on antitumor activity in animal models, a variety of Cdk inhibitors are undergoing clinical evaluation either as a single agent or in combination with other approved drugs. In our anticancer drug discovery program, a novel series of flavones have been synthesized for evaluation against the activity of Cdk4-D1. This enzyme catalyzes the phosphorylation of retinoblastoma protein, thus inhibiting its function. We have identified a series of potent Cdk4-D1 inhibitors with IC(50) below 250 nmol/L. In this report, we have described the properties of one of the best compound, P276-00 of the flavone's series. P276-00 shows 40-fold selectivity toward Cdk4-D1, compared with Cdk2-E. The specificity toward 14 other related and unrelated kinases was also determined. P276-00 was found to be more selective with IC(50)s <100 nmol/L for Cdk4-D1, Cdk1-B, and Cdk9-T1, as compared with other Cdks, and less selective for non-Cdk kinases. It showed potent antiproliferative effects against various human cancer cell lines, with an IC(50) ranging from 300 to 800 nmol/L and was further compared for its antiproliferative activity against cancer and normal fibroblast cell lines. P276-00 was found to be highly selective for cancer cells as compared with normal fibroblast cells. To delineate its mechanism of action, the effect of P276-00 on cell cycle proteins was studied in human breast cancer cell line (MCF-7) and human non-small cell lung carcinoma (H-460). A significant down-regulation of cyclin D1 and Cdk4 and a decrease in Cdk4-specific pRb Ser(780) phosphorylation was observed. P276-00 produced potent inhibition of Cdk4-D1 activity that was found to be competitive with ATP and not with retinoblastoma protein. The compound also induced apoptosis in human promyelocytic leukemia (HL-60) cells, as evidenced by the induction of caspase-3 and DNA ladder studies. These data suggest that P276-00 has the potential to be developed as an anti-Cdk chemotherapeutic agent.
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PMID:In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. 1736 86

Shikonin has been reported to induce apoptosis and inhibit angiogenesis in vivo and in vitro. 6-(1-propoxyiminoalkyl)-5,8-dimethoxyoxy 1,4-naphtoquinone S-64 (DMNQ S-64) was synthesized as a shikonin derivative. In this article, the underlying apoptotic mechanism of DMNQ S-64 was examined. DMNQ S-64 exerted cytotoxicity against A549 lung carcinoma cells with IC(50) of 27.3 microM. Apoptotic bodies were observed in DMNQ S-64-treated A549 cells by 4'-6-diamidino-2-phenylindole (DAPI) staining assay. DMNQ S-64 also increased sub-G1 DNA portion in a concentration-dependent manner by flow cytometric analysis. Western blotting has revealed that DMNQ S-64 effectively activates the expression of caspase 8, 9, and 3, cleaves poly (ADP-ribose) polymerase, and increases the ratio of Bax/Bcl-2. Furthermore, cytochrome c was released in a concentration-dependent manner by DMNQ S-64. Similarly, DMNQ S-64 significantly increased caspase 3 activity by enzyme-linked immunosorbent assay (ELISA). It also significantly inhibited the level of prostaglandin E2 (PGE(2)) by ELISA and downregulated the expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner. Taken together, DMNQ S-64 may exhibit cytotoxicity against A549 cells via caspase activation and COX-2 inhibition.
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PMID:DMNQ S-64 induces apoptosis via caspase activation and cyclooxygenase-2 inhibition in human nonsmall lung cancer cells. 1740 12

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

The JC virus (JCV) infects a large proportion of the population world wide and can cause progressive multifocal leucoencephalopathy in the context of immunodeficiency. Recent reports provide evidence that it may also be oncogenic. Here, JCV was examined by targeting its T-antigen in lung carcinomas (n=103) and normal lung tissues (n=18) by nested-PCR followed by Southern blot, real-time PCR, immunohistochemistry, in situ hybridization and in situ PCR. Additionally, expression of Ki-67, caspase-3, beta-catenin, p53, and Rb was analysed by immunohistochemistry on tissue microarrays of lung carcinomas. Copy numbers of JCV were compared with clinicopathological features. Normal lung tissue was positive significantly less frequently, and contained a lower copy number of JCV than lung carcinomas (p<0.05), and copies were lower in lung adenocarcinomas than in squamous, small or large cell carcinomas (p<0.05). In situ PCR and immunolabelling revealed JCV positivity in the nuclei of lung carcinoma cells. The JCV copy number correlated closely with sex, and expression of Ki-67 and membrane beta-catenin (p<0.05), but not with age, tumour size, pleural invasion, lymph node metastasis, expression of caspase-3, cytoplasmic beta-catenin, p53 or Rb, prognosis, smoking or cancer family history (p>0.05). Age and UICC staging were independent prognostic factors for lung carcinoma patients. These data suggest that JCV may be involved in lung carcinogenesis, especially in tumour types other than adenocarcinoma. Lung carcinomas with higher JCV copy numbers display high proliferation and down-regulation of cell adhesion mediated by membrane beta-catenin.
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PMID:Oncogenic role of JC virus in lung cancer. 1753 44

Cancer immunotherapy with dendritic cell-tumor cell fusion hybrids induces polyclonal stimulation against a variety of tumor antigens, including unknown antigens. Hybrid cells can prime CTLs, which subsequently develop antitumor responses. The aim of this study was to enhance the known antitumor effect of hybrid vaccination (HC-Vacc) and hybrid-primed adoptive T-cell therapy (HC-ACT) using the poorly immunogenic Lewis lung carcinoma (LLC1) model. The strategy used was a combination of a double HC-Vacc alternating with HC-ACT (HC-Vacc/ACT). Using flat-panel volumetric computer tomography and immunohistochemistry, we showed a significant retardation of tumor growth (85%). In addition, a significant delay in tumor development, a reduction in the number of pulmonary metastases, and increased survival times were observed. Furthermore, the tumors displayed significant morphologic changes and increased apoptosis, as shown by up-regulation of gene expression of the proapoptotic markers Fas, caspase-8, and caspase-3. The residual tumor masses seen in the HC-Vacc/ACT-treated mice were infiltrated with CD4+ and CD8+ lymphocytes and showed elevated IFNgamma expression. Moreover, splenic enlargement observed in HC-Vacc/ACT-treated mice reflected the increased functionality of T cells, as also indicated by increased expression of markers for CTL activation, differentiation, and proliferation (Cd28, Icosl, Tnfrsf13, and Tnfsf14). Our findings indicate that the combination therapy of dendritic cell-tumor cell HC-Vacc/ACT is a very effective and a promising immunotherapeutic regimen against poorly immunogenic carcinomas.
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PMID:A combination hybrid-based vaccination/adoptive cellular therapy to prevent tumor growth by involvement of T cells. 1754 26

Histone deacetylase inhibitor such as romidepsin (depsipeptide, FR901228, FK228) is a promising new class of antineoplastic agent with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, their precise mechanism of action is uncertain. Histone acetylation and deacetylation are involved in transcriptional activation and transcriptional repression, respectively. Romidepsin induced histone hyperacetylation can be correlated with the cell cycle arrest and apoptosis. In the present study, we investigated the effects of romidepsin on cell proliferation, cell cycle arrest, apoptosis and histone hyperacetylation. Expression of Cdc2/Cdk-1, cyclin B1, cyclin A, p21/Cip1, pRb, pRb2/p130, histone H4 and H3 acetylation status were studied with western blot analysis. The induction of apoptosis has been demonstrated by annexin V-FITC binding assay. Extent of apoptosis has been assessed measuring the activity of caspase-3. Romidepsin led to substantial decrease in the expression of Cdc2/Cdk-1, cyclin B1 and phosphorylated pRb and increase in p21. The pRb protein was found to be one of the targets for the romidepsin induced cell cycle arrest. Flow cytometric analysis showed that romidepsin induced cell cycle arrest at G2-M transition, with significant induction of apoptosis at 25 and 50 nM concentration of romidepsin, with an increase in the number of both early and late apoptotic cells. From this study it is concluded that romidepsin inhibit advanced human lung carcinoma (A549) cell proliferation by altering the expression of cell cycle regulators and apoptotic protein.
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PMID:Romidepsin (depsipeptide) induced cell cycle arrest, apoptosis and histone hyperacetylation in lung carcinoma cells (A549) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. 1764 1


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