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)

The functional benefit of cell transplantation after a myocardial infarction is diminished by early cell losses. IGF-1 enhances cell proliferation and survival. We hypothesized that IGF-1-transfected smooth muscle cells (SMCs) would enhance cell survival and improve engraftment after cell transplantation. The IGF-1 gene was transfected into male SMCs and compared with SMCs transfected with a plasmid vector (vector control) and nontransfected SMCs (cell control). IGF-1 mRNA (n=10/group) and protein levels (n=6/group) were higher (P <0.05 for all groups) at 3, 7, and 14 days compared with controls. VEGF was also increased in parallel to enhanced IGF-1 expression. IGF-1-transfected cells demonstrated greater cell proliferation, stimulated angiogenesis, and decreased caspase-3 activity after simulated ischemia and reperfusion (P <0.05 for all groups compared with vector or cell controls). A uniform left ventricular injury was produced in female rats using a cryoprobe. Three weeks later, 2 x 10(6) cells from three groups were implanted into the scar. One week later, IGF-1-transfected SMCs had increased myocardial IGF-1 and VEGF levels, increased Bcl2 expression, limited cell apoptosis, and enhanced vessel formation in the myocardial scar compared with the two control groups (P <0.05 for all groups). The proportion of SMCs surviving in the implanted region was greater (P <0.05) in the IGF-1-transfected group than in the vector or cell controls. Gene enhancement with IGF-1 improved donor cell proliferation, survival, and engraftment after cell transplantation, perhaps mediated by enhanced angiogenesis and reduced apoptosis.
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PMID:Enhanced IGF-1 expression improves smooth muscle cell engraftment after cell transplantation. 1533 70

Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, exhibits both anti-proliferative and anti-angiogenic activities. Atiprimod inhibited proliferation of all human cancer cell lines included in the National Cancer Institute panel with IC50 values in the low micromolar range. Notably, metastatic cell lines were more sensitive to the compound compared to the non-metastatic cell lines derived from the same tumor tissue types. Atiprimod also induced apoptosis and activated both caspase-9 and caspase-3 in T84 colon carcinoma cells. Hence, the anti-proliferative activity could partly be due to its pro-apoptotic activity. Regarding angiogenesis in vitro, atiprimod inhibited both bFGF and VEGF induced proliferation and migration of human umbilical vein endothelial cells (HUVECs), resulting in disruption of cord formation. In addition, atiprimod also suppressed formation of new blood vessels in a chorioallantoic membrane assay. Previous studies have also shown that atiprimod treatment reduced production of IL-6, VEGF and inhibited activation of Stat3, a constitutively activated protein in majority of human cancers. Together these findings suggest that atiprimod acts on several molecules that are essential for tumor growth, invasion and metastasis.
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PMID:Atiprimod is an inhibitor of cancer cell proliferation and angiogenesis. 1584 57

We have demonstrated that VEGF receptor blockade in combination with chronic hypoxia causes in rats severe angioproliferative pulmonary hypertension (SAPH) associated with arterial occlusion by proliferating endothelial cells, and we postulate that the established, lumen-occluding lesions are the result of the emergence of apoptosis-resistant proliferating cells. To study the dependence of exuberant endothelial cell proliferation on initial apoptosis, we adapted the CELLMAX artificial capillary system to analyze the effects of a VEGF receptor antagonist (SU5416) on human pulmonary microvascular endothelial cells under pulsatile shear stress. Immunohistochemical staining for caspase-3 and PCNA and flow cytometry for Annexin-V and BrdU supported our concept, since SU5416 caused initial apoptosis (35.8% at 24 h after the SU5416 addition and 4.8% in control cells) whereas the surviving cells became hyperproliferative (PCNA positive). Flow cytometry showed that apoptosis inhibition prevented the proliferation following the initial apoptosis. These lumen-filling endothelial cells were apoptosis resistant, grew without serum, and were phenotypically altered in that they express the tumor marker survivin. Hyperproliferative apoptosis-resistant cells were also generated by adding apoptosed cells instead of the VEGF receptor blocker to the CELLMAX system. In conclusion, endothelial cell death resulted in the selection of an apoptosis-resistant, proliferating phenotypically altered endothelial cell phenotype.
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PMID:Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. 1589 32

One of the most clinically relevant biological activities of curcumin is its anti-cancer property, implicating multiple intracellular pathways in the process. In the present report, we investigated the effect of curcumin on the activation of apoptotic and anti-angiogenic pathways in Ehrlich Ascites Tumor (EAT) cells. Treatment with curcumin in vivo resulted in inhibition of proliferation of EAT cells and ascites formation. Further, we demonstrate that the induction of apoptosis in EAT cells showed nuclear condensation, DNA fragmentation and translocation of caspase-activated DNase (CAD) to nucleus upon curcumin treatment. Curcumin-induced apoptosis is mediated through activation of caspase-3, which is specifically inhibited by the caspase-3 inhibitor, Ac-DEVD-CHO. On the other hand, the decreased secretion of ascites by EAT cells is corroborated by reduction in VEGF secretion upon curcumin treatment. Further, CD31 immunohistological staining of peritoneum sections in curcumin-treated mice suggests its efficacy in acting as anti-angiogenic compound in EAT cells by inhibiting proliferation of endothelial cells in mouse peritoneum. However, immunoflurescence studies of NF-kB revealed that the inhibition of nuclear translocation of NF-kB p65, a transcription factor required for VEGF gene expression, in curcumin-treated EAT cells. These results suggest a further possible clinical application of this diet-derived compound curcumin, as both proapoptotic and anti-angiogenic compound in association with conventional chemotherapeutic agents.
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PMID:Mechanism of inhibition of ascites tumor growth in mice by curcumin is mediated by NF-kB and caspase activated DNase. 1601 40

Butyrate, a short-chain fatty acid produced in the colon, induces cell cycle arrest, differentiation, and apoptosis in transformed cell lines. In this report, we study the effects of butyrate (BuA) on the growth of Ehrlich ascites tumor (EAT) cells in vivo. BuA, when injected intraperitoneally (i.p) into mice, inhibited proliferation of EAT cells. Further, induction of apoptosis in EAT cells was monitored by nuclear condensation, annexin-V staining, DNA fragmentation, and translocation of caspase-activated DNase into nucleus upon BuA-treatment. Ac-DEVD-CHO, a caspase-3 inhibitor, completely inhibited BuA-induced apoptosis, indicating that activation of caspase-3 mediates the apoptotic pathway in EAT cells. The proapoptotic effect of BuA also reflects on the antiangiogenic pathway in EAT cells. The antiangiogenic effect of BuA in vivo was demonstrated by the downregulation of the secretion of VEGF in EAT cells. CD31 immunohistochemical staining of peritoneum sections clearly indicated a potential angioinhibitory effect of BuA in EAT cells. These results suggest that BuA, besides regulating other fundamental cellular processes, is able to modulate the expression/secretion of the key angiogenic growth factor VEGF in EAT cells.
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PMID:Butyrate-induced proapoptotic and antiangiogenic pathways in EAT cells require activation of CAD and downregulation of VEGF. 1610 46

The senescence-accelerated mouse (SAM) is a naturally occurring animal model for accelerated aging after normal development and maturation. SAMP1 strain was reported to show age-related structural and functional changes in lung and to be a murine model of senile lung. We postulated that aging of lung is an important intrinsic process for development of emphysema and even in a short period of tobacco smoke exposure may be able to generate emphysema. At age 12 wk, SAMP1 inhaled air or 1.5% tobacco smoke (total particulate matter 23.9 mg/m3) through the nose for 30 min/day, 5 days/wk, and for 8 wk. The mean linear intercepts (MLI) and destructive index (DI) of lung were significantly increased [air vs. smoke (means+/-SE); MLI, 68.76+/-0.69 vs. 75.34+/-1.70 microm, P<0.05 and DI, 8.61+/-0.38 vs. 16.18+/-1.54%, P<0.05], whereas no significant changes were observed in SAMR1, control mice that show normal aging. In contrast, smoke-induced emphysema was completely prevented by concomitant ingestion of lycopene given as tomato juice [MLI: smoke with/without lycopene (mean+/-SE), 62.87+/-0.8 vs. 66.90+/-1.33 microm, P<0.05]. Smoke exposure increased apoptosis and active caspase-3 of airway and alveolar septal cells and reduced VEGF in lung tissues, but tomato juice ingestion significantly reduced apoptosis and increased tissue VEGF level. We conclude that SAMP1 is a useful model for tobacco smoke-induced emphysema and a valuable tool to explore both pathophysiological mechanisms and the effect of therapeutic intervention on smoke-induced emphysema.
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PMID:Tomato juice prevents senescence-accelerated mouse P1 strain from developing emphysema induced by chronic exposure to tobacco smoke. 1621 12

Taxanes, a new class of antitumor drugs, are effective against a large number of human tumors, although there are problems with drug resistance. The novel taxane, IDN5109, is characterized by its high tolerability, antitumor efficacy, ability to overcome multidrug resistance, and oral bioavailabilty. We investigated the cellular response of IDN5109 to head and neck squamous cell carcinoma (HNSCC), and compared the antitumor activity of IDN5109 with that of paclitaxel. This is the first demonstration of antitumor effects of IDN5109 on HNSCC. In in vitro experiments, IDN5109 showed antiproliferative effects against HNSCC cell lines. After treatment with IDN5109, Bcl-2 and Bcl-XL were down-regulated, Bax was up-regulated, and caspase-3 was activated. After treatment with IDN5109, concentrations of both VEGF and IL-8 in the culture supernatant of HNSCC cells decreased. In in vivo experiments, the oral administration of IDN5109 showed antitumor effects against HNSCC tumor xenografts. Immunohistochemistry showed that IDN5109 inhibited tumor angiogenesis and induced apoptosis in HNSCC cells, producing a decreased blood vessel density and increased apoptosis index. On the basis of these results, IDN5109 is useful as a chemotherapeutic agent against HNSCC.
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PMID:Antitumor effects of IDN5109 on head and neck squamous cell carcinoma. 2678 Sep 76

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-gamma agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.
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PMID:Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. 1669 53

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.
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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

Administration of the VEGF receptor blocker SU5416 to rats causes alveolar septal cell apoptosis and emphysema; both can be prevented by a superoxide dismutase mimetic. Here we show that SU5416 induces the expression of heme oxygenase-1 in the lung tissue and that administration of antioxidant N-acetyl-l-cysteine protects alveolar septal cells against apoptosis, as demonstrated by caspase-3 lung immunohistochemistry, and against emphysema.
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PMID:N-acetylcysteine treatment protects against VEGF-receptor blockade-related emphysema. 1699 36


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