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)

Dysregulated expression of CD44 isoforms occurs consistently in colon carcinogenesis, and this change occurs also in most other types of cancer. One of the basic features of malignant transformation is the acquisition of resistance to apoptosis. We previously found that the colonic epithelium of mice, deficient in CD44 is predisposed to apoptosis. In this study, we asked whether the expression of CD44 alters the response of the colon to an apoptotic stimulus, and what are the mechanisms involved. For this, we assessed the susceptibility of the murine colon to apoptosis by total body irradiation to induce apoptosis. Apoptotic and concomitant changes relevant to the mechanisms of apoptosis were monitored by molecular markers of apoptosis. We found enhanced susceptibility to apoptosis in CD44 deficient colonic epithelium based on an increase in the number of apoptotic bodies, and activation of caspase 3. This was not associated with alterations in proliferations as shown by comparable Ki-67 expression and BrdU labeling. Furthermore, upregulated active caspase 3 in CD44 deficient colon was accompanied by concomitant molecular alterations in caspase 9 and not caspase 8, and this indicated the involvement of the mitochondrial pathway in apoptosis execution. Overall, this is the first report demonstrating CD44 mediated resistance to apoptosis in the colonic epithelium in vivo. This implicates CD44 in promoting cell transformation into a malignant phenotype, in conjunction with other anti-apoptotic factors.
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PMID:CD44 promotes resistance to apoptosis in murine colonic epithelium. 1560 6

B-cell chronic lymphocytic leukemia (CLL) has been traditionally described as a disease characterized by an accumulation of quiescent small lymphocytes with decreased susceptibility to apoptotic cell death. However, small numbers of "atypical" lymphocytes and prolymphocytes (PL) are frequently observed in the bone marrow (BM) of patients with CLL. In this study, we examined BM biopsy and aspirate specimens obtained from seven patients with atypical CLL. Using a double labeling (Ki-67+/CD20+) immunohistochemical method, we found that an appreciable number of the atypical CLL cells expressed the proliferation-associated protein Ki-67. Because CLL is characterized by a slow change in the peripheral blood (PB) lymphocyte count, we reasoned that a subpopulation of CLL cells probably undergoes spontaneous apoptosis. Using Western blot analysis, we observed expression of procaspase-9, procaspase-10, and poly(ADP-ribose) polymerase by the neoplastic cells in all seven cases of CLL, and procaspase-3 and procaspase-8 expression in six neoplasms. We also detected cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase in four and five CLL cases, respectively. To determine whether CLL cells undergo spontaneous apoptosis, we performed the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay using BM biopsy specimens. We found TUNEL-positive lymphocytes in areas infiltrated by CLL. In summary, our data show that subpopulations of B-lymphocytes are proliferating or undergoing spontaneous apoptotic cell death in patients with atypical CLL.
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PMID:Aberrant morphology, proliferation, and apoptosis of B-cell chronic lymphocytic leukemia cells. 1562 35

Despite new approaches, treatment options for malignant gliomas are still limited, calling for further development of therapeutic strategies. The peroxisome proliferator-activated receptor (PPAR)gamma, a member of the nuclear hormone receptor family, represents a possible new target for neoplastic therapies. Synthetic PPARgamma agonists were developed and are already in clinical use for the treatment of type II diabetes, since PPARgamma plays a crucial role in lipid metabolism and regulation of insulin sensitivity. Beyond these metabolic effects, PPARgamma agonists exhibit antineoplastic effects in various malignant tumor cells. Here, we investigated the antineoplastic effects of the nonthiazolidinedione tyrosine-based PPARgamma ligand (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester (GW7845) in rat and human glioma cells. GW7845 reduced cellular viability of rat C6 glioma and human glioma cells in a time-dependent manner. Analysis of GW7845-treated tumor cells revealed induction of apoptotic cell death as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and cleaved caspase-3 activation. Furthermore, GW7845 reduced proliferation of C6 glioma cells as measured by Ki-67 immunore-activity. There was also a reduction of migration and invasion, assessed by Boyden chamber and spheroid experiments. Together, these data indicate that the PPARgamma agonist GW7845 may be of potential use in treatment of malignant gliomas.
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PMID:The nonthiazolidinedione tyrosine-based peroxisome proliferator-activated receptor gamma ligand GW7845 induces apoptosis and limits migration and invasion of rat and human glioma cells. 1566 44

Laminar necrosis of placental membranes (LN), a band of coagulative necrosis at the choriodecidual interphase, is a histologic lesion of unclear pathogenesis that has been reported in placentas from preeclampsia, preterm premature rupture of membranes, and preterm abruption. To better explore other possible correlations of LN, we performed a retrospective case-control study in which data on pregnancy risks and outcomes, neonate conditions, and placental gross, routine microscopic, and selected immunohistochemistry examinations in 52 consecutive cases of LN were compared with 52 gestational age-matched control cases without LN. Maternal hypertensive disorders and combinations of 2 or more maternal, fetal, neonatal, or placental conditions known to be potentially associated with uteroplacental hypoxia were more prevalent in patients with LN than in control patients. By immunohistochemistry, LN areas were positive for complement 9 (marker of necrosis) and negative for active caspase 3 (marker of irreversible apoptosis), nitrotyrosine residues (marker of oxidative stress), and Ki-67 (proliferation marker), thus confirming their necrotic rather than apoptotic nature. However, LN areas were flanked by caspase 3 positivity, and the positivity for nitrotyrosine residues was more pronounced in the decidua and mesenchyme in the same membrane rolls as LN, which indicates a probable role of apoptosis and oxidative stress in the development of LN. Based on these immunohistochemical results and clinicopathologic correlations, we believe LN should be recognized and reported as a hypoxic placental lesion.
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PMID:Laminar necrosis of placental membranes: a histologic sign of uteroplacental hypoxia. 1680 36

The purpose of the present paper was to examine the level of apoptosis and the relationships among apoptosis, apoptosis-associated proteins, and proliferating potential in lymphoma tissues to clarify the characteristics of apoptosis in diffuse large B-cell lymphomas (DLBCL) of the central nervous system (CNS). The formalin-fixed, paraffin-embedded tissues of CNS and non-CNS DLBCL (20 cases each) were studied by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) and immunohistochemistry, using antibodies against single-stranded DNA (ssDNA), cleaved caspase-3, bcl-2, bax, p53, Fas and Ki-67. The cleaved caspase-3 immunohistochemistry detected apoptosis of the lymphoma cells most sensitively compared to TUNEL and ssDNA immunohistochemistry. High expression (grade + + or + + +) of cleaved caspase-3 was found more frequently in CNS DLBCL (11 cases, 55%) than non-CNS DLBCL (three cases, 15%; P = 0.009). Bax-positivity of lymphoma cells was increased in six cases of CNS DLBCL, which also showed high positivity of cleaved caspase-3. There was no significant correlation between the cleaved caspase-3-positivity and the Ki-67 positivity. The present study indicates that the number of apoptotic cells and expression level of cleaved caspase-3 were significantly higher in CNS DLBCL than non-CNS DLBCL, and that the correlation of bax and cleaved caspase-3 expression was often present in CNS DLBCL.
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PMID:Immunohistochemical analysis of cleaved caspase-3 detects high level of apoptosis frequently in diffuse large B-cell lymphomas of the central nervous system. 1574 20

We compare the effects of Imatinib mesylate (Glivec) on chronic myeloid leukemia derived cell lines K562 and JURL-MK1. In both cell lines, the cell cycle arrests in G(1)/G(0) phase within 24 h after the addition of 1 microM Imatinib. This is followed by a decrease of Ki-67 expression and the induction of apoptosis. In JURL-MK1 cells, the apoptosis is faster in comparison with K562 cells: the caspase-3 activity reaches the peak value (20 to 30 fold of the control) after about 40 h and the apoptosis proceeds to its culmination point, the DNA fragmentation, within 48 h following 1 microM Imatinib addition. Unlike K562 cells, JURL-MK1 cells possess a probably functional p53 protein inducible by TPA (tetradecanoyl phorbol acetate) or UV-B irradiation. However, no increase in p53 expression was observed in Imatinib-treated JURL-MK1 cells indicating that the difference in the apoptosis rate between the two cell lines is not due to the lack of p53 in K562 cells. Imatinib also triggers erythroid differentiation both in JURL-MK1 and K562 cells. Glycophorin A expression occurred simultaneously with the apoptosis, even at the single cell level. In K562 cells, but not in JURL-MK1 cells, the differentiation process involved increased hemoglobin synthesis. However, during spontaneous evolution of JURL-MK1 cells in culture, the effects produced by Imatinib progressively changed from the fast apoptosis to the more complete erythroid differentiation. We suggest that the apoptosis and the erythroid differentiation are parallel effects of Imatinib and their relative contributions, kinetics and completeness are related to the differentiation stage of the treated cells.
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PMID:Fast apoptosis and erythroid differentiation induced by imatinib mesylate in JURL-MK1 cells. 1577 Jun 64

It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.
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PMID:Trimodal cancer treatment: beneficial effects of combined antiangiogenesis, radiation, and chemotherapy. 1586 59

The objective of this study was to examine the incidence of apoptosis in placentas of intrauterine growth restriction (IUGR) without maternal disease. We focused on cases of IUGR with both unknown causes and no maternal complications. In addition, apoptosis of IUGR placentas was correlated with the expression of proteins involved in apoptosis and cell turnover. The term placentas were obtained from 16 normal and 10 IUGR pregnancies without maternal symptoms. We analyzed the localization of apoptosis and counted >2000 nuclei by TUNEL assay and transmission electron microscopy in placentas from normal and IUGR cases. We found the incidence of apoptosis to be significantly higher in placentas with IUGR (2.98%) than in normal placentas (1.46%) by TUNEL assay (p=0.03). In addition, immunohistochemical analysis was performed to examine the expression of proteins related to apoptosis and general cell turnover, including the active form of caspase-3, Bax, p53, and Ki-67. Expression of the active form of caspase-3 was significantly higher in IUGR than in a normal pregnancy (p=0.03). These results suggest that enhanced execution of apoptosis through caspase-3 may play a role in IUGR without maternal symptoms.
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PMID:Frequent apoptosis in placental villi from pregnancies complicated with intrauterine growth restriction and without maternal symptoms. 1594 81

Multinucleated epithelial giant cells (MEG) simulating viral cytopathic effect and/or dysplasia have been reported in the esophagus in association with inflammation, but the occurrence of similar cells in the colon has not been documented. Twenty-three colon specimens (22 biopsies and 1 partial colectomy) featuring MEG from 21 patients were evaluated for a variety of histologic features and correlated with clinical, endoscopic, and follow-up data. Patients included 9 males and 12 females (mean age, 64.9 years; range, 45-86 years). Eleven cases were obtained from 10 asymptomatic patients undergoing surveillance biopsies. Presenting symptoms in the remaining patients were dyspepsia, anemia, abdominal pain, and hematochezia. Over half (13 of 23) of the specimens were from descending and rectosigmoid colon, and almost all were visualized as polyps on endoscopy. Microscopically, all but 1 of the cases featured multiple MEG (range, 6 to >50 cells per biopsy) in the base and mid crypt zones of inflamed polyps with serrated architecture. Immunohistochemical stains for CMV, HSV, adenovirus, EBV, and polyoma virus were negative and no viral particles were identified on ultrastructural examination. Nuclear staining for hMLH1 and hMSH2, markers of microsatellite instability, was similar in distribution to adjacent serrated crypts, but reduced staining intensity was noted in occasional multinucleated cells. Expression of Ki-67 and cleaved caspase 3 was consistent with a quiescent or low proliferative state. Clinical follow-up was available for 9 patients (mean duration, 22.7 months). One patient died of heart failure; all others were well at last follow-up. Bizarre MEG may occasionally be seen within the crypts of inflamed polyps with serrated architecture, raising concern for dysplasia or viral infection. Immunohistochemical and ultrastructural studies fail to establish a viral etiology, and follow-up does not indicate clinically aggressive disease. These changes appear to represent a nonspecific, possibly degenerative response to inflammation and injury, and should be distinguished from dysplasia.
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PMID:Multinucleated epithelial giant cells in colorectal polyps: a potential mimic of viropathic and/or dysplastic changes. 1595 56

FTY720, a derivative of fungus, has demonstrated dramatic anticancer effect in several malignancies recently. Our study evaluates the therapeutic potential of FTY720 in the treatment of androgen-independent prostate cancer using a human prostate cancer xenograft in nude mice. CWR22R, an androgen-independent human prostate tumor xenograft was inoculated into castrated nude mice and the animals were administrated with either normal saline or FTY720 (10 mg/kg) through intraperitoneal (i.p.) injection for 20 days. Body weight and tumor volume were recorded every 2 days, and serum prostate specific antigen (PSA) levels were also measured before and after the treatment. The effect of FTY720 on tumor cell proliferation was examined using antibodies against PCNA and Ki-67 by immunohistochemical staining, MTT assay and colony forming assay, whereas apoptotic effect of FTY720 was evaluated by TUNEL assay and immunostaining using antibodies against cleaved caspase 3 and Bcl-2. In addition, the potential inhibitory effect of FTY720 on prostate cancer angiogenesis and metastasis was investigated by immunostaining of CD31, VEGF, E-cadherin and beta-catenin. Our results showed that FTY720 treatment led to suppression of CWR22R tumor growth without causing any detectable side effects in nude mice. The FTY720-induced tumor suppression was correlated with decreased serum PSA level as well as reduced proliferation rate, suppression of angiogenic factors, and restoration of E-cadherin and beta-catenin expression. In addition, the FTY720-treated tumors showed increased apoptosis rate demonstrated by increased TUNEL- and cleaved caspase 3-positive cells, and decreased Bcl-2 expression. Our results suggest a potential novel agent in the suppression of androgen-independent prostate cancer.
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PMID:FTY720, a fungus metabolite, inhibits in vivo growth of androgen-independent prostate cancer. 1598 40


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