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)

The outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically with current therapy resulting in an event free survival exceeding 75% for most patients. However significant challenges remain including developing better methods to predict which patients can be cured with less toxic treatment and which ones will benefit from augmented therapy. In addition, 25% of patients fail therapy and novel treatments that are focused on undermining specifically the leukemic process are needed urgently. In Section I, Dr. Carroll reviews current approaches to risk classification and proposes a system that incorporates well-established clinical parameters, genetic lesions of the blast as well as early response parameters. He then provides an overview of emerging technologies in genomics and proteomics and how they might lead to more rational, biologically based classification systems. In Section II, Drs. Mary Relling and Stella Davies describe emerging findings that relate to host features that influence outcome, the role of inherited germline variation. They highlight technical breakthroughs in assessing germline differences among patients. Polymorphisms of drug metabolizing genes have been shown to influence toxicity and the best example is the gene thiopurine methyltransferase (TPMT) a key enzyme in the metabolism of 6-mercaptopurine. Polymorphisms are associated with decreased activity that is also associated with increased toxicity. The role of polymorphisms in other genes whose products play an important role in drug metabolism as well as cytokine genes are discussed. In Sections III and IV, Drs. James Downing and Cheryl Willman review their findings using gene expression profiling to classify ALL. Both authors outline challenges in applying this methodology to analysis of clinical samples. Dr. Willman describes her laboratory's examination of infant leukemia and precursor B-ALL where unsupervised approaches have led to the identification of inherent biologic groups not predicted by conventional morphologic, immunophenotypic and cytogenetic variables. Dr. Downing describes his results from a pediatric ALL expression database using over 327 diagnostic samples, with 80% of the dataset consisting of samples from patients treated on a single institutional protocol. Seven distinct leukemia subtypes were identified representing known leukemia subtypes including: BCR-ABL, E2A-PBX1, TEL-AML1, rearrangements in the MLL gene, hyperdiploid karyotype (i.e., > 50 chromosomes), and T-ALL as well as a new leukemia subtype. A subset of genes have been identified whose expression appears to be predictive of outcome but independent verification is needed before this type of analysis can be integrated into treatment assignment. Chemotherapeutic agents kill cancer cells by activating apoptosis, or programmed cell death. In Section V, Dr. John Reed describes major apoptotic pathways and the specific role of key proteins in this response. The expression level of some of these proteins, such as BCL2, BAX, and caspase 3, has been shown to be predictive of ultimate outcome in hematopoietic tumors. New therapeutic approaches that modulate the apoptotic pathway are now available and Dr. Reed highlights those that may be applicable to the treatment of childhood ALL.
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PMID:Pediatric acute lymphoblastic leukemia. 1463 79

Abrin-a consists of A-chain with N-glycosidase activity, which inhibits protein synthesis, and lectin-like B-chain responsible for binding with cell-surface receptors and penetrating of abrin-a molecule into the cells. As a lectin component, the B-chain can also participate in cell signal transduction. It has been reported that abrin induces apoptosis, but the molecular mechanism(s) of this induction have been obscure and several alternative variants have been discussed. The present study demonstrates that abrin-a induces apoptosis in human cultured cell lines, derived from acute lymphoblastic leukemia (ALL) (Jurkat, CCRF-CEM, MOLT-4, HPB-ALL). The apoptosis was estimated by: phosphatidylserine (PSer) exposure at the cell surface, activation of caspase cascade, and DNA fragmentation. The penetrating of abrin-a into the cells was detected by fluorescent confocal microscopy, using fluorescein isothiocyanate (FITC) as a fluorescent marker. It was established that the effect of abrin-a on the apoptosis induction in leukemic cells was dose- and time-dependent. The process was initiated 1 h after abrin-a application (before its penetrating into the cells) and was characterized with PSer translocation from the inner to the outer monolayer of plasma membrane, caspase activation on the first to second hour after beginning of treatment, with maximum on the third to fourth hour, and DNA fragmentation on the fourth to sixth hour, depending of the cell line. The exposure of PSer on the cell surface was detected in Jurkat, CCRF-CEM, and MOLT-4 cells. In HPB-ALL, no significant changes in PSer exposure on the cell surface was observed. Activation of caspase-3, -8, and -9 was detected in Jurkat, MOLT-4, and HPB-ALL. Surprisingly, the activity of caspase-3 increased on the first hour after beginning of treatment, while the activity of caspase-8 and -9 began to increase on the second hour. In CCRF-CEM, activation of caspases was not measured, but the apoptosis progressed to DNA fragmentation in a dose- and time-dependent manner. DNA fragmentation was also detected in Jurkat, but not in MOLT-4 and HPB-ALL cells. It seems that the mechanisms of abrin-a-induced apoptosis are different and the progress of apoptosis depends of the cell line. There was a very good positive correlation between the agglutinating activity of abrin-a and development of apoptosis to DNA fragmentation. The time-dependent effects of abrin-a on apoptosis as well as its time-dependent penetration into the cells suggest that the B-chain probably triggers the apoptosis, while the A-chain and breakage of the disulfide bond are responsible for its progress.
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PMID:Plant-derived abrin-a induces apoptosis in cultured leukemic cell lines by different mechanisms. 1499 84

Glucocorticoids (GCs) induce apoptosis in lymphocytes and are effective agents for the treatment of leukemia. The activated glucocorticoid receptor initiates a transcriptional program leading to caspase activation and cell death, but the critical signaling intermediates in GC-induced apoptosis remain largely undefined. We have observed that GC induction of the three major protein products of the Bcl-2 relative Bim (BimEL, BimS, and BimL) correlates with GC sensitivity in a panel of human precursor B-cell (pre-B) acute lymphoblastic leukemia (ALL) cell lines. To test the hypothesis that Bim facilitates GC-induced apoptosis, we reduced BIM mRNA levels and Bim protein levels by RNA interference in highly GC-sensitive pre-B ALL cells. Reducing Bim proteins by either electroporation of synthetic small interfering RNA (siRNA) duplexes or lentivirus-mediated stable expression of short hairpin RNA inhibited the activation of caspase-3 and increased cell viability following GC exposure. We also observed that the extent of GC resistance correlated with siRNA silencing potency. siRNA duplexes that reduced only BimEL or BimEL and BimL (but not BimS) exhibited less GC resistance than a potent siRNA that silenced all three major isoforms, implying that induction of all three Bim proteins contributes to cell death. Finally, the modulation of GC-induced apoptosis caused by Bim silencing was independent of Bcl-2 expression levels, negating the hypothesis that the ratio of Bim to Bcl-2 regulates apoptosis. These results offer evidence that the induction of Bim by GC is a required event for the complete apoptotic response in pre-B ALL cells.
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PMID:Inhibition of glucocorticoid-induced apoptosis by targeting the major splice variants of BIM mRNA with small interfering RNA and short hairpin RNA. 1550 54

Programmed cell death, or apoptosis, is a physiological means of eliminating unwanted cells and maintaining immune homeostasis. One of the primary mechanisms is the Fas (CD95)/Fas ligand system. Its inactivation in normal cells and malignant cells may be involved in malignant trans-formation and refractory clinical course, respectively. We established a Fas resistant clone and evaluated the molecular basis for its mechanism of resistance. The Fas-sensitive leukemia cell line, MML-1, was established from a child with B-precursor acute lymphoblastic leukemia. A Fas resistant clone, MML-1R, was obtained by co-culture selection with anti-Fas antibody CH-11. Flow cytometry analysis showed both cell lines had equivalent expression of cell surface CD13, 15, 19, 22 and Fas receptor. Western blot analysis revealed equal expression of FADD (Fas-associated death domain protein), caspase-3 and -8. MML-1 was quite sensitive to both CH-11 and etoposide-induced apoptotis. By contrast, MML-1R had similar sensitivity to etoposide but no response to CH-11. Fas receptor mutation analysis showed a heterozygous death domain A --> G point mutation at 1009 bp, causing a switch from glutamine to glycine at amino acid 256. Immunoprecipitation assay showed decreased binding of Fas to FADD. We also found that etoposide bypassed Fas-FADD interaction in MML-1R by activating caspase-8 and caspase-3. These results indicate that Fas resistance can result from mutations of the gene encoding the Fas receptor which result in decreased FADD binding, thereby blocking formation of the death inducing signaling complex. Screening for similar Fas mutations in therapy resistant malignancies would lead to a better understanding of tumorigenesis and recurrence.
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PMID:Acquisition of Fas resistance by Fas receptor mutation in a childhood B-precursor acute lymphoblastic leukemia cell line, MML-1. 1601 Apr 41

The chromosomal translocation t(4;11) marks infant acute lymphoblastic leukemia associated with a particularly dismal prognosis. The leukemogenic role of the corresponding fusion gene MLL-AF4 is not well understood. We show that transient inhibition of MLL-AF4 expression with small interfering RNAs impairs the proliferation and clonogenicity of the t(4; 11)-positive human leukemic cell lines SEM and RS4;11. Reduction of mixed-lineage leukemia (MLL)-ALL-1 fused gene from chromosome 4 (AF4) levels induces apoptosis associated with caspase-3 activation and diminished BCL-X(L) expression. Suppression of MLL-AF4 is paralleled by a decreased expression of the homeotic genes HOXA7, HOXA9, and MEIS1. MLL-AF4 depletion inhibits expression of the stem-cell marker CD133, indicating hematopoietic differentiation. Transfection of leukemic cells with MLL-AF4 siRNAs reduces leukemia-associated morbidity and mortality in SCID mice that received a xenotransplant, suggesting that MLL-AF4 depletion negatively affects leukemia-initiating cells. Our findings demonstrate that MLL-AF4 is important for leukemic clonogenicity and engraftment of this highly aggressive leukemia. Targeted inhibition of MLL-AF4 fusion gene expression may lead to an effective and highly specific treatment of this therapy-resistant leukemia.
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PMID:Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells. 1604 33

Oridonin, an ent-kaurane diterpenoid derived from the herbal Rabdosia rubescens, has been recently reported to have antitumor effects on a large variety of cancer cells. The present study was undertaken to investigate the in vitro antiproliferation and apoptosis inducing effects of oridonin on HPB-ALL cell lines and its mechanisms of action. HPB-ALL cells in culture medium in vitro were treated with different concentrations of oridonin (16-56 micromol/L). MTT assay was used to detect the cell growth inhibitory rate, and the cell viability was assessed by the trypan blue dye-exclusion method. Cell apoptosis and the mitochondrial membrane potential (delta psi m) were investigated by flow cytometry (FCM), Hoechst 33258 staining, and DNA fragmentation analysis. The expression of caspase-3 and different apoptosis modulators, including Fas and Bcl-2 family members, was analyzed by Western blotting. The results revealed that oridonin could significantly inhibit the growth of HPB-ALL cells and cause apoptosis, and the suppression was both time- and dose-dependent. After treatment with oridonin for 48 hr, the percentage of disruption of delta psi m gradually increased in a dose-dependent manner along with marked changes of cell apoptosis, and necrotic cells increased remarkably after the cells were treated with oridonin for 72 hr; Western blotting showed cleavage of the caspase-3 zymogen protein (32 kDa) with the appearance of its 20-kDa subunit when apoptosis occurred; expression of Bcl-2 and Bcl-XL was downregulated remarkably while expression of Bax and Bid was upregulated concurrently after the cells were treated with oridonin for 24 hr. Of note, the expressions of Fas and other Bcl-2 family members including Bak and Bad remained constant before and after apoptosis occurred. We therefore conclude that oridonin has significant antiproliferation effects on HPB-ALL cells by induction of apoptosis as well as directly causing cell necrosis and that oridonin-induced apoptosis on HPB-ALL cells is mainly related to the disruption of delta psi m and activation of caspase-3 as well as downregulation of anti-apoptotic protein Bcl-2, Bcl-XL, and upregulation of pro-apoptotic proteins Bax and Bid. The results indicate that oridonin may serve as a potential antileukemia reagent.
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PMID:Antiproliferation effects of oridonin on HPB-ALL cells and its mechanisms of action. 1643 62

Deficient activation of apoptosis signaling pathways may be responsible for treatment failure in acute leukemia. Here, we address the impact of intact apoptosis signaling in 78 patients with pediatric precursor B-cell acute lymphoblastic leukemia (ALL) by analysis of 2 key apoptogenic events: caspase-3 activation and cytochrome c release in leukemia cells cultured in vitro. Both events correlated only in the group of patients who had a good response and patients in continuous remission, suggesting that intact apoptosis signaling is a characteristic for favorable outcome. By combining both parameters, we identified a novel indicator, cytochrome c-related activation of caspase-3 (CRAC). CRAC directly connects the extent of caspase-3 activation to cytochrome c release in single cells in an individual patient sample. In CRAC-positive patients, indicating proficient apoptosis signaling, the number of persisting leukemia cells on day 15 was significantly lower than in the CRAC-negative patient group (n = 27, mean 6.0% versus n = 36, mean 22.6%; P = .003). At a median follow-up of 31 months, disease-free survival was 84 months (95% CI = 76 to 91 months) and 66 months (95% CI = 52 to 80 months) for patients with positive and negative CRAC, respectively (P = .019). CRAC may serve as a functionally defined risk factor for treatment stratification.
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PMID:Cytochrome c-related caspase-3 activation determines treatment response and relapse in childhood precursor B-cell ALL. 1646 6

Acute lymphoblastic leukemia (ALL), especially T-acute lymphoblastic leukemia (T-ALL), is a common childhood malignant neoplastic disorder. Chemotherapy agents, particularly those that can induce apoptosis, are the major intervening strategy in the treatment of ALL. In this study, we investigated in T-ALL cell line, CCRF-CEM, the in vitro cytotoxic effect and the mechanism of action of baicalin, a compound extracted from Scutellaria baicalensis Georgi and S. rivularis Benth (Labiateae). Results demonstrated that baicalin displayed a remarkable cytotoxic effect in CCRF-CEM, with an IC(50) value of 10.6 microg/ml. It triggered apoptotic effect by fragmentizing cellular DNA and arrested the cell cycle at G(0)/G(1) phase. Baicalin (37.5 microg/ml) had not effected the expression of p53 and Fas protein. It was shown to decline the expression of Bcl-2 (22.0 pg/ml), which consequently caused the loss (52.7%) of transmembrane potential (Delta Psi m) in the mitochondria after 72 hours of treatment. Baicalin (37.5 microg/ml) also elevated the amount of cytosolic cytochrome c (19.2 microg/ml), which finally triggered the activation of caspase-3 (50.1 pmol/min). In conclusion, baicalin was found to induce apoptosis in T-ALL cell lines through multiple pathways. This finding encourages further investigation of baicalin in its role as a potential candidate for chemotherapeutic agents in T-ALL.
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PMID:Baicalin-induced apoptosis is mediated by Bcl-2-dependent, but not p53-dependent, pathway in human leukemia cell lines. 1655 36

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of BCR-ABL-mediated transformation in vitro and in vivo. To investigate whether PTP1B modulates the biological effects of the abl kinase inhibitor STI571 in BCR-ABL-positive cells, we transfected Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cell-derived K562 cells with either wild-type PTP1B (K562/PTP1B), a substrate-trapping dominant-negative mutant PTP1B (K562/D181A), or empty vector (K562/mock). Cells were cultured with or without STI571 and analyzed for its effects on proliferation, differentiation, and apoptosis. In both K562/mock and K562/PTP1B cells, 0.25 to 1 mumol/L STI571 induced dose-dependent growth arrest and apoptosis, as measured by a decrease of cell proliferation and an increase of Annexin V-positive cells and/or of cells in the sub-G(1) apoptotic phase. Western blot analysis showed increased protein levels of activated caspase-3 and caspase-8 and induction of poly(ADP-ribose) polymerase cleavage. Low concentrations of STI571 promoted erythroid differentiation of these cells. Conversely, K562/D181A cells displayed significantly lower PTP1B-specific tyrosine phosphatase activity and were significantly less sensitive to STI571-induced growth arrest, apoptosis, and erythroid differentiation. Pharmacologic inhibition of PTP1B activity in wild-type K562 cells, using bis(N,N-dimethylhydroxamido)hydroxooxovanadate, attenuated STI571-induced apoptosis. Lastly, comparison of the STI571-sensitive Ph+ acute lymphoblastic leukemia cell line SupB15 with a STI571-resistant subline revealed significantly decreased PTP1B activity and enhanced BCR-ABL phosphorylation in the STI571-resistant SupB15 cells. In conclusion, functional PTP1B is involved in STI571-induced growth and cell cycle arrest, apoptosis, and differentiation, and attenuation of PTP1B function may contribute to resistance towards STI571.
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PMID:Inhibition of phosphotyrosine phosphatase 1B causes resistance in BCR-ABL-positive leukemia cells to the ABL kinase inhibitor STI571. 1660 11

Lipids, especially sphingolipids, are emerging as inducer of apoptosis in a wide range of immortal cells, potentiating their therapeutic application in cancer. In the present study, a sphingolipid rich lipid fraction (denoted here as ALL), isolated from an attenuated strain of Leishmania donovani promastigote, was tested for its tumoricidal activity taking melanoma, the dreaded form of skin cancer cells, as model. ALL was found to induce chromatin condensation, internucleosomal DNA fragmentation and phosphatidylserine externalization with enhanced cell population in sub-G1 region in both mouse and human melanoma systems, namely B16F10 and A375 respectively. These are the hallmarks of cells undergoing apoptosis. Further analysis demonstrated that ALL treated melanoma cells showed significant increase in ROS generation, mitochondrial membrane potential depolarization, release of cytochrome c, and caspase-3 activation, which are the events closely involved in apoptosis. These findings indicate that one or more bioactive sphingolipid(s)/ceramide(s) present in ALL could be the causative agent(s) for the induction of apoptosis in melanoma cells. Further studies are thus necessary to identify these specific bioactive sphingolipid(s)/ceramide(s) and to establish their mechanism of action, in order to explore their use as anticancer agents.
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PMID:A sphingolipid rich lipid fraction isolated from attenuated Leishmania donovani promastigote induces apoptosis in mouse and human melanoma cells in vitro. 1671 68


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