Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal cell carcinoma (RCC) is known to be resistant to chemo- and radiotherapy due to a high apoptotic threshold. Smac and XIAP (X-linked inhibitor of apoptosis protein) proteins were detected in all RCC cell lines and tissue samples examined. We modulated the function of XIAP, either through its constitutional downregulation with an shRNA vector or by applying a Smac-mimicking peptide. Among RCC cell lines, Caki1 expresses the highest levels of XIAP. We transfected Caki1 with XIAP-targeting shRNA vector and generated stable clones. XIAP was knocked down by RNA interference in clone no. 14 by 81.6% and in clone no. 19 by 85.3%. Compared to the parental and mock-transfected cells, neither clone was more sensitive to conventional chemotherapeutic agents, but both clones were more susceptible to Fas stimulation (P<0.0001) and to pharmacological Bcl-2 inhibition (P<0.0001), as well as to a combination of the two (P<0.0001). Mature Smac binds to XIAP via the N-terminal residues, disrupting its interaction with caspases and promoting their activity. We determined that exposure of Caki1 cells to Smac-N7 peptide (AVPIAQK) resulted in a slight but significant decrease in viability (P=0.0031) and potentiated cisplatin's effect (P=0.0027). In contrast with point targeting of XIAP by shRNA, Smac-N7 peptide is active against several IAP (inhibitor of apoptosis protein) family members, which can explain its role in sensitising cells to cisplatin. Our results suggest that multiple targeting of both Bcl-2 and XIAP or, alternatively, of several IAP family members by the Smac-N7 peptide is a potent way to overcome resistance of RCC to apoptosis-triggering treatment modalities, and might be a new tool for molecular targeted therapy.
 ...
PMID:Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis. 1828 11

Novel dietary agents for prevention and therapy of prostate cancer (PCa) are desired. The aim of this study was to determine the effect of fisetin, a tetrahydroxyflavone, on inhibition of cell growth and induction of apoptosis in human PCa cells. Treatment of fisetin (10-60 microM, 48 h) was found to result in a decrease in the viability of LNCaP, CWR22Rupsilon1 and PC-3 cells but had only minimal effects on normal prostate epithelial cells as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide assay. Treatment of LNCaP cells with fisetin also resulted in G(1)-phase arrest that was associated with a marked decrease in the protein expression of cyclins D1, D2 and E and their activating partner cyclin-dependent kinases 2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. Fisetin treatment also resulted in induction of apoptosis, poly (ADP-ribose) polymerase (PARP) cleavage, modulation in the expressions of Bcl-2 family proteins, inhibition of phosphatidyl inositol 3-kinase and phosphorylation of Akt at Ser(473) and Thr(308). There was also induction of mitochondrial release of cytochrome c into cytosol, downregulation of X-linked inhibitor of apoptosis protein and upregulation of second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI on treatment of cells with fisetin. Treatment of cells with fisetin also resulted in significant activation of caspases-3, -8 and -9. Pretreatment of cells with caspase inhibitor (Z-VAD-FMK) blocked fisetin-induced activation of caspases. These data provide the first evidence that fisetin could be developed as an agent against PCa.
 ...
PMID:Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. 1835 61

Spongistatin 1 is a new experimental chemotherapeutic agent isolated from marine sponges. Here we show that spongistatin 1 potently induces cell death in patient primary acute leukemic cells with higher efficiency than 8/10 clinically used cytotoxic drugs and prevents long-term survival of leukemic cell lines. Spongistatin 1 triggers caspase-dependent apoptosis in Jurkat T cells by the release of cytochrome c, Smac/DIABLO and Omi/HtrA2. As caspase-9 acts as an initiator caspase and Bcl-2 and Bcl-xL overexpression suppress spongistatin 1-induced apoptosis, cell death is mediated through the mitochondrial apoptosis pathway. Importantly, spongistatin 1 leads to the degradation of the antiapoptotic X-linked inhibitor of apoptosis protein. In apoptosis-resistant leukemic tumor cells overexpressing XIAP, spongistatin 1 effectively causes cell death and potentiates cell death induction by other apoptosis-promoting factors that might be caused by spongistatin 1-mediated degradation of XIAP. Our data show that spongistatin 1 represents a promising novel therapeutic agent for the treatment of leukemic tumor cells especially in the clinically highly relevant situation of chemoresistance due to overexpression of XIAP.
 ...
PMID:Spongistatin 1: a new chemosensitizing marine compound that degrades XIAP. 1854 2

Mitochondrial outer membrane permeabilization and the release of intermembrane space proteins, such as cytochrome c, are early events during intrinsic (mitochondria-mediated) apoptotic signaling. Although this process is generally accepted to require the activation of Bak or Bax, the underlying mechanism responsible for their activation during true intrinsic apoptosis is not well understood. In the current study, we investigated the molecular requirements necessary for Bak activation using distinct clones of Bax-deficient Jurkat T-lymphocytes in which the intrinsic pathway had been inhibited. Cells stably overexpressing Bcl-2/Bcl-x(L) or stably depleted of Apaf-1 were equally resistant to apoptosis induced by the DNA-damaging anticancer drug etoposide as determined by phosphatidylserine externalization and caspase activation. Strikingly, characterization of mitochondrial apoptotic events in all three drug-resistant cell lines revealed that, without exception, resistance to apoptosis was associated with an absence of Bak activation, cytochrome c release, and mitochondrial membrane depolarization. Furthermore, we found that etoposide-induced apoptosis and mitochondrial events were inhibited in cells stably overexpressing either full-length X-linked inhibitor of apoptosis protein (XIAP) or the BIR1/BIR2 domains of XIAP. Combined, our findings suggest that caspase-mediated positive amplification of initial mitochondrial changes can determine the threshold for irreversible activation of the intrinsic apoptotic pathway.
 ...
PMID:Caspase-mediated Bak activation and cytochrome c release during intrinsic apoptotic cell death in Jurkat cells. 1892 73

1. The liver, the main site of ethanol oxidation, is extremely vulnerable to the toxic effects of alcohol. Chronic alcohol intake has been shown to result in alcoholic liver disease, although the precise mechanism of action remains poorly understood. 2. The present study was designed to examine the impact of facilitated acetaldehyde metabolism via overexpression of aldehyde dehydrogenase-2 (ALDH2) on chronic alcohol ingestion-induced hepatic damage. Mice (wild-type Friend Virus B (FVB) and ALDH2 transgenic mice) were placed on a 4% alcohol or control diet for 12 weeks. Pro- and anti-apoptotic proteins, including p53, Omi/HtrA2, Bcl-2, Bax, X-linked inhibitor of apoptosis protein (XIAP), Akt, phosphorylated (p) Akt, the Akt downstream signalling molecule Pim and pPim, were examined using immunoblot analysis. Apoptosis and protein damage were assessed using the caspase 3 assay and protein carbonyl formation, respectively. 3. The data revealed that alcohol intake enhanced expression of p53, Omi/HtrA2, Bcl-2 and Bax without affecting XIAP expression or the Bcl-2/Bax ratio. Total Akt and pPim were downregulated in response to alcohol, whereas total Pim was upregulated in conjunction with unchanged pAkt. As a result, the pAkt : Akt and pPim : Pim ratios were elevated and reduced, respectively, in response to alcohol. All these effects that resulted from alcohol exposure were attenuated or ablated by ALDH2. 4. Collectively, the results suggest that ALDH2 may effectively ameliorate alcohol-induced hepatic apoptosis and changes in Akt as well as Pim signalling.
 ...
PMID:Overexpression of aldehyde dehydrogenase-2 attenuates chronic alcohol exposure-induced apoptosis, change in Akt and Pim signalling in liver. 1921 30

Inhibitors of cyclin-dependent kinases (Cdks) have been reported to have activities in chronic lymphocytic leukemia cells by inhibiting Cdk7 and Cdk9, which control transcription. Here we studied the novel Cdk inhibitor SNS-032, which exhibits potent and selective inhibitory activity against Cdk2, Cdk7, and Cdk9. We hypothesized that transient inhibition of transcription by SNS-032 would decrease antiapoptotic proteins, resulting in cell death. SNS-032 effectively killed chronic lymphocytic leukemia cells in vitro regardless of prognostic indicators and treatment history. This was associated with inhibition of phosphorylation of RNA polymerase II and inhibition of RNA synthesis. Consistent with the intrinsic turnover rates of their transcripts and proteins, antiapoptotic proteins, such as Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), were rapidly reduced on exposure to SNS-032, whereas Bcl-2 protein was not affected. The initial decrease of Mcl-1 protein was the result of transcriptional inhibition rather than cleavage by caspase. Compared with flavopiridol and roscovitine, SNS-032 was more potent, both in inhibition of RNA synthesis and at induction of apoptosis. SNS-032 activity was readily reversible; removal of SNS-032 reactivated RNA polymerase II, which led to resynthesis of Mcl-1 and cell survival. Thus, these data support the clinical development of SNS-032 in diseases that require short-lived oncoproteins for survival.
 ...
PMID:Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. 1923 40

Chronic intake of alcohol results in multiple organ damage including brain. This study was designed to examine the impact of facilitated acetaldehyde breakdown via transgenic overexpression of mitochondrial aldehyde dehydrogenase-2 (ALDH2) on alcohol-induced cerebral cortical injury. ALDH2 transgenic mice were produced using the chicken beta-actin promoter. Wild-type FVB and ALDH2 mice were placed on a 4% alcohol or control diet for 12 weeks. Protein damage and apoptosis were evaluated with carbonyl formation, caspase and TUNEL assays. Western blot was performed to examine expression (or its activation) of ALDH2, the pro- and anti-apoptotic proteins caspase-8, Bax, Bcl-2, Omi/HtrA2, apoptosis repressor with caspase recruitment domain (ARC), FLICE-like inhibitory protein (FLIP), X-linked inhibitor of apoptosis protein (XIAP), Akt, glycogen synthase kinase-3beta (GSK-3beta), p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Chronic alcohol intake led to elevated apoptosis in the absence of overt protein damage, the effect of which was ablated by the overexpression of ALDH2 transgene. Consistently, ALDH2 transgene significantly attenuated alcohol-induced upregulation of Bax, Omi/HtrA2 and XIAP as well as downregulation of Bcl-2 and ARC without affecting alcohol-induced increase of FLIP in cerebral cortex. Phosphorylation of Akt and GSK-3beta was dampened while total/phosphorylated JNK and p38 phosphorylation were elevated following chronic alcohol intake, the effects of which were abrogated by ALDH2 transgene. Expression of total Akt, GSK-3beta, p38 and ERK (total or phosphorylated) was not affected by either chronic alcohol intake or ALDH2 transgene. Our results suggested that transgenic overexpression of ALDH2 rescues chronic alcoholism-elicited cerebral injury possibly via a mechanism associated with Akt, GSK-3beta, p38 and JNK signaling.
 ...
PMID:Aldehyde dehydrogenase-2 transgene ameliorates chronic alcohol ingestion-induced apoptosis in cerebral cortex. 1942 58

Activation of executioner caspases during receptor-mediated apoptosis in type II cells requires the engagement of the mitochondrial apoptotic pathway. Although it is well established that recruitment of mitochondria in this context involves the cleavage of Bid to truncated Bid (tBid), the precise post-mitochondrial signaling responsible for executioner caspase activation is controversial. Here, we used distinct clones of type II Jurkat T-lymphocytes in which the mitochondrial apoptotic pathway had been inhibited to investigate the molecular requirements necessary for Fas-induced apoptosis. Cells overexpressing either Bcl-2 or Bcl-x(L) were protected from apoptosis induced by agonistic anti-Fas antibody. By comparison, Apaf-1-deficient Jurkat cells were sensitive to anti-Fas, exhibiting Bid cleavage, Bak activation, the release of cytochrome c and Smac, and activation of executioner caspase-3. Inhibiting downstream caspase activation with the pharmacological inhibitor Z-DEVD-fmk or by expressing the BIR1/BIR2 domains of X-linked inhibitor of apoptosis protein (XIAP) decreased all anti-Fas-induced apoptotic changes. Additionally, pretreatment of Bcl-x(L)-overexpressing cells with a Smac mimetic sensitized these cells to Fas-induced apoptosis. Combined, our findings strongly suggest that Fas-mediated activation of executioner caspases and induction of apoptosis do not depend on apoptosome-mediated caspase-9 activation in prototypical type II cells.
 ...
PMID:Caspase-9 activation by the apoptosome is not required for fas-mediated apoptosis in type II Jurkat cells. 1975 96

The purpose of the present study is to evaluate the effects of arsenic trioxide (ATO) on human acute promyelocytic leukemia NB-4 cells. Microculture tetrazolium test, bromodeoxyuridine (BrdU) cell proliferation assay, caspase 3 activity assay, cell-based nuclear factor kappa B (NF-kappaB) phosphorylation measurement by ELISA and real-time RT-PCR were employed to appraise the effects of ATO on metabolic activity, DNA synthesis, induction of programmed cell death and NF-kappaB activation. The suppressive effects of ATO on metabolic potential, cell proliferation and NF-kappaB activation were associated with induction of apoptosis in NB-4 cells. In addition, an expressive enhancement in mRNA levels of p73, cyclin-dependent kinase inhibitor 1A (p21), tumor protein 53-induced nuclear protein 1 (TP53INP1), WNK lysine deficient protein kinase 2 (WNK2) and lipocalin 2 coupled with a significant reduction in transcriptional levels of NF-kappaB inhibitor beta (IKK2), Nemo, BCL2-like 1 (BCL-X(L)), inhibitor of apoptosis protein 1 (cIAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin, Bcl-2, TIP60, ataxia telangiectasia (ATM), SHP-2 and sirtuin (SIRT1) were observed. Altogether, these issues show for the first time that ATO treatment could trammel cell growth and proliferation as well as induces apoptosis in NB-4 cells through induction of transcriptional levels of p73, TP53INP1, WNK2, lipocalin 2 as well as suppression of NF-kappaB-mediated induction of BCL-X(L), cIAP2, XIAP and survivin. Furthermore, the inductionary effects of ATO on transcriptional stimulation of p73 might be through cramping the NF-kappaB module (through suppression of p65 phosphorylation as well as transcriptional hindering of IKK2, ATM and Nemo) along with diminishing the mRNA expression of TIP60, SHP-2 and SIRT1.
 ...
PMID:Arsenic trioxide induces apoptosis in NB-4, an acute promyelocytic leukemia cell line, through up-regulation of p73 via suppression of nuclear factor kappa B-mediated inhibition of p73 transcription and prevention of NF-kappaB-mediated induction of XIAP, cIAP2, BCL-XL and survivin. 1976 17

1. Cardiotoxin (CTX) III, a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has potential anticancer therapeutic activity. The aim of the present study was to investigate the apoptotic effect (and the underlying mechanism of action) of CTX III in human adenocarcinoma A549 cells. 2. It was found that CTX III induces apoptosis in A549 cells, as indicated by an increase in the sub-G(1) population, phosphatidylserine externalization, loss of mitochondrial membrane potential (Psi(m)) with cytochrome c release and activation of caspases 9 and 3. These actions were correlated with upregulation of Bax and Bad and downregulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), Mcl-1, X-linked inhibitor of apoptosis protein (XIAP) and p-Bad in CTX III-treated cells. 3. The signal transduction pathways involved in the effects of CTX III in A549 cells were evaluated using 5 micromol/L AG1478, an inhibitor of the epidermal growth factor receptor (EGFR), and exposing cells to the drug for 8 h. The results indicated that CTX III suppresses phosphorylation of EGFR and activation of phosphatidylinositol 3-kinase (PI3-K)/Akt and Janus tyrosine kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, all of which are downstream molecules in the EGFR signalling pathway. 4. Exposure of cells for 8 h to the PI3-K inhibitor wortmannin (10 micromol/L) blocked JAK2 and STAT3 activation, whereas exposure of cells to the JAK2 inhibitor AG490 (5 micromol/L) decreased levels of phosphorylated (p-) JAK2 and p-STAT3 without affecting PI3-K/Akt activation. These observations suggest that PI3-K is an upstream activator of JAK2/STAT3. Furthermore, 5 micromol/L AG490 and 10 micromol/L wortmannin treatment of A549 cells for 8 h resulted in upregulation of Bax and Bad and downregulation of Bcl-2, Bcl-X(L), XIAP and p-Bad. 5. Together, the results of the present study indicate that CTX III induces apoptosis in A549 cells by inactivating the EGFR, PI3-K/Akt and JAK2/STAT3 signalling pathways.
 ...
PMID:Concomitant inactivation of the epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt and Janus tyrosine kinase 2/signal transducer and activator of transcription 3 signalling pathways in cardiotoxin III-treated A549 cells. 2045 25


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>