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)

The differentiation and apoptosis-sensitizing effects of the Bcr-Abl-specific tyrosine kinase inhibitor CGP57148B, also known as STI-571, were determined in human Bcr-Abl-positive HL-60/Bcr-Abl and K562 cells. First, the results demonstrate that the ectopic expression of the p185 Bcr-Abl fusion protein induced hemoglobin in the acute myeloid leukemia (AML) HL-60 cells. Exposure to low-dose cytosine arabinoside (Ara-C; 10 nmol/L) increased hemoglobin levels in HL-60/Bcr-Abl and in the chronic myeloid leukemia (CML) blast crisis K562 cells, which express the p210 Bcr-Abl protein. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells were resistant to apoptosis induced by Ara-C, doxorubicin, or tumor necrosis factor-alpha (TNF-alpha), which was associated with reduced processing of caspase-8 and Bid protein and decreased cytosolic accumulation of cytochrome c (cyt c). Exposure to CGP57148B alone increased hemoglobin levels and CD11b expression and induced apoptosis of HL-60/Bcr-Abl and K562 cells. CGP57148B treatment down-regulated antiapoptotic XIAP, cIAP1, and Bcl-x(L), without affecting Bcl-2, Bax, Apaf-1, Fas (CD95), Fas ligand, Abl, and Bcr-Abl levels. CGP57148B also inhibited constitutively active Akt kinase and NFkappaB in Bcr-Abl-positive cells. Attenuation of NFkappaB activity by ectopic expression of transdominant repressor of IkappaB sensitized HL-60/Bcr-Abl and K562 cells to TNF-alpha but not to apoptosis induced by Ara-C or doxorubicin. Importantly, cotreatment with CGP57148B significantly increased Ara-C- or doxorubicin-induced apoptosis of HL-60/Bcr-Abl and K562 cells. This was associated with greater cytosolic accumulation of cyt c and PARP cleavage activity of caspase-3. These in vitro data indicate that combinations of CGP57148B and antileukemic drugs such as Ara-C may have improved in vivo efficacy against Bcr-Abl-positive acute leukemia.
 ...
PMID:CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. 1097 73

In present studies, treatment with tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL, also known as Apo-2 ligand [Apo-2L]) is shown to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following treatment of Jurkat cells with 0.25 microg/mL of Apo-2L (95.0% +/- 3.5% of apoptotic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53(wt) function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibitors of apoptosis proteins (IAP) family. Apo-2L-induced apoptosis was associated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo-2L-induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-x(L). Cotreatment with either a caspase-8 or a caspase-9 inhibitor suppressed Apo-2L-induced apoptosis. Treatment of human leukemic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, Fas, DcR1, DcR2, Fas ligand, or Apo-2L levels. Importantly, sequential treatment of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide, doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileukemic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L-induced apoptosis. (Blood. 2000;96:3900-3906)
 ...
PMID:Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells. 1109 76

The pyrimidine analogue Ara-C and the purine analogues fludarabine and cladribine (2-CdA) are essential compounds in the treatment of acute myeloid leukemia (AML). Inhibition of cell proliferation and induction of apoptosis are the major mechanisms of cytotoxic agents to cause tumor cell death. Therefore, we studied whether Ara-C in combination with the purine analogues exerts synergistic or antagonistic effects on cell proliferation, phosphatidylserine exposure and disruption of mitochondrial membrane potential (MMP) in the AML cell lines HL60 and HEL. Furthermore, effects of the combination of Ara-C with bendamustine, a new bifunctional agent with alkylating activity and a purine nucleus, was investigated. Assessment by combination index analysis showed that Ara-C combined with fludarabine or bendamustine exhibited additive to antagonistic effects on inhibition of cell proliferation, induction of apoptosis as well as on disruption of mitochondrial membrane potential, independent of a simultaneous or consecutive (purine analogues before Ara-C) incubation schedule. In contrast, the combination of Ara-C with 2-CdA exclusively yielded synergistic effects. While inducing IC50 levels of apoptosis neither the antagonistic nor the synergistic drug combinations caused a specific expression pattern of apoptosis-associated proteins such as the pro- or antiapoptotic Bcl-2 family members, executioner caspases, IAPs (inhibitor of apoptosis proteins), proapoptotic Par-4, PARP, or p53. In conclusion, we here demonstrate that the in vitro efficacy of drug combinations containing Ara-C and purine analogues depends on the purine analogue applied, whereas incubation schedules or escalating dosages do not contribute to the synergistic effects.
 ...
PMID:In AML cell lines Ara-C combined with purine analogues is able to exert synergistic as well as antagonistic effects on proliferation, apoptosis and disruption of mitochondrial membrane potential. 1269 Nov 59

Tumour necrosis factor-alpha (TNF alpha) is a cytokine that induces apoptosis in various cell systems by binding to a TNF receptor (TNFR). To study TNF alpha-induced apoptosis, we isolated and characterized a novel TNF alpha resistant variant, U937/TNF clone II-5, from human monocytic leukaemia U937 cells. The II-5 cells resist apoptosis by TNF alpha and anti-Fas antibody but not by anticancer drugs, such as VP-16 and Ara-C. Somatic cell hybridization between U937 and II-5 showed that the apoptosis resistance to TNF alpha in II-5 was genetically dominant. This dominant mutation in II-5 cells blocks TNF alpha-induced disruption of mitochondrial membrane potential and caspase-3 activation. Expression of TNFR, Fas and Bcl-2 family proteins were not changed in II-5 cells. These results suggest that the apoptosis-resistant II-5 cells could have a functional defect in apoptosis signalling from TNFR to mitochondria and caspase activation. The II-5 cells could be useful in studying the signalling linkage between TNFR and mitochondria.
 ...
PMID:Establishment of a mutant from human monocytic leukaemia U937 that exhibits a genetically dominant resistance to TNF alpha-induced apoptosis. 1464 88

Several studies document ALL cell response to survival signals from bone marrow stromal cells. The current study suggests a requirement for active Akt in ALL cells for optimal stromal cell protection during chemotherapy. ALL cells expressing dominant negative Akt were not efficiently rescued from Ara-C or etoposide-induced apoptosis by stromal cell co-culture. In addition, inhibition of ALL cell PI-3 kinase activity diminished stromal cells support of tumor cells during treatment. ALL cell lines co-cultured with bone marrow stromal cells during chemotherapy maintained higher levels of phosphorylated Akt protein and reduced PP2A activity when compared to ALL cells treated in medium alone. Chemotherapy-induced PARP and Bcl-2 cleavage was reduced in ALL cells cultured with a stromal cell layer compared to tumor cells exposed to drug in medium alone. However, interaction with stromal cells was not able to efficiently block treatment-induced PARP or Bcl-2 cleavage in leukemic cells with blunted Akt activity. These data suggest a pivotal role for Akt in mediating stromal cell regulation of ALL cell apoptosis.
 ...
PMID:Stromal cell protection of B-lineage acute lymphoblastic leukemic cells during chemotherapy requires active Akt. 1515 95

To investigate whether F951, a novel bcl-2 antisense oligodeoxynucleotide, increases the sensitivity of HL-60 cells to Ara-C, HL-60 cells were cultured with F951 in different doses alone or with F951 combined with low-dose Ara-C; the proliferation of HL-60 cells was assayed by MTT and trypan blue exclusion test; expression of Bcl-2 protein and its mRNA were measured by FACS and RT-PCR, respectively; the apoptotic cells were detected by DNA ladder and TUNEL assay. The results showed that F951 combined with low dose Ara-C revealed stronger effects in the aspects of inhibiting the HL-60 cells proliferation than in different doses of F951 alone or Ara-C alone. HL-60 cells treated with F951 + Ara-C had significantly lower trypan blue exclusion rate than that treated with Ara-C alone. The inhibition rates of HL-60 cells treated with FNS, Ara-C, F951 and F951 + Ara-C were -2.8%, 27.63%, 37.66%, 57.24%, respectively. F951 significantly down-regulated the expression of bcl-2 mRNA and protein in HL-60 cells. HL-60 cells treated with F951 + Ara-C showed more apparent DNA ladder and more apoptotic cells. It is concluded that F951 can inhibit bcl-2 gene expression and enhance the cytotoxicity of Ara-C through promoting apoptosis in HL-60 cells, hence increases the antitumor effect of Ara-C.
 ...
PMID:[A novel bcl-2 antisense oligodeoxynucleotide F951 increases sensitivity of HL-60 cells to Ara-C]. 1563 54

To study the mechanism of apoptosis of HL-60 cells induced by cytarabine (Ara-C), morphological changes of the HL-60 cells stained with Giemsa were observed by microscopy; the DNA fragments were detected by agarose gel electrophoresis; the expressions of Bcl-2 and bax gene-related apoptosis were investigated by immunohistochemistry. The results showed that HL-60 cells in experimental groups had changed in morphology since they were cultured for 8 hours. HL-60 cells stained with Giemsa showed that their nuclear membranes were splitted. The purplish red chromatins were concentrated into pieces and apoptosis bodies were formed. The apoptosis rate increased in the experimental groups compared with the control group. The expression of Bcl-2 protein was lower and the expression of Bax protein was higher and the ratio of Bcl-2/Bax proteins in the experimental groups was lower than those in the control group. It is concluded that Ara-c can effectively induce apoptosis of HL-60 cells and simultaneously decrease the level of expression of Bcl-2 protein and elevate the level of expression of Bax protein. Decrease of expression ratio of Bcl-2/Bax proteins may be one of the main mechanisms in HL-60 apoptosis induced by Ara-C.
 ...
PMID:[Study on mechanism of apoptosis of HL-60 cells induced by cytarabine]. 1612 37

The study was aimed to explore the role of gene JWA, a novel retinoic acid responsible and cytoskeleton associate gene, in regulating committed differentiation of HL-60 cell and the molecular mechanism in the course of differentiation and apoptosis of leukemic cells. By using FCM, the changes of CD13, CD14, CD15, CD11b and cell cycles were detected in HL-60 cells treated with ATRA (10(-6) mol/L), Ara-C (10 ng/ml) and TPA (10(-8) mol/L) respectively. The samples were determined by semi-quantitative reverse transcript-polymerase chain reaction (RT-PCR) and Western blot for the expression of JWA, Bcl-2, HSP27 and HSP70 at day 0, 2, 4, 6, 8. The results showed that HL-60 cells committedly differentiated into granulocyte-, monocyte-, macrophage-like cells. As a result, JWA was up-regulated in a time-dependent manner, while Bcl-2 was down- regulated at the same time. In ATRA and TPA group, the change of HSP70 had positive correlation with JWA, and negative correlation with Bcl-2. The expression of HSP27 was not detected. Contrast to the cells from APL patient, the expression of JWA need not be activated by ATRA in advance. In this study, we also exposed HL-60 cells in higher dose of Ara-C (20 ng/ml), and JWA expression underwent opposite trend comparing with in lower dose of Ara-C (10 ng/ml). It is concluded that JWA may play double important roles in regulating ATRA and TPA-induced differentiation and apoptosis in leukemic cells. The JWA expression had a negative correlation between induction and cytotoxic response. The difference of JWA expressions between HL-60 cell and ANLL patient cells would be involved in different leukemia pathogenesis.
 ...
PMID:[JWA gene in regulating committed differentiation of HL-60 cells induced by ATRA, Ara-C and TPA]. 1627 46

The aim was to study the mechanisms of HL-60 cell apoptosis induced by nimodipine (NMDP) and cytarabine (Ara-C). The DNA fragment was detected by agarose gel electrophoresis. The expressions of bcl-2 and bax gene proteins related with apoptosis were investigated by immunohistochemistry. The results showed that HL-60 cell apoptosis rate had been increasing in the experimental groups compared with the control group since culturing 8 hours. The expression of Bcl-2 protein was lower and the expression of Bax protein was higher in the experimental groups than that in the control group, while ratio of bcl-2/bax was lower in the experimental groups than that in the control group. It is concluded that NMDP and Ara-C induce apoptosis of HL-60 cells, and the mechanism of apoptosis induced by them may down-regulate the expression of bcl-2 gene and up-regulate the expression of bax gene. The mechanism of HL-60 cell apoptosis induced by Ara-C and NMDP is probably associated with the down-regulation of Bcl-2 protein expression.
 ...
PMID:[Effect of nimodipine on mechanisms of HL-60 cell apoptosis induced by cytarabine]. 1749 May 25

Cytosine arabinoside (1-beta-D-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite used to induce remission in acute leukemia, but cellular resistance to Ara-C reflects a poor prognosis in cancer chemotherapy. To further investigate the mechanisms of resistance to Ara-C, we have established Ara-C-resistant NALM-6 cells. The activation of nuclear factor kappaB (NF-kappaB) was accompanied by the acquisition of Ara-C resistance. Telomerase activity has also increased with the acquisition of Ara-C resistance. The expression of Bid, Bax, or p53 proteins have been shown to increase correlated with the acquisition of Ara-C resistance. In contrast to the increase in these proteins, Bcl-2, Bcl-x, and Bag-1 proteins remained unchanged with the acquisition of Ara-C resistance. Fas expression increased with the acquisition of Ara-C resistance in the late stage. The induction of apoptosis and reduction of cell viability by cytotoxic anti-Fas antibody was more susceptible in resistant cells than parental cells. In conclusion, this report has shown that resistance to Ara-C up-regulates the activation of NF-kappaB, telomerase activity and Fas expression.
 ...
PMID:Resistance to Ara-C up-regulates the activation of NF-kappaB, telomerase activity and Fas expression in NALM-6 cells. 1797 77


<< Previous 1 2 3 Next >>