Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we show that all-trans retinoic acid (ATRA) treatment leads to a rapid decrease in telomerase activity, which was associated with the reduction in myeloblasts and occurs before the appearance of myelocytes, in a patient with acute promyelocytic leukemia (APL). Microarray analysis by ATRA treatment for 48 hr in peripheral blood mononuclear cells (in vivo) and in cultured bone marrow mononuclear cells (in vitro) from a patient with APL revealed upregulation of CD11b, CD11c, CCAAT enhancer binding protein epsilon, Rb1, Mad, and tumor necrosis factor-related genes; and downregulation of hTERT, c-Myc, WT1, bcl-2, and eukaryotic translation elongation factor 1alpha2. The results might offer the potential to define the molecular mechanism underlying ATRA-induced granulocytic differentiation in patients with APL, and provide clues to identify novel molecular therapeutic targets.
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PMID:Analysis of telomerase activity and RNA expression in a patient with acute promyelocytic leukemia treated with all-trans retinoic acid. 1577 Jun 38

Proliferation and cell death are regarded as key targets for the optimization of animal cell culture processes and for the maximization of product yield. Although chemical and physical factors are vitally important, of primary interest is the utilization of genetic engineering to regulate cellular processes. CHO cells were first genetically modified to enhance proliferation rate in both suspension and monolayer cultures. Under the constitutive control of c-myc overexpression the CHO cultures showed an increase in growth rate and maximum cell number accompanied by a similar decrease in specific glucose consumption rate. Although the c-myc transfected cell line exhibited apoptosis at much lower rates than is widely reported and associated with the overexpression of c-Myc, it was nevertheless apparent that c-Myc was responsible for the induction of higher apoptotic rates when compared with the control cell line. Hence, the anti-apoptotic gene bcl-2 was also used to transfect the c-Myc CHO cell line, to reduce cell death. Overexpression of both oncoproteins resulted in a cell line that exhibited higher proliferation rates and maximum cell numbers, with a decrease in apoptosis when compared to the parental cell line. In conclusion, it was shown that Bcl-2 protein overexpression specifically abrogates c-Myc-induced apoptosis without affecting the c-Myc mitogenic function.
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PMID:Regulation of cell proliferation and apoptosis in CHO-K1 cells by the coexpression of c-Myc and Bcl-2. 1593 41

Treatment of adult Philadelphia chromosome-positive lymphocytic leukemia is rarely successful. We report here the effects of TZD18, a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) on Ph(+) lymphocytic leukemia cell lines BV173, SD1, and SupB-15. Exposure of these cells to TZD18 resulted in growth inhibition in a dose- and time-dependent manner that was associated with G(1) cell cycle arrest. This effect was much stronger than that mediated by the PPARgamma ligand pioglitazone (PGZ), which also belongs to the thiazolidinediones (TZD) class of ligands. However, it may not be mediated through PPARgamma or PPARalpha activation because antagonists of PPARgamma and PPARalpha cannot reverse it. Study of the key regulators of cell cycle progression by Western blot analysis showed that the expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1), but not that of p21(cip1), was enhanced, whereas that of c-Myc, cyclin E, cyclin D2, and cyclin-dependent kinases 2 and 4 (CDK-2 and CDK-4) was decreased when these cells were treated with TZD18 (10 or 20 microM). Therefore, the up-regulation of p27(kip1) and the down-regulation of CDK-2 and CDK-4 may, at least in part, account for the G(1) cell cycle arrest. Furthermore, a remarkable induction of apoptosis was observed in the cells treated with this dual ligand. No obvious alteration of bcl-2 protein level occurred, but bax was up-regulated in these TZD18-treated cells. Activation of caspase 8 and caspase 9 by TZD18 was also observed. Importantly, NF-kappaB DNA-binding activity was markedly decreased by the TZD18 treatment. In addition, TZD18 enhanced the growth inhibitory effect of imatinib, a specific tyrosine kinase inhibitor therapeutically used in the treatment of Ph(+) leukemia. Overall, our findings strongly suggest that TZD18 may offer a new therapeutic approach to aid in the treatment of Ph(+) lymphocytic leukemia.
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PMID:Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARalpha/gamma ligand TZD18. 1640 7

The study was aimed to investigate the effects of emodin on the proliferation and apoptosis of adriamycin-resistant HL-60/ADR cells, and to explore the underlying mechanism. The cell viability and colony formation were detected by MTT assay and colony formation assay respectively. Apoptotic cells were tested by means of cell cycle analysis, mitochondrial transmembrane potential levels, caspase-3 activity detection, Annexin V FITC/PI staining and TUNEL labeling. RT-PCR was used to analyze the bcl-2 and c-myc mRNA expressions. The protein expressions of Bcl-2, c-Myc and caspase-3 precursor were determined by Western blot. The results showed that HL-60/ADR cell growth was significantly inhibited by emodin in dose and time dependent manners. Cell colony formation obviously decreased with IC50 5.79 micromol/L. G0/G1 phase cell population increased while G2/M phase cells decreased in 40 and 80 micromol/L groups compared with control group (p < 0.01), and no significant difference of cell cycle was observed in 20 micromol/L group (p > 0.05). The typical hypo-diploid peak (apoptotic peak) appeared in each dose group. The levels of mitochondrial transmembrane potential of HL-60/ADR cells decreased and caspase-3 activity increased when incubated with emodin for 12 and 24 hours respectively. Apoptosis occurred in a dose-dependent manner, and its earlier and later stages were identified by Annexin-V FITC/PI staining and TUNEL labeling methods respectively. The expressions of bcl-2, c-myc mRNA and Bcl-2, c-Myc, caspase-3 precursor protein were all down-regulated in a time-dependent manner after treatment with emodin at different times. It is concluded that emodin efficiently inhibits growth and induces apoptosis on HL-60/ADR cells, which may be related with the down-regulation of mitochondrial transmembrane potential and expressions of bcl-2 and c-myc, as well as up-regulation of caspase-3 activity.
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PMID:[Inhibitory effects of emodin on drug-resistant HL-60/ADR cell proliferation and its induction of apoptosis]. 1795 69

The relevance of fish research has been rising due to the expansion of aquaculture and to the increasing use of fish as replacements for mammals in the study of human physiological and pathological issues. Fish have much smaller genomes compared to mammals, and zebrafish, fugu, medaka and spotted green puffer fish have the sequence of their genomes completed or near completion. Fish have several of the virtues of Drosophila melanogaster and Caenorhabditis elegans for apoptosis research, but offer additional advantages because they are vertebrates and have a developed immune system and apoptotic pathways similar to those of mammals. Many phenotypes in the zebrafish resemble human diseases and this fish has been increasingly used in pharmaceutical design of apoptosis modulating drugs. The roles of microRNAs, bcl-2, p53, insulin-like growth factor-binding protein-3, and cellular apoptosis susceptibility (CAS) and c-Myc genes (involved in the interaction apoptosis/cancer), and Abeta peptides, presenilin enhancer 2, cyclin-dependent kinase 5 and tau (factors with relevant roles in apoptosis-associated human neurodegenerative disorders), have also been successfully investigated in fish models. Results of research with fish that have advanced the knowledge on the participation of apoptosis in viral infections and of apoptosis and secondary necrosis in bacterial infections are also reviewed. It is expectable that the use of fish for research on apoptosis-related issues relevant for human physiology and pathology and for the design of apoptosis-modulating drugs will continue to increase.
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PMID:Fish and apoptosis: studies in disease and pharmaceutical design. 1822 Aug 28

Kinetic resistance plays a major role in the failure of chemotherapy towards many solid tumors. Kinetic resistance to cytotoxic drugs can be reproduced in vitro by growing the cells as multicellular spheroids (Multicellular Resistance) or as hyperconfluent cultures (Confluence-Dependent Resistance). Recent findings on the cell cycle regulation have permitted a better understanding why cancer cells which arrest in long quiescent phases are poorly sensitive to cell-cycle specific anticancer drugs. Two cyclin-dependent kinase inhibitors (CDKI) seem particularly involved in the cell cycle arrest at the G1 to S transition checkpoint: the p53-dependent p21(cip1) protein which is activated by DNA damage and the p27(kip1) which is a mediator of the contact inhibition signal. Cell quiescence could alter drug-induced apoptosis which is partly dependent on an active progression in the cell cycle and which is facilitated by overexpression of oncogenes such as c-Myc or cyclins. Investigations are yet necessary to determine the influence of the cell cycle on the balance between antagonizing (bcl-2, bcl-X(L)...) or stimulating (Bax, Bcl-X(S), Fas...) factors in chemotherapy-induced apoptosis. Quiescent cells could also be protected from toxic agents by an enhanced expression of stress proteins, such as HSP27 which is induced by confluence. New strategies are required to circumvent kinetic resistance of solid tumors: adequate choice of anticancer agents whose activity is not altered by quiescence (radiation, cisplatin), recruitment from G1 to S/G2 phases by cell pretreatment with alkylating drugs or attenuation of CDKI activity by specific inhibitors.
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PMID:New insights into the kinetic resistance to anticancer agents. 1900 94

We found that several major chromosomal fragile sites in human lymphomas, including the bcl-2 major breakpoint region, bcl-1 major translocation cluster, and c-Myc exon 1-intron 1 boundary, contain distinctive sequences of consecutive cytosines exhibiting a high degree of reactivity with the structure-specific chemical probe bisulfite. To assess the inherent structural variability of duplex DNA in these regions and to determine the range of structures reactive to bisulfite, we have performed bisulfite probing on genomic DNA in vitro and in situ; on duplex DNA in supercoiled and linearized plasmids; and on oligonucleotide DNA/DNA and DNA/2'-O-methyl RNA duplexes. Bisulfite is significantly more reactive at the frayed ends of DNA duplexes, which is expected given that bisulfite is an established probe of single-stranded DNA. We observed that bisulfite also distinguishes between more subtle sequence/structural differences in duplex DNA. Supercoiled plasmids are more reactive than linear DNA; and sequences containing consecutive cytosines, namely GGGCCC, are more reactive than those with alternating guanine and cytosine, namely GCGCGC. Circular dichroism and x-ray crystallography show that the GGGCCC sequence forms an intermediate B/A structure. Molecular dynamics simulations also predict an intermediate B/A structure for this sequence, and probe calculations suggest greater bisulfite accessibility of cytosine bases in the intermediate B/A structure over canonical B- or A-form DNA. Electrostatic calculations reveal that consecutive cytosine bases create electropositive patches in the major groove, predicting enhanced localization of the bisulfite anion at homo-C tracts over alternating G/C sequences. These characteristics of homo-C tracts in duplex DNA may be associated with DNA-protein interactions in vivo that predispose certain genomic regions to chromosomal fragility.
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PMID:Conformational variants of duplex DNA correlated with cytosine-rich chromosomal fragile sites. 1910 4

This study was purposed to explore the effects of baicalin on proliferation and apoptosis of adriamycin-resistant human myeloid leukemia cell line HL-60/ADR. HL-60/ADR cells were in vitro cultured and its proliferation inhibition was detected by MTT assay. The cell apoptosis was tested by Annexin V FITC/PI double staining analysis, DNA fragmentation and TUNEL labeling method. The expressions of c-myc and bcl-2 mRNA were detected by RT-PCR, and the protein expressions of C-MYC, BCL-2, caspase-3 precursor (procaspase-3), PARP and BAD were determined by Western blot. The results showed that baicalin could remarkably inhibited the HL-60/ADR cell proliferation, the cell doubling time was 48 hours, with an IC50 value of 28 micromol/L. Apoptosis occurred in dose dependent manner (20, 40, 80 micromol/L), and cell apoptosis in earlier and later stages could be detected by Annexin V FITC/PI double staining analysis, DNA fragmentation and TUNEL labeling method. The expressions of c-myc and bcl-2 mRNA in baicalin-treated cells decreased in a time-dependent manner (12, 24, 48 hours). Meanwhile, protein expressions of C-MYC, BBL-2, procaspase-3 and PARP (116 kD) were down-regulated in a time-dependent manner, while the expression of PARP (85 kD) and BAD were up-regulated. It is concluded that the baicalin efficiently induces proliferative inhibition and apoptosis in HL-60/ADR cells. All of above related genes and proteins may be involved in these processes.
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PMID:[Effects of baicalin on proliferation and apoptosis of adriamycin-resistant human leukemia HL-60/ADR cells]. 1984 Apr 49

Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that has increased in incidence over the past few decades and is incurable, usually poorly responsive to standard chemotherapy combinations, and associated with poor prognoses. Discovering new therapeutic agents with low toxicity that produce better outcomes in patients with MCL is an ongoing challenge. Recent studies showed that degrasyn, a novel small-molecule inhibitor of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway, exerts antitumor activity in lymphoid tumors by inhibiting key growth and survival signaling (JAK/STAT) pathways. In the present study, we found that treatment of both typical and blastoid-variant MCL cells with degrasyn in combination with bortezomib resulted in synergistic growth inhibition and apoptosis induction in vitro. The apoptosis in these cells was correlated with the downregulation of constitutive NF-kappaB and phosphorylated STAT3 activation, leading to the inhibition of c-Myc, cyclin D1, and bcl-2 protein expression and the upregulation of bax protein expression. In vivo, degrasyn and bortezomib interacted to synergistically prevent tumor development and prolong survival durations in a xenotransplant severe combined immunodeficient mouse model of MCL. These findings suggest that agents such as degrasyn that can pharmacologically target constitutively expressed NF-kappaB and STAT3 in MCL cells may be useful therapeutic agents for MCL when administered together with bortezomib.
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PMID:Degrasyn potentiates the antitumor effects of bortezomib in mantle cell lymphoma cells in vitro and in vivo: therapeutic implications. 2060 45

Tanshinone A is a novel derivative of phenanthrene-quinone extracted from Salvia miltiorrhiza BUNGE, a traditional herbal medicine. Cytotoxic effect of tanshinone A was observed in this study. Additionally its mechanism of promoting apoptosis was also investigated. MTT and SRB assays were applied to measure the effects of tanshinone A on the cell viability, the cell cycle distribution and cell apoptosis were measured by flow cytometry using PI staining and Annexin V/PI double staining method respectively. The changes of mitochondrial membrane potential were also detected by flow cytometry. Spectrophotometric method was used to detect the changes of caspase-3 activity. Western blotting assay was used to evaluate the expression of bcl-2, bax and c-Myc proteins. Results indicated that tanshinone A displayed a significant inhibitory effect on the growth of K562 cells in a dose- and time-dependent manner, and showed obvious minor damage to LO2 cells. Tanshinone A could arrest K562 cells in the G(0)/G(1) phase and induce apoptosis, decrease the mitochondrial transmembrane potential, decrease the expressions of bcl-2 and c-Myc proteins, increase the expression of bax protein and the activity of caspase-3. Accordingly, it was presumed that the apoptosis induction may be through the endogenous pathway. Subsequently, tanshinone A could be a promising candidate in the development of a novel antitumor agent.
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PMID:Cytotoxic effect and apoptotic mechanism of tanshinone A, a novel tanshinone derivative, on human erythroleukemic K562 cells. 2169 93


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