cyclic-gmp and Leukemia--Myeloid--Acute

RNA helicases are involved in almost every aspect of RNA, from transcription to RNA decay. DExD/H-box helicases comprise the largest SF2 helicase superfamily, which are characterized by two conserved RecA-like domains. In recent years, an increasing number of unexpected functions of these proteins have been discovered. They play important roles not only in innate immune response but also in diseases like cancers and chronic hepatitis C. In this review, we summarize the recent literatures on one member of the SF2 superfamily, the DEAD-box protein DDX41. After bacterial or viral infection, DNA or cyclic-di-GMP is released to cells. After phosphorylation of Tyr414 by BTK kinase, DDX41 will act as a sensor to recognize the invaders, followed by induction of type I interferons (IFN). After the immune response, DDX41 is degraded by the E3 ligase TRIM21, using Lys9 and Lys115 of DDX41 as the ubiquitination sites. Besides the roles in innate immunity, DDX41 is also related to diseases. An increasing number of both inherited and acquired mutations in DDX41 gene are identified from myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML) patients. The review focuses on DDX41, as well as its homolog Abstrakt in Drosophila, which is important for survival at all stages throughout the life cycle of the fly.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Bacterial Infections; Cyclic GMP; DEAD-box RNA Helicases; Drosophila melanogaster; Drosophila Proteins; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Nuclear Proteins; Protein-Tyrosine Kinases; Virus Diseases

(-)-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors.

Topics: Apoptosis; Catechin; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Synergism; Enzyme Activation; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Nitric Oxide Synthase Type III; Oncogene Protein v-akt; Phosphodiesterase 5 Inhibitors; Primary Cell Culture; Receptors, Laminin; Signal Transduction; Sphingomyelin Phosphodiesterase

This study was performed to investigate whether measurement of cyclic GMP (cGMP), a marker for nitric oxide production, before and after allogeneic bone marrow transplantation (BMT) with total body irradiation (TBI) conditioning was of prognostic value. cGMP levels were monitored in 23 consecutive patients who received TBI as conditioning for BMT, and were compared with the outcome. cGMP became positive during the aplastic phase after BMT in 12 patients. In nine of these 12 patients, cGMP level decreased during the recovery phase. Eight of the nine patients survived, one dying after relapse. In three other patients, the cGMP level continued to increase even during the recovery phase and they died of severe complications. cGMP became positive on day 0 of BMT and during the leukocyte recovery phase after BMT in two and seven of the 23 patients, respectively. Subsequently, all patients died of severe complications. The two patients who were negative for cGMP both before and after BMT survived without complications. These results suggest that monitoring cGMP from early after BMT may be useful for predicting outcome and that it may be a useful prognostic marker.

Topics: Adolescent; Adult; Biomarkers; Blast Crisis; Bone Marrow Transplantation; Cyclic GMP; Cyclosporine; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Methotrexate; Methylprednisolone; Monitoring, Physiologic; Myelodysplastic Syndromes; Neoplasm Staging; Nitric Oxide; Prognosis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

We report an improved single-step synthesis to generate the membrane-permeant acetoxymethyl esters (AM-esters) of cGMP and three cGMP-analogues. These bioactivatable compounds were found to induce cell death in rat IPC-81 cells, a model system for acute myelocytic leukemia, in micromolar doses, while the corresponding non-modified cGMP-analogues were inactive.

Topics: Animals; Antineoplastic Agents; Biotransformation; Cell Death; Cell Line; Cell Membrane Permeability; Cyclic GMP; Humans; Leukemia, Experimental; Leukemia, Myeloid, Acute; Rats; Structure-Activity Relationship; Tumor Cells, Cultured

ML-1 cell proliferation is dependent on the presence of serum growth factors. Removing serum from the culture medium results in growth arrest and promotes differentiation. In this study, we found that a 4-aminopyridine-sensitive K+ channel was highly expressed in proliferating ML-1 cells and significantly diminished in G1-arrested ML-1 cells induced by serum deprivation but was restored within 30 min in these cells with addition of 10% fetal bovine serum (FBS) or 5 ng/ml epidermal growth factor (EGF). Intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, but not guanosine 3',5'-cyclic monophosphate, were significantly increased in serum-deprived cells stimulated by FBS or EGF, and the effects of FBS and EGF on the channel activation were mimicked by exogenous cAMP. In inside-out patches, K+ channel activity was significantly increased by the cAMP-dependent protein kinase catalytic subunit, whereas the effect of EGF on K+ channel activation was blocked by Rp-8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphothioate. Together, our results demonstrate that serum growth factors stimulate K+ channel activity in proliferation of ML-1 cells through protein kinase-induced phosphorylation and suggest an important molecular mechanism for serum growth factor-stimulated mitogenesis in ML-1 cells.

Topics: 4-Aminopyridine; Animals; Barium Compounds; Blood; Cattle; Cell Cycle; Cell Division; Chlorides; Culture Media, Serum-Free; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Epidermal Growth Factor; G1 Phase; Growth Substances; Humans; Kinetics; Leukemia, Myeloid, Acute; Membrane Potentials; Patch-Clamp Techniques; Potassium; Potassium Channels; Quinine; Tetraethylammonium; Thionucleotides; Tumor Cells, Cultured

To verify the clinical usefulness of extracellular cyclic nucleotide determinations as tumour markers in preneoplastic syndromes, plasma cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were monitored in 47 patients with refractory anaemia with excess of blasts (35 RAEB and 12 RAEBt), 20 of whom progressed to acute leukaemia during the observation period. The control group consisted of 45 healthy subjects matched for age and sex. In all groups of patients plasma cAMP levels were within the normal range, whereas plasma cGMP levels were significantly higher than those of normal subjects in both RAEB and RAEBt patients, and increased further when progression to acute leukaemia occurred. These data suggest that serial determinations of plasma cGMP may be useful to monitor the progression of the disease, though there is no evidence that cGMP values at diagnosis may have a prognostic significance.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory, with Excess of Blasts; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Preleukemia

Topics: Cells, Cultured; Cyclic AMP; Cyclic GMP; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocytes; Prostaglandins E

Topics: Adult; Aged; Cells, Cultured; Cyclic AMP; Cyclic GMP; Folic Acid; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocytes; Middle Aged; Prostaglandins E; Sialic Acids; Vitamin B 12

Because recent observations indicate that metabolism of cyclic nucleotides may be altered in neoplastic cells, the intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) were measured in mononuclear leukaemic and normal human leucocytes. The activities of adenylate cyclase, guanylate cyclase and cyclic nucleotide phosphodiesterases were also determined. Under basal conditions, cAMP levels were always higher in the normal leucocytes, whilst cGMP levels were of the same order of magnitude in both normal and leukaemic cells, causing the cAMP/cGMP ratios to be significantly lower in leukaemic leucocytes. Leukaemic cells significantly increased cyclic nucleotide levels in response to theophylline, but did not respond to serotonin, carbamylcholine or D,L-isoproterenol. Preincubation of these leucocytes with theophylline produced a detectable cAMP response to D,L-isoproterenol but no cGMP response to serotonin or carbamylcholine was found. Adenylate cyclase and guanylate cyclase were significantly lower in leukaemic than in normal cells, which could largely explain the abnormal cyclic nucleotide pattern found in human leukaemic leucocytes. In our experiments, cAMP phosphodiesterase activity was comparable in normal and leukaemic cells, whereas cGMP phosphodiesterase activity was undetectable inall mononuclear-leucocyte preparations with the methods used.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenylyl Cyclases; Carbachol; Cyclic AMP; Cyclic GMP; Guanylate Cyclase; Humans; Isoproterenol; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukocytes; Serotonin; Theophylline

Plasma and 24-h urinary adenosine 3':5'-monophosphate (cyclic AMP) and guanosine 3':5'-monophosphate (cyclic GMP) were measured by radioimmunoassay in 12 normal subjects, 33 patients with six types of non-neoplastic disease (cholelithiasis, peptic ulcer, coronary heart disease, hypertension, regional ileitis, and cirrhosis), and 34 patients with five types of disseminated neoplastic disease (acute myelocytic leukemia; Hodgkin's disease; and metastatic cancer of the lung, colon, and breast). In patients with non-neoplastic disease, cyclic nucleotide values in plasma and urine did not differ significantly (P greater than 0.05) from those in normal subjects. In patients with disseminated cancer, cyclic AMP values in plasma and urine likewise did not differ significantly from those in normal subjects. Plasma cyclic GMP, in contrast, was significantly elevated in all five types of cancer patients, and urinary cyclic GMP was significantly elevated (five times the normal mean) in patients with acute myelogenous leukemia and Hodgkin's disease.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Hodgkin Disease; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Metastasis; Neoplasms