cyclic-gmp and Leukemia

While current treatment regimens for acute leukemia can dramatically improve patient survival, there remains room for improvement. Due to its roles in cell differentiation, cell survival, and apoptotic signaling, modulation of the cyclic AMP (cAMP) pathway has provided a meaningful target in hematological malignancies. Several studies have demonstrated that gene expression profiles associated with increased pro-survival cAMP activity or downregulation of various pro-apoptotic factors associated with the cAMP pathway are apparent in acute leukemia patients. Previous work to increase leukemia cell intracellular cAMP focused on the use of cAMP analogs, stimulating cAMP production via transmembrane-associated adenylyl cyclases, or decreasing cAMP degradation by inhibiting phosphodiesterase activity. However, targeting cyclic nucleotide efflux by ATP-binding cassette (ABC) transporters represents an unexplored approach for modulation of intracellular cyclic nucleotide levels. Preliminary studies have shown that inhibition of cAMP efflux can stimulate leukemia cell differentiation, cell growth arrest, and apoptosis, indicating that targeting cAMP efflux may show promise for future therapeutic development. Furthermore, inhibition of cyclic nucleotide transporter activity may also contribute multiple anticancer benefits by reducing extracellular pro-survival signaling in malignant cells. Hence, several opportunities for drug repurposing may exist for targeting cyclic nucleotide transporters.

Topics: Animals; Antineoplastic Agents; ATP-Binding Cassette Transporters; Cyclic AMP; Cyclic GMP; Drug Discovery; Drug Repositioning; Humans; Leukemia

Levels of cyclic guanosine 3',5'-monophosphate (cGMP) are elevated in plasma and urine from patients with some cardiovascular diseases and some types of cancer.. This paper is based on studies of cGMP as a biomarker.. It is well documented that cGMP levels are elevated in plasma in patients with heart failure and various leukaemias and in urine from patients with gynaecological cancers. Because of great interindividual variation in levels, cGMP is less suitable in primary diagnostics, but appears to be a sensitive marker in individual follow up in some diseases.

Topics: Biomarkers; Biomarkers, Tumor; Cardiovascular Diseases; Cyclic GMP; Female; Heart Failure; Humans; Leukemia; Male; Neoplasms

Proteasomes are highly expressed in rapidly growing neoplastic cells and essential for controlling the cell cycle process and mitochondrial homeostasis. Pharmacological inhibition of the proteasome shows a significant anticancer effect on hematopoietic malignancies that is usually associated with the generation of reactive oxygen species. In this study, we comprehensively investigated the role of endogenous oxidants in various cellular events of K562 leukemic cells in response to treatment with MG132, a proteasome inhibitor. MG132 at 1.4 µM potently triggered G2/M arrest, mitochondrial depolarization, and apoptosis. By such treatment, the protein level of inducible nitric oxide synthase (iNOS) was doubled and cellular oxidants, including nitric oxide, superoxide, and their derivatives, were increasingly produced. In MG132-treated cells, the increase in iNOS-derived oxidants was responsible for mitochondrial depolarization and caspase-dependent apoptosis, but was insignificant in G2/M arrest. The amount of iNOS was negatively correlated with that of manganese superoxide dismutase (MnSOD). Whereas iNOS activity was inhibited by aminoguanidine, cellular MnSOD levels as well as mitochondrial membrane potentials were upregulated, and consequentially G2/M arrest and apoptosis were thoroughly reversed. It is suggested that cells rich in functional mitochondria possess improved proteasome activity, which antagonizes the cytotoxic and cytostatic effects of MG132. In contrast to iNOS, endothelial NOS-driven cGMP-dependent signaling promoted mitochondrial function and survival of MG132-stressed cells. In conclusion, the functional interplay of proteasomes and mitochondria is crucial for leukemic cell growth, wherein iNOS plays a key role.

Topics: Apoptosis; Caspases; Cyclic GMP; Cysteine Proteinase Inhibitors; G2 Phase Cell Cycle Checkpoints; Humans; K562 Cells; Leukemia; Leupeptins; Membrane Potential, Mitochondrial; Mitochondria; Nitric Oxide; Nitric Oxide Synthase Type II; Proteasome Endopeptidase Complex; Signal Transduction; Superoxide Dismutase

Increases in plasma cyclic GMP levels have been shown to correlate with increased plasma levels of atrial natriuretic peptide (ANP) in patients with fluid overload due to increased secretion of ANP. There is evidence that plasma cyclic GMP levels are also elevated in some patients with acute leukemia, but increased ANP secretion has not been demonstrated. To elucidate the possibility that a newly expressed guanylyl cyclase may be responsible for the increase of plasma cyclic GMP levels patients with acute and chronic leukemia as well as patients with lymphoma and healthy volunteers were studied. Plasma levels of cyclic GMP were measured and isolated peripheral blood mononuclear or bone marrow cells were incubated with increasing concentrations of ANP. The stimulation of cells was measured as cGMP accumulation in the supernatant. Furthermore guanylyl cyclase activity was measured in membrane preparations of peripheral blood mononuclear cells. While leukocytes of healthy subjects were devoid of detectable ANP-stimulated particulate guanylyl cyclase activity, ANP-sensitivity was observed in seven patients with acute lymphoblastic and in three patients with acute myelogenous leukemia. Cyclic GMP in the supernatant of cells was elevated between 2- and 132-fold of basal when cells were incubated with 1 microM ANP for 60 minutes. Like in healthy volunteers, no effect of ANP on freshly isolated mononuclear cells was observed in cases with chronic leukemia or in patients with lymphoma. Expression of ANP-sensitive particulate gunaylyl cyclase may be connected with malignant transformation of lymphocytes in patients with acute leukemia and might be useful for their diagnosis and classification.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Bone Marrow; Child, Preschool; Cyclic GMP; Female; Guanylate Cyclase; Humans; In Vitro Techniques; Leukemia; Leukocytes, Mononuclear; Male; Middle Aged; Receptors, Atrial Natriuretic Factor

After the leukemic cell lines were treated with monoclonal antibodies (McAbs) and interferon (IFN-alpha), the changes of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the corresponding leukemic cell lines were measured by radioimmunoassay. The results showed that when the ratio of antigen to antibody was 80 to 1, the cAMP levels in the leukemic cell lines were obviously higher than those in the controls while the cGMP levels were obviously lower after being treated with the corresponding McAbs for 16-24 h (P < 0.001). The average level of intracellular cAMP was remarkably increased and that of cGMP underwent no significant changes in the leukemic cell lines after treatment with IFN-alpha.

Topics: Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Cyclic AMP; Cyclic GMP; Humans; Immunoglobulin Isotypes; Interferon-alpha; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Promyelocytic, Acute; Plasmacytoma; Tumor Cells, Cultured

To verify the clinical usefulness of extracellular cyclic nucleotide determination as a tumor marker, plasma cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were measured in 70 normal subjects and 173 acute leukemia patients studied in different stages of their disease. Mean plasma cAMP levels were similar in leukemic and normal subjects, although in 48 patients in the active stage of the disease, first diagnosis, or relapse, the cAMP values were below the normal range, and most of these patients failed to respond to chemotherapy. Plasma cGMP levels were markedly elevated in untreated patients, normalized in all patients who attained complete remission, and increased promptly to pretreatment values in patients who relapsed, suggesting that their determination may be useful to monitor the patients' response to treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia; Male; Middle Aged; Nucleotides, Cyclic

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

Level of plasma cyclic nucleotides was determined in 47 normal subjects and 63 patients with leukemia. Follow-up was carried out in 20 of these patients. The relation between the level of cyclic nucleotides and cell-mediated immunity was studied.. There was no significant difference in cyclic adenosine monophosphate (cAMP) between the normal subjects and leukemic patients, whereas cyclic guanosine monophosphate (cGMP) level was markedly elevated and cAMP/cGMP ratio was obviously reduced in the untreated and unrelieved patients. There was no significant difference in the various types of leukemia. In patients with complete remission (CR) after treatment, their cyclic nucleotides were similar to those in normal subjects, but they remained abnormal in patients without clinical remission after treatment. In CR patients treated regularly for half a year, the cGMP level when first diagnosed was lower than that of patients who died soon or were unrelieved. Plasma cGMP level was negatively correlated to E-rosette forming cell (E-RFC) and cAMP/cGMP ratio was positively correlated to E-RFC. These results suggest that the plasma cGMP be used as additional parameter to monitor the treatment response and prognosis. Reduced E-RFC in leukemia may be related to the elevated cGMP and/or lowered cAMP/cGMP ratio.

Topics: Adolescent; Adult; Cyclic AMP; Cyclic GMP; Female; Humans; Immunity, Cellular; Leukemia; Male; Middle Aged; Nucleotides, Cyclic; Prognosis; Rosette Formation

To verify the clinical usefulness of plasma cyclic nucleotide determination as a tumor marker, levels were measured in 52 normal subjects and in 106 acute leukemia patients. In untreated patients plasma cyclic GMP (cGMP) levels were markedly elevated, whereas cyclic AMP levels did not significantly differ from those of normal subjects. Plasma cGMP levels normalized in all patients who attained complete remission and remained in the normal range during all the remission period. In the patients who relapsed, an early increase in cGMP levels to the pretreatment values was observed, thus suggesting that their determination may be of clinical relevance in monitoring the patients' response to treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia; Male; Middle Aged; Monitoring, Physiologic

Topics: Acute Disease; Adult; Blood Cell Count; Bone Marrow; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Middle Aged

Topics: Adenosine Triphosphate; Adult; Blood Platelets; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia; Male; Middle Aged; Nucleotides, Cyclic; Platelet Adhesiveness; Platelet Aggregation

Plasma levels of cyclic AMP and cyclic GMP were determined in 35 guinea pigs for up to 9 days following subcutaneous passage of L2C leukemia cells. Twenty guinea pigs into which normal syngeneic guinea pig thymocytes were passaged served as controls. Cyclic AMP levels in plasma showed little change and were only elevated significantly in test animals on day 9 after passage. In contrast cyclic GMP levels reached a maximum on day 5 after passage of leukemia cells with two to threefold rises over day 1 levels. Increases in leukocyte counts were not observed until day 7 in test animals. Of the other tumour growth indices which were examined, the axillary (draining) node index gave the earliest indication of cell proliferation, with significant elevations on day 3 after passage. The authors conclude that plasma cyclic GMP increases precede increases in white cell counts by at least 2 days, and may reflect an early increase in axillary node growth.

Topics: Animals; Cyclic AMP; Cyclic GMP; Guinea Pigs; Leukemia; Leukocyte Count; Lymph Nodes; Neoplasm Transplantation; Nucleotides, Cyclic; Organ Size; Spleen; Time Factors

Plasma and urine levels of cyclic adenosine 3',5'-monophosphate (cAMP) and of cyclic guanosine 3',5'-monophosphate (cGMP) were measured in 35 normal subjects, in 24 patients with nonneoplastic diseases (iron deficiency anemia, peptic ulcer, and cholelithiasis), and in 50 leukemic patients. The leukemic group included patients with acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. All patients were recently diagnosed and untreated, except for 5 patients with blastic transformation of chronic myelogenous leukemia who had been previously treated. There were no significant differences in plasma and urine cyclic nucleotide levels between normal subjects and patients with nonneoplastic diseases. In leukemic patients, plasma and urine cAMP levels were similar to those of normal subjects, whereas plasma and urine cGMP levels were markedly elevated. There were no significant differences in cGMP values between the various types of leukemia. After starting treatment, plasma cyclic nucleotide levels were periodically measured in 21 of the patients with acute leukemia; cGMP levels were normalized in all the 16 subjects who attained complete remission, whereas both cAMP and cGMP levels were apparently unaffected in the patients who did not respond to treatment. This suggests that plasma or urine cGMP could be used as an additional parameter to monitor the patient's response to treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Anemia, Hypochromic; Cholelithiasis; Chronic Disease; Cyclic GMP; Female; Humans; Leukemia; Male; Middle Aged; Nucleotides, Cyclic; Peptic Ulcer

Cyclic GMP is thought to be involved in lymphocytic cell proliferation and leukemogenesis. In general, the nucleotide is elevated in leukemic vs. normal lymphocytes and changes have been reported to occur during remission and relapse of this disease. Although the cA/cG ratios are higher for normal lymphocytes the basal guanylate cyclase (EC 4.6.1.2) activities do not correlate with altered cyclic GMP levels. The crude guanylate cyclases display classical Michaelis-Menten kinetics with Kms for Mn-GTP of 463 mumol/l and 20-90 mumol/l for normal and leukemic lymphocytes, respectively. An extract from the bitter melon (Momordica charantia) preferentially inhibits the soluble guanylate cyclase from leukemic lymphocytes. This inhibition correlates with its preferential cytotoxic effects for these same cells. Analyses of nine other cytotoxic plant extracts revealed that only an extract from the Lawson's cypress, Chamaecyparis lawsonianna, exhibits comparable cytotoxicity and guanylate cyclase inhibition levels.

Topics: Cyclic AMP; Cyclic GMP; Guanylate Cyclase; Humans; Kinetics; Leukemia; Lymphocytes; Plant Extracts

Topics: Adolescent; Adult; Cyclic AMP; Cyclic GMP; Female; Humans; Leukemia; Leukocytes; Male; Middle Aged

Cyclic cytidine 3':5'-monophosphate (cyclic CMP), cyclic guanosine 3':5'-monophosphate (cyclic GMP), and cyclic adenosine 3':5'-monophosphate (cyclic AMP) contents of leukocytes and urines of leukemic patients have been investigated. We have studied four types of leukemia: acute myeloblastic leukemia; chronic myelocytic leukemia; acute lymphoblastic leukemia; and chronic lymphocytic leukemia. As controls, the cyclic nucleotide content of leukocytes and urines of healthy volunteers and patients with solid tumors selected for their normal hemogram has been determined. It has also been measured in phytohemagglutinin-stimulated lymphocytes. Our data show that: (a) the concentration of cyclic CMP is always lower than that of cyclic GMP or cyclic AMP; (b) in urines, the concentrations of the three nucleotides are higher in patients than in healthy volunteers, the greatest differences being observed between the cyclic CMP concentrations of acute leukemia patients and controls; and (c) in white blood cells, cyclic AMP concentration is lower in leukemic than in normal cells. The cyclic GMP concentration is the same everywhere except in monoblastic cells and leukocytes from solid tumor patients. High cyclic CMP levels are associated only with acute leukemia, whether myeloblastic, monoblastic, or lymphoblastic, a fact which suggests that cyclic CMP could be a biochemical marker of hematopoietic stem cell malignancy.

Topics: Adult; Aged; Cyclic AMP; Cyclic CMP; Cyclic GMP; Female; Humans; Leukemia; Leukocytes; Male; Middle Aged; Nucleotides, Cyclic; Radioimmunoassay

The present study shows an increased urinary cyclic guanosine 3'.5'-monophosphate (cyclic GMP) excretion rate in children of all age groups bearing malignant tumours or lymphomas. The incidence of increased cyclic GMP excretion was highly significant (79%). Follow-up studies of up to three years have revealed that during periods of remission of malignant disease the urinary cyclic GMP excretion drops to near normal values, whereas recurrences are accompanied by a new increase of cyclic GMP excretion.

Topics: Age Factors; Child; Child, Preschool; Cyclic GMP; Female; Fetus; Follow-Up Studies; Humans; Infant; Infant, Newborn; Leukemia; Lymphoma; Neoplasms; Pregnancy

Topics: Blood Cells; Bone Marrow; Bone Marrow Cells; Cyclic AMP; Cyclic GMP; Humans; Immunoenzyme Techniques; Leukemia; Leukocytes

Topics: Cyclic AMP; Cyclic GMP; Granulocytes; Humans; Leukemia; Leukocytes; Lymphocytes

Topics: Cell Line; Concanavalin A; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; Humans; Leukemia; Lymphocyte Activation; Lymphocytes; Plant Extracts

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

Cyclic adenosine 3':5'-monophosphate-dependent protein kinase (kinase A) and cyclic guanosine 3':5'-monophosphate-dependent protein kinase (kinase G) were assayed in lymphocytes of normal subjects, adults with chronic lymphocytic leukemia (CLL), and children with acute lymphocytic leukemia (ALL). There was a good correlation between the activity of the two kinases and the level of the corresponding cyclic nucleotides. This was true for cultured phytohemagglutinin-stimulated normal lymphocytes and CLL lymphocytes as well. Kinase A activity was low and kinase G activity was high in leukemic cells in the absence of the respective cyclic nucleotides [5 and 8 units (pmol 32P incorporated into histone per min per mg protein) for kinase A and 98 and 51 units for kinase G in ALL and CLL lymphocytes, respectively]. Upon addition of cyclic adenosine 3':5'-monophosphate and cyclic guanosine 3':5'-monophosphate in vitro, values for kinase A activity returned to normal (approximately 30 units), whereas those for kinase G increased further (212 units for ALL and 85 units for CLL lymphocytes; 22 units was the kinase activity for normal lymphocytes). These findings suggest that cyclic nucleotides achieve thetr specificity in the regulation of the cell, in part, through the activation of the dependent protein kinases and that both kinase A and kinase G may be functionally intact in leukemic cells.

Topics: Adult; B-Lymphocytes; Child; Cyclic AMP; Cyclic GMP; Humans; Leukemia; Leukemia, Lymphoid; Lymphocytes; Phytohemagglutinins; Protein Kinases; T-Lymphocytes; Time Factors

Extracts of leukemic lymphocytes and leukemic myelomonocytic cells bind significantly more cAMP/mg protein than do normal cells. The binding of cAMP in leukemic cells is non-specific since the binders are unable to effectively discriminate between cAMP and cGMP in contrast to normal cells. When normal lymphocytes are activated in vitro with mitogens, their cAMP-binding capacity is increased, but the binding retains the specificity of normal cells. Thus in malignantly transformed leukocytes, cAMP-binding is characterized by a high degree of non-specificity, compared with the binding in resting or proliferating normal leukocytes.

Topics: Cyclic AMP; Cyclic GMP; Humans; Leukemia; Leukocytes; Protein Binding

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Concanavalin A; Cyclic GMP; Guanylate Cyclase; Humans; Kinetics; Leukemia; Lymphocyte Activation; Lymphocytes; Plant Extracts

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Calmodulin; Cyclic GMP; Dipyridamole; In Vitro Techniques; Kinetics; Leukemia; Leukemia L1210; Lymphocytes; Mice; Mice, Inbred DBA; Phosphodiesterase Inhibitors