guanosine-monophosphate and Neoplasms

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self-DNA in the cytoplasm. Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein stimulator of interferon genes (STING), which then activates the kinases IKK and TBK1 to induce the secretion of interferons and other cytokines. Recently, a series of studies demonstrated that the cGAS-STING pathway, a vital component of host innate immunity, might play an important role in anticancer immunity, though its mechanism remains to be elucidated. In this review, we highlight the latest understanding of the cGAS-STING pathway in tumor development and the advances in combination therapy of STING agonists and immunotherapy.

Topics: Cyclic GMP; DNA; Guanosine Monophosphate; Humans; Immunotherapy; Interferons; Membrane Proteins; Neoplasms; Nucleotidyltransferases

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Guanosine Monophosphate; Humans; IMP Dehydrogenase; Neoplasms; Ribavirin; Signal Transduction

Magnesium deficiency causes renal complications. The appearance of several diseases is related to its depletion in the human body. In radiotherapy, as well as in chemotherapy, especially in treatment of cancers with cis-platinum, hypomagnesaemia is observed. The site effects of chemotherapy that are due to hypomagnesaemia are decreased using Mg supplements. The role of magnesium in DNA stabilization is concentration dependent. At high concentrations there is an accumulation of Mg binding, which induces conformational changes leading to Z-DNA, while at low concentration there is deficiency and destabilization of DNA. The biological and clinical consequences of abnormal concentrations are DNA cleavage leading to diseases and cancer. Carcinogenesis and cell growth are also magnesium-ion concentration dependent. Several reports point out that the interaction of magnesium in the presence of other metal ions showed that there is synergism with Li and Mn, but there is magnesium antagonism in DNA binding with the essential metal ions in the order: Zn>Mg>Ca. In the case of toxic metals such as Cd, Ga and Ni there is also antagonism for DNA binding. It was found from radiolysis of deaerated aqueous solutions of the nucleoside 5'-guanosine monophosphate (5'-GMP) in the presence as well as in the absence of magnesium ions that, although the addition of hydroxyl radicals (*OH) has been increased by 2-fold, the opening of the imidazole ring of the guanine base was prevented. This effect was due to the binding of Mg2+ ions to N7 site of the molecule by stabilizing the five-member ring imitating cis-platinum. It was also observed using Fourier Transform Infrared spectroscopy, Raman spectroscopy and Fast Atom Bombardment mass spectrometry that *OH radicals subtract H atoms from the C1', C4' and C5' sites of the nucleotide. Irradiation of 5'-GMP in the presence of oxygen (2.5 x 10(-4) M) shows that magnesium is released from the complex. There is spectroscopic evidence that superoxide anions (O2-*) react with magnesium ions leading to magnesium release from the complex. From radiolysis data it was suggested that magnesium ions can act as radiosensitizers in the absence of oxygen, while in the presence of oxygen they act as protectors and stabilizers of DNA.

Topics: Animals; Cations, Divalent; DNA; DNA Damage; DNA Repair; Guanine; Guanosine Monophosphate; Humans; Hydrogen Bonding; Hydroxyl Radical; Immunologic Deficiency Syndromes; Magnesium; Magnesium Deficiency; Neoplasms; Nucleic Acid Conformation; Oxidative Stress; Radiation Injuries; Radiation Tolerance; Radiotherapy; Rats; Superoxides; Whole-Body Irradiation

Intensified adenosine triphosphate (ATP) degradation following therapeutic hyperthermia is often observed in solid tumors. As a result, accumulation of purine catabolites can be expected together with formation of protons at several stages during degradation to the final product, uric acid. Proton formation in turn can contribute to the development of heat-induced acidosis. Furthermore, oxidation of hypoxanthine and xanthine may result in generation of reactive oxygen species, which may lead to DNA damage, lipid peroxidation and protein denaturation, thus also contributing to heat-induced cytotoxicity. In hyperthermia experiments a tumor-size-dependent, significant increase in the levels of the following catabolites has been demonstrated: [symbol: see text] [IMP + GMP] (sum of guanosine and inosine monophosphate levels), inosine, hypoxanthine, xanthine and uric acid, along with a drop in ATP and guanosine triphosphate (GTP) levels. These data suggest that formation of reactive oxygen species and protons during purine degradation may indeed play a significant role in the antitumor effect of hyperthermia.

Topics: Adenosine Triphosphate; Animals; Guanosine Monophosphate; Guanosine Triphosphate; Humans; Hyperthermia, Induced; Inosine Monophosphate; Models, Biological; Neoplasms; Neoplasms, Experimental; Purines; Ribonucleotides

Topics: Adenosine Monophosphate; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Deoxyribonucleotides; Gene Expression Regulation; Gluconeogenesis; Guanosine Monophosphate; Humans; Inosine Monophosphate; Isoxazoles; Kidney Neoplasms; Liver Neoplasms; Liver Regeneration; Models, Biological; Neoplasms; Purines; Pyrimidines; Ribonucleotides

A dinuclear platinum(II) complex that was recently investigated in our group was tested for its cytostatic activity and found to be active against HeLa S3 cells. The complex consists of a bidentate N,N-donor chelating ligand system in which the two platinum centers are connected by an aliphatic chain of 10 methylene groups. The complex [Pt(2)(N(1),N(10)-bis(2-pyridylmethyl)-1,10-decanediamine)(OH(2))(4)](4+) (10NNpy) is of further special interest, since only little is known about the substitution behavior of such dinuclear platinum complexes that contain a bidentate coordination sphere. The complex was investigated using different biologically relevant nucleophiles, such as thiourea (tu), L-methionine (L-Met), glutathione (GSH), and guanine-5'-monophosphate (5'-GMP), at two different pH values (2 and 7.4). The substitution of coordinated water by these nucleophiles was studied under pseudo-first-order conditions as a function of nucleophile concentration, temperature, and pressure, using stopped-flow techniques and UV-vis spectroscopy. The reactivity of 10NNpy with the selected nucleophiles was found to be tu ≫ 5'-GMP > L-Met > GSH at pH 2 and GSH > tu > L-Met at pH 7.4. The results for the dinuclear 10NNpy complex were compared to those for the corresponding mononuclear reference complex [Pt(aminomethylpyridine)(OH(2))(2)](2+), Pt(amp), studied before in our group, by which the effect of the addition of an aliphatic chain, an increase in the overall charge, and a shift in the pK(a) values of the coordinated water ligands could be investigated. The reactivity order for Pt(amp) was found to be tu > GSH > L-Met at pH 7.4.

Topics: Antineoplastic Agents; Chelating Agents; Cytostatic Agents; Glutathione; Guanosine Monophosphate; HeLa Cells; Humans; Methionine; Neoplasms; Organoplatinum Compounds; Thiourea

The new heterobimetallic Cu(II)-Sn(2)(IV)/Ni(II)-Sn(2)(IV) complexes 1 and 2 bearing bioactive pharmacophore ligand scaffold; 1,10-phenanthroline and ethylenediamine were synthesized and characterized by spectroscopic (IR, UV-vis, NMR, ESI-MS) and analytical methods. The in vitro DNA binding studies of 1 and 2 with CT-DNA were carried out by employing various biophysical methods which reveal strong electrostatic binding via phosphate backbone of DNA helix, in addition to partial intercalation in the minor groove and stabilized by intramolecular hydrogen bonding. To gain further insight into the molecular recognition at the target site, UV-vis titrations of 1 with 5'-GMP was carried out and validated by (1)H and (31)P NMR. Complex 1 cleaved pBR322 DNA via oxidative pathway and exhibited high inhibition activity against Topo-I at 20 μM. Furthermore, the cytotoxicity of 1 was examined on a panel of human tumor cell lines of different histological origins showing promising antitumor activity.

Topics: Antineoplastic Agents; Base Sequence; Cell Line, Tumor; Copper; DNA; DNA Cleavage; DNA Topoisomerases, Type I; Ethidium; Guanosine Monophosphate; Humans; Molecular Docking Simulation; Neoplasms; Nucleic Acid Conformation; Organometallic Compounds; Protein Conformation; Reactive Oxygen Species; Tin; Topoisomerase I Inhibitors; Viscosity

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Guanosine Monophosphate; Homeostasis; Humans; Neoplasms; Ribavirin

Methyl 2,3-O-isopropylidene-D-ribofuranoside (1) was converted to 1-O-acetyl-5-bromo-5-deoxy-2,3-di-O-benzoyl-D-ribofuranose (6) in five steps with good yield. The Arbuzov condensation of compound 6 with triethyl phosphite resulted in the synthesis of 1-O-acetyl-2,3-di-O-benzoyl-5-deoxy-5-(diethoxyphosphinyl)-D-ribofuranos e (7). Compound 7 was used for direct glycosylation of both purine and pyrimidine bases. The glycosylation was accomplished with the dry silylated heterocyclic base in the presence of trimethylsilyl triflate. Deblocking of the glycosylation products gave exclusively the beta anomer of the 5'-phosphonate analogues of 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]adenine (13), 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]guanosin e (16), 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]hypoxant hine (17), and 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]cytosine (15), described here for the first time. The target compounds as well as their intermediates showed no in vitro antiviral or antitumor activity, although phosphorylation of 15 and 16 to di- and triphosphate analogues was demonstrated with use of isolated cellular enzymes.

Topics: Adenosine Monophosphate; Animals; Chemical Phenomena; Chemistry; Colonic Neoplasms; Cytidine Monophosphate; Cytosine Nucleotides; Guanine Nucleotides; Guanosine Monophosphate; Humans; Inosine Monophosphate; Inosine Nucleotides; Leukemia; Leukemia L1210; Magnetic Resonance Spectroscopy; Mice; Molecular Structure; Neoplasms; Phosphorylation; Spectrophotometry, Ultraviolet; Structure-Activity Relationship; Tumor Cells, Cultured; Viruses

Topics: Animals; Antineoplastic Agents; Azaguanine; Guanine; Guanosine Monophosphate; Lymphoma; Mice; Neoplasms; Rats