oxalates and Neoplasms

The hypoxia-inducible factor (HIF) family of transcription factors is responsible for coordinating the cellular response to low oxygen levels in animals. By regulating the expression of a large array of target genes during hypoxia, these proteins also direct adaptive changes in the hematopoietic, cardiovascular, and respiratory systems. They also play roles in pathological processes, including tumorogenesis. In recent years, several oxygenases have been identified as key molecular oxygen sensors within the HIF system. The HIF hydroxylases regulate the stability and transcriptional activity of the HIF-alpha subunit by catalyzing hydroxylation of specific proline and asparaginyl residues, respectively. They require oxygen and 2-oxoglutarate (2OG) as co-substrates, and depend upon non-heme ferrous iron (Fe(II)) as a cofactor. This article summarizes current understanding of the biochemistry of the HIF hydroxylases, identifies targets for their pharmacological manipulation, and discusses their potential in the therapeutic manipulation of the HIF system.

Topics: Anemia; Animals; Brain Ischemia; Enzyme Inhibitors; Gastrointestinal Diseases; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1; Iron; Iron Chelating Agents; Ketoglutaric Acids; Kidney Diseases; Mice; Myocardial Ischemia; N-substituted Glycines; Neoplasms; Oxalates; Oxygen; Procollagen-Proline Dioxygenase; Rats

Cancer is one of the main causes of death worldwide. Platinum complexes (i. e., cisplatin, carboplatin, and others) are currently heavily used for the treatment of different types of cancer, but unwanted effects occur. Ruthenium complexes have been shown to be potential promising alternatives to these metal-based drugs. In this work, we performed a structure-activity relationship (SAR) study on two small series of Ru(II) polypyridyl complexes of the type [Ru(L1)

Topics: Antineoplastic Agents; Carboplatin; Cisplatin; Coordination Complexes; Humans; Ligands; Malonates; Neoplasms; Oxalates; Platinum; Ruthenium; Structure-Activity Relationship

Topics: Acetic Acid; Antineoplastic Agents; Cardiovascular Agents; Heart Diseases; Humans; Neoplasms; Oxalates

A previous study showed that all kinds of wines or ethanol extended lifespan. Skrott et al. described the death-preventing effect of the alcohol-abuse drug disulfiram. However, this effect, perhaps mediated at least in part by overconsumption of ethanol, cannot be excluded. Carcinogenesis can be resulted from the local buildup of HCl. Similar in molecular structure to oxalate, wines or ethanol of all kinds and acetic acid extend lifespan, despite that ethanol is moderately carcinogenic. Cancer cells are likely to overproduce organic acids such as oxalate to counteract strong acids, and the insoluble calcium oxalate is stressful to cells. It is postulated that ethanol inhibits the generation of oxalate, and thus reduces cancer mortality. To confirm this hypothesis, an extensive epidemiological studies can be performed on cancer patients to show that heavy wine drinkers have lower mortality rates than control groups without the use of alcohol-abuse drugs. This experiment will illuminate the positive and negative sides of ethanol intake, and pave the way for establishing better strategies to treat cancer.

Topics: Acetic Acid; Acids; Alcohol Drinking; Alcoholism; Calcium Oxalate; Disulfiram; Ethanol; Humans; Hydrogen Bonding; Neoplasms; Oxalates; Wine

A series of new ternary palladium(II) complexes of the type [Pd(L1-4)ox]·xH2O where L=formamidine ligands and ox=oxalate, were synthesized and characterized by elemental analyses, magnetic susceptibility, UV-Vis, infrared (IR) and mass spectroscopy and thermal analysis. The spectroscopic data indicated that the formamidine ligands act as bidentate N2 donors and the oxalate as O2 ligand. The complexes (1-4) are diamagnetic and the optimization of their structures indicated that the geometry is distorted square planer with O-Pd-O and N-Pd-N bond angles ranged 82.70-83.87° and 88.21-95.02°; respectively which is acceptable for the heteroleptic complexes. The dipole moment of the complexes (13.97-18.77Debye) indicating that the complexes are more polarized than the ligands (1.93-4.96Debye). The complexes are thermally stable as shown from their relatively higher overall activation energies (441-688kJmol(-1)). The ligands and the complexes are proved to have good cytotoxicity with IC50 (μM) in the range of (0.011-0.168) against MCF-7, (0.012-0.150) against HCT-116, (0.042-0.094) against PC-3 and (0.006-0.222) against HepG-2 cell lines, which open the field for further application as antitumor compounds.

Topics: Amidines; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Coordination Complexes; Humans; Ligands; Models, Molecular; Neoplasms; Oxalates; Palladium

Circulating microRNAs (miRNAs) have emerged as candidate biomarkers of various diseases and conditions including malignancy and pregnancy. This approach requires sensitive and accurate quantitation of miRNA concentrations in body fluids. Herein we report that enzyme-based miRNA quantitation, which is currently the mainstream approach for identifying differences in miRNA abundance among samples, is skewed by endogenous serum factors that co-purify with miRNAs and anticoagulant agents used during collection. Of importance, different miRNAs were affected to varying extent among patient samples. By developing measures to overcome these interfering activities, we increased the accuracy, and improved the sensitivity of miRNA detection up to 30-fold. Overall, the present study outlines key factors that prevent accurate miRNA quantitation in body fluids and provides approaches that enable faithful quantitation of miRNA abundance in body fluids.

Topics: Anticoagulants; Biomarkers, Tumor; Cells, Cultured; DNA-Directed RNA Polymerases; Heparin Lyase; Humans; MicroRNAs; Neoplasms; Oxalates; Plasma; Real-Time Polymerase Chain Reaction; RNA Stability; Sensitivity and Specificity; Sodium Fluoride; Specimen Handling

The reactions of potassium bis(oxalato)platinate dihydrate with two molar equivalents of the potent adenine-based cyclin-dependent kinase inhibitor 2-(1-ethyl-2-hydroxyethylamino)-N6-(benzyl)-9-isopropyladenine (Roscovitine; Ros) and its benzyl-substituted analogues, i.e. 2-(1-ethyl-2-hydroxyethylamino)-N6-(2-methoxybenzyl)-9-isopropyladenine (2OMeRos), 2-(1-ethyl-2-hydroxyethylamino)-N6-(3-methoxybenzyl)-9-isopropyladenine (3OMeRos) and 2-(1-ethyl-2-hydroxyethylamino)-N6-(4-methoxybenzyl)-9-isopropyladenine (4OMeRos), were performed and the [Pt(ox)(Ros)(2)].(3/4)H(2)O (1), [Pt(ox)(2OMeRos)(2)].H(2)O (2), [Pt(ox)(3OMeRos)(2)].(1/2)H(2)O (3) and [Pt(ox)(4OMeRos)(2)].(3/4)H(2)O (4) platinum(II) oxalato complexes were obtained. The methods of the elemental analysis, IR, Raman and NMR spectroscopy, ESI + mass spectrometry, molar conductivity measurement and TG/DTA thermal analysis were performed to characterize the obtained products. The complexes 1-4 involve tetracoordinated central Pt(II) atom with one bidentate-coordinated oxalate dianion (ox) and two monodentate adenine-based molecules (nRos), thus giving the square-planar geometry around the metal centre with a PtN(2)O(2) donor set. In vitro cytotoxic activity of the complexes against ovarian carcinoma (A2780), cisplatin resistant ovarian carcinoma (A2780cis), malignant melanoma (G-361), lung carcinoma (A549), cervix epitheloid carcinoma (HeLa), breast adenocarcinoma (MCF7) and osteosarcoma (HOS) human cancer cell lines was evaluated. All the tested complexes exceeded the in vitro cytotoxicity of cisplatin and oxaliplatin against HeLa, A2780cis and, except for 2, also against HOS cancer cells. The complex 1 was also tested for its cytotoxicity in primary cultures of human hepatocytes and it was not found to be hepatotoxic up to the concentration of 50.0 microM.

Topics: Antineoplastic Agents; Cell Line; Cell Survival; Cells, Cultured; Cyclin-Dependent Kinases; Hepatocytes; Humans; Neoplasms; Organoplatinum Compounds; Oxalates; Protein Kinase Inhibitors; Purines; Roscovitine; Spectrum Analysis

Oxaliplatin displays a frequent dose-limiting neurotoxicity due to its interference with neuron voltage-gated sodium channels through one of its metabolites, oxalate, a calcium chelator. Different clinical approaches failed in neurotoxicity prevention, except calcium-magnesium infusions. We characterized oxalate outcome following oxaliplatin administration and its interference with cations and amino acids. We then looked for genetic predictive factors of oxaliplatin-induced neurotoxicity.. We first tested patients for cations and oxalate levels and did amino acid chromatograms in urine following oxaliplatin infusion. In the second stage, before treatment with FOLFOX regimen, we prospectively looked for variants in genes coding for the enzymes involved (a) in the oxalate metabolism, especially glyoxylate aminotransferase (AGXT), and (b) in the detoxification glutathione cycle, glutathione S-transferase pi, and for genes coding for membrane efflux proteins (ABCC2).. In the first 10 patients, urinary excretions of oxalate and cations increased significantly within hours following oxaliplatin infusion, accompanied by increased excretions of four amino acids (glycine, alanine, serine, and taurine) linked to oxalate metabolism. In a further 135 patients, a minor haplotype of AGXT was found significantly predictive of both acute and chronic neurotoxicity. Neither glutathione S-transferase pi nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity.. These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXT genotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.

Topics: Aged; Antineoplastic Agents; Calcium; Genotype; Glutathione Transferase; Humans; Magnesium; Middle Aged; Models, Biological; Multidrug Resistance-Associated Protein 2; Neoplasms; Neurotoxins; Organoplatinum Compounds; Oxalates; Oxaliplatin; Predictive Value of Tests; Sequence Analysis, DNA; Sodium Channels

A plasma membrane glycoprotein (P-gp) of 170 kd is over-expressed in most of the drug resistant cells. P-gp is encoded in humans by the gene mdrl and is thought to function as a broad substrate ATP-dependent drug efflux pump. P-gp is also present in many types of normal cells. A good number of chemicals inhibit or deactivate P-gp and thus reverse multidrug resistance (MDR). Most of the reported resistance modifying agents (RMAs) are effective in vitro and have adverse effect on the hosts. Hence, the development of nontoxic RMA is of immense importance in the field of cancer chemotherapy. With this end in view, a nontoxic resistance modifying agent, viz., oxalyl bis (N-phenyl) hydroxamic acid (OPHA) has been developed on the basis of the structural commonalities of the reported RMAs. We reported earlier that OPHA reverses doxorubicin resistance in vitro and also reduces glutathione and glutathione S-transferase in a non P-gp expressing cell line. In the present report, the inhibition of P-gp by the compound, OPHA in human cervical cancer cell line, HeLa, has been described by western blotting, study of immunofluorescence and enzyme linked immunofluorescence assay (ELISA). The inhibition of P-gp by OPHA is significantly higher than that of verapamil. The high IC50 values of OPHA against different cell lines indicate the non toxic nature of the compound. This work underscores the possibility of using the present hydroxamic acid derivative as the nontoxic modulator of the MDR phenotype.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzeneacetamides; Blotting, Western; Cell Line; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; HeLa Cells; Humans; Hydroxamic Acids; Neoplasms; Oxalates; Verapamil

Topics: Glucocorticoids; Humans; Hypercalcemia; Hyperthyroidism; Neoplasms; Oxalates; Phosphates; Phytic Acid; Plicamycin; Prognosis

Topics: Animals; Antineoplastic Agents; Cell Line; Culture Media; Culture Techniques; Dactinomycin; Female; Floxuridine; Glyceraldehyde; Hexoses; Hot Temperature; Leukemia L1210; Melphalan; Mice; Neoplasms; Oxalates; Sodium; Vinblastine

Topics: Blood Platelets; Citrates; Edetic Acid; Electrophoresis, Disc; Freezing; Heparin; Humans; Isoenzymes; L-Lactate Dehydrogenase; Liver Cirrhosis; Neoplasms; Osmosis; Oxalates; Polycythemia Vera; Potassium; Thrombosis; Vibration

Topics: Calcium; Calcium Oxalate; Cell Biology; Chemistry Techniques, Analytical; Crystallography; Electrons; Humans; Kidney; Kidney Diseases; Kidney Tubules; Liver Diseases; Microscopy; Microscopy, Electron; Neoplasms; Oxalates; X-Ray Diffraction

Topics: Chloroform; Clinical Enzyme Tests; Enzyme Inhibitors; Erythrocytes; Hepatitis A; Iodine; Keto Acids; L-Lactate Dehydrogenase; Liver; Myocardial Infarction; Myocardium; NAD; Neoplasms; Oxalates; Pyridines; Research; Sulfonic Acids; Zinc

Topics: Adrenal Cortex; Humans; Intestine, Large; Intestines; Neoplasms; Oxalates