ascorbic-acid and Sarcoma

The creatine/creatine kinase (CK) system plays a key role in cellular energy buffering and transport. In vertebrates, CK has four isoforms expressed in a tissue-specific manner. In the process of creatine biosynthesis several other important metabolites are formed. The anticancer effect of creatine had been reported in the past, and recent literature has reported low creatine content in several types of malignant cells. Furthermore, creatine can protect cardiac mitochondria from the deleterious effects of some anticancer compounds. Previous work from our laboratory showed progressive decrease of phosphocreatine, creatine and CK upon transformation of skeletal muscle into sarcoma. It was convincingly demonstrated that prominent expression of creatine-synthesizing enzymes L-arginine: glycine amidinotransferase and N-guanidinoacetate methyltransferase occurs in sarcoma, Ehrlich ascites carcinoma and sarcoma 180 cells; whereas, both these enzymes are virtually undetectable in skeletal muscle. Creatine transporter also remained unaltered in malignant cells. The anticancer effect of methylglyoxal had been known for a long time. The present work shows that this anticancer effect of methylglyoxal is significantly augmented in presence of creatine. On creatine supplementation the effect of methylglyoxal plus ascorbic acid was further augmented and there was no visible sign of tumor. Moreover, creatine and CK, which were very low in sarcoma tissue, were significantly elevated with the concomitant regression of tumor.

Topics: Amidinotransferases; Animals; Antineoplastic Agents; Ascorbic Acid; Cell Transformation, Neoplastic; Creatine; Creatine Kinase; Guanidinoacetate N-Methyltransferase; Humans; Membrane Transport Proteins; Mice; Muscle Neoplasms; Muscle, Skeletal; Pyruvaldehyde; Sarcoma

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Carcinoma 256, Walker; Guinea Pigs; Leukemia; Neoplasms; Neoplasms, Experimental; Rats; Research; Sarcoma; Sarcoma, Experimental; Sarcoma, Yoshida

Soft tissue sarcomas are a histologically heterogeneous group of rare mesenchymal cancers for which treatment options leading to increased overall survival have not improved in over two decades. The current study shows that pharmacological ascorbate (systemic high dose vitamin C achieving ≥ 20mM plasma levels) is a potentially efficacious and easily integrable addition to current standard of care treatment strategies in preclinical models of fibrosarcoma and liposarcoma both in vitro and in vivo. Furthermore, enhanced ascorbate-mediated toxicity and DNA damage in these sarcoma models were found to be dependent upon H

Topics: Animals; Antimetabolites, Antineoplastic; Ascorbic Acid; Cell Line, Tumor; Deoxycytidine; DNA Damage; Female; Gemcitabine; Humans; Hydrogen Peroxide; Iron; Mice, Nude; Oxidation-Reduction; Radiation-Sensitizing Agents; Sarcoma

The anticancer activity of 8-hydroxyquinolines relies on complex formation with redox active copper and iron ions. Here we employ UV-visible spectrophotometry and EPR spectroscopy to compare proton dissociation and complex formation processes of the reference compound 8-hydroxyquinoline (Q-1) and three related Mannich bases to reveal possible correlations with biological activity. The studied derivatives harbor a CH2-N moiety at position 7 linked to morpholine (Q-2), piperidine (Q-3), and chlorine and fluorobenzylamino (Q-4) substituents. Solid phase structures of Q-3, Q-4·HCl·H2O, [(Cu(HQ-2)2)2]·(CH3OH)2·Cl4·(H2O)2, [Cu(Q-3)2]·Cl2 and [Cu(HQ-4)2(CH3OH)]·ZnCl4·CH3OH were characterized by single-crystal X-ray diffraction analysis. In addition, the redox properties of the copper and iron complexes were studied by cyclic voltammetry, and the direct reaction with physiologically relevant reductants (glutathione and ascorbic acid) was monitored. In vitro cytotoxicity studies conducted with the human uterine sarcoma MES-SA/Dx5 cell line reveal the significant cytotoxicity of Q-2, Q-3, and Q-4 in the sub- to low micromolar range (IC50 values 0.2-3.3 μM). Correlation analysis of the anticancer activity and the metal binding properties of the compound series indicates that, at physiological pH, weaker copper(ii) and iron(iii) binding results in elevated toxicity (e.g.Q4: pCu = 13.0, pFe = 6.8, IC50 = 0.2 μM vs.Q1: pCu = 15.1, pFe = 13.0 IC50 = 2.5 μM). Although the studied 8-hydroxyquinolines preferentially bind copper(ii) over iron(iii), the cyclic voltammetry data revealed that the more cytotoxic ligands preferentially stabilize the lower oxidation state of the metal ions. A linear relationship between the pKa (OH) and IC50 values of the studied 8-hydroxyquinolines was found. In summary, we identify Q-4 as a potent and selective anticancer candidate with significant toxicity in drug resistant cells.

Topics: Antineoplastic Agents; Ascorbic Acid; Cell Line, Tumor; Cell Survival; Coordination Complexes; Copper; Drug Resistance, Neoplasm; Female; Ferric Compounds; Glutathione; Humans; Inhibitory Concentration 50; Mannich Bases; Oxyquinoline; Sarcoma; Uterine Neoplasms

Increased oxidative stress may contribute to cancer anorexia, which could be ameliorated by antioxidant supplementation. methylcholanthrene (MCA) sarcoma-bearing Fisher rats were studied. After tumour inoculation, rats were randomly assigned to standard diet (CTR group, n = 6), or to an antioxidant-enriched diet (AOX group, n = 8). Eight more rats (STD-AOX group) switched from standard to antioxidant diet when anorexia developed. At the end of the study, food intake (FI, g/d), body weight and tumour weight (g) were recorded, and plasma samples were obtained. On day 16, anorexia has appeared only in CTR and STD-AOX animals. At the end of the study, FI in AOX animals was still higher than in the other groups (p = 0.08). No differences in body and tumour weights were observed among groups. However, hydrogen peroxide and interleukin-1β levels were significantly reduced only in AOX rats. Data obtained suggest that early antioxidant supplementation improves cancer anorexia, ameliorates oxidative stress and reduces inflammation.

Topics: Animals; Anorexia; Antioxidants; Ascorbic Acid; Body Weight; Diet; Dietary Supplements; Disease Models, Animal; Drug Administration Schedule; Energy Intake; Hydrogen Peroxide; Interleukin-1beta; Male; Methylcholanthrene; Oxidative Stress; Random Allocation; Rats, Inbred F344; Sarcoma; Vitamin E

A specific nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract has demonstrated a broad spectrum of antitumor activity against a number of cancer cell lines. In this study, our main objective was to investigate the comparative effects of NM on anticancer parameters, such as cytotoxicity, matrix metalloproteinase (MMP) secretion and Matrigel invasion in the human uterine sarcoma drug-resistant MES-SA/Dx5 and the drug-sensitive MES-SA cell lines. In addition we studied the effects of NM on P-glycoprotein (Pgp) on these cell lines. Cell proliferation was evaluated by MTT assay, MMPs by gelatinase zymography, invasion through Matrigel, morphology by H&E and Pgp expression by Western blot analysis and immunodetection using FITC-conjugated antibody and rhodamine 123 (Rh123) accumulation and efflux assays. NM exhibited antiproliferative effects on MES-SA/Dx5, by 20% at 50 and 100 µg/ml and by 36, 40 and 48% at 250, 500 and 1,000 µg/ml, respectively. By contrast, NM treatment of MES-SA cells resulted in significantly increased cytotoxicity: 40, 46, 65 and 72% at 50, 100, 500 and 1,000 µg/ml, respectively. In both cell lines, zymography demonstrated a band corresponding to MMP-2 in normal cells and MMP-9 with phorbol 12-myristate 13-acetate treatment. The two MMPs showed dose-response inhibition by NM. As shown by Western blot analysis and immunodetection, NM treatment resulted in a dose-dependent decrease in Pgp expression in the MES-SA/Dx5 cell line. The MES-SA cell line does not exhibit Pgp. NM enhanced the accumulation and efflux of the Pgp substrate, Rh123, in the MES-SA/Dx5 uterine sarcoma cell line but not in the drug-sensitive cell line, MES-SA. Therefore, it can be concluded that NM demonstrates potent anticancer effects in both the drug-resistant and sensitive cell lines and modulates Pgp, suggesting its potential therapeutic effects in drug-resistant as well as sensitive cancers.

Topics: Antineoplastic Agents; Ascorbic Acid; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Food; Humans; Lysine; Plant Extracts; Proline; Sarcoma; Tea; Uterine Neoplasms

To test the carcinostatic effects of ascorbic acid, we challenged the mice of seven experimental groups with 1.7 x 10(-4) mol high dose concentration ascorbic acid after intraperitoneal administrating them with sarcoma S-180 cells. The survival rate was increased by 20% in the group that received high dose concentration ascorbic acid, compared to the control. The highest survival rate was observed in the group in which 1.7 x 10(-4) mol ascorbic acid had been continuously injected before and after the induction of cancer cells, rather than just after the induction of cancer cells. The expression of three angiogenesis-related genes was inhibited by 0.3 times in bFGF, 7 times in VEGF and 4 times in MMP2 of the groups with higher survival rates. Biopsy Results, gene expression studies, and wound healing analysis in vivo and in vitro suggested that the carcinostatic effect induced by high dose concentration ascorbic acid occurred through inhibition of angiogenesis.

Topics: Animals; Antineoplastic Agents; Antioxidants; Ascites; Ascorbic Acid; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Drug; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Matrix Metalloproteinase 2; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; NIH 3T3 Cells; Sarcoma; Survival Rate; Vascular Endothelial Growth Factor A

The results of several experimental studies have shown that ascorbic acid inhibits tumor growth and metastasis. Ascorbic acid is an antioxidant that acts as a scavenger for a wide range of reactive oxygen species (ROS). Both tumour metastasis and cell migration have been correlated with the intracellular ROS level, so it was postulated that the inhibitory effect of ascorbic acid derivatives on cell motility may be caused by scavenging of ROS. Time-lapse analyses of Walker 256 carcinosarcoma cell migration showed that both the speed of movement and the cell displacement were inhibited by ascorbic acid applied in concentrations ranging from 10 to 250 microM. This effect correlated with a reduction in the intracellular ROS level in WC 256 cells, suggesting that ROS scavenging may be a mechanism responsible for the inhibition of WC 256 cell migration. However, another potent antioxidant, N-acetyl-L-cysteine, also efficiently decreased the intracellular ROS level in WC 256 cells, but did not affect the migration of the investigated cells. These results demonstrate that intact, unmodified ascorbic acid applied in physiologically relevant and non-toxic concentrations exerts an inhibitory effect on the migration of WC 256 carcinosarcoma cells, and that this may be one of the factors responsible for the anti-metastatic activity of vitamin C. However, our data does not support the hypothesis that the scavenging of intracellular ROS is the main mechanism in the inhibition of cancer cell migration by ascorbic acid.

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinoma 256, Walker; Cell Line, Tumor; Cell Migration Inhibition; Cell Movement; Rats; Reactive Oxygen Species; Sarcoma

A human chondrosarcoma cell line, CS-1, was treated successively with increasing concentrations of the marine chemotherapeutic Ecteinascidin-743 (ET-743), yielding a variant cell line displaying a significant degree of resistance to the cytotoxic action of this drug. Various experiments were performed to discern molecular aberrations between the parent and resistant cell line, and also identify potential molecular markers indicative of drug resistance. Although no significant differences in the levels of membrane transporters such as P-glycoprotein or multidrug resistance protein 1 (MRP1) were detected, the cell migratory ability of the ET-743-resistant cell variant was reduced, as was its attachment capability to gelatin-coated cell culture dishes. Staining of the actin-containing cytoskeleton with fluorescent-labeled phalloidin revealed marked differences in the cytoskeleton architecture between the parent and ET-743-resistant CS-1 cell lines. Comparison of serum-free conditioned medium from both cell lines showed conspicuous differences in the levels of several proteins, including a quartet of high molecular weight proteins (> or =140 kDa). The protein sequences of two of these high molecular weight proteins, present at significantly higher concentrations in conditioned medium obtained from the parent cell line, corresponded to subunits of types I and IV collagen. Analysis of type I collagen alpha1 chain mRNA revealed a significantly lower level in the ET-743-resistant CS-1 cell line. Thus, prolonged exposure to ET-743 may cause changes in cell function through cytoskeleton rearrangement and/or modulation of collagen levels.

Topics: Actins; Antineoplastic Agents, Alkylating; Ascorbic Acid; Biological Transport; Cell Adhesion; Cell Movement; Collagen; Dioxoles; Drug Resistance, Neoplasm; Humans; Isoquinolines; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Sarcoma; Tetrahydroisoquinolines; Trabectedin; Tumor Cells, Cultured

CBA female mice treated with 1,2-dimethylhydrazine (DMH) alone or in combination with oestradiol dipropionate (EP) or ascorbic acid (AA) developed, as expected, a high incidence of uterine sarcomas. In addition, sarcomatous lesions at unusual sites (mainly in the forestomach) were evident. The incidence of sarcomatous lesions at other sites was 53/220 in mice having uterine sarcomas and 0/186 in mice treated with DMH but without uterine sarcomas. The difference between the two groups was highly statistically significant (P < 0.001) and demonstrates non-coincidental association of the above sarcomatous lesions with uterine sarcomas. Uterine sarcomas which presented in association with lesions at other sites were of a larger size than those found in isolation, and the difference in weights in three out of four groups was statistically significant (P = 0.008, 0.035 and 0.011). Histologically, sarcomatous lesions were similar in structure to those of uterine sarcomas, i.e. were of a fibroblastic-histiocytic nature with admixture of giant cells. On the basis of the above data the sarcomatous lesions described appear to represent uterine sarcoma metastases rather than independent primary tumours. AA did not have any influence on carcinogenesis induced by DMH alone but inhibited the growth of uterine sarcomas (whether or not they were associated with other sarcomatous lesions) induced by DMH combined with oestradiol dipropionate.

Topics: 1,2-Dimethylhydrazine; Animals; Ascorbic Acid; Carcinogens; Colonic Neoplasms; Dimethylhydrazines; Estradiol; Female; Incidence; Mice; Mice, Inbred CBA; Mutagens; Sarcoma; Stomach Neoplasms; Uterine Neoplasms

Topics: Adenocarcinoma; Animals; Antioxidants; Ascorbic Acid; Carcinoma, Squamous Cell; Male; Methylnitronitrosoguanidine; Neoplasms; Rats; Rats, Inbred F344; Sarcoma; Stomach Neoplasms

Determination of LD50 values showed 3 human neuroblastoma cell lines to be 2-8-fold more sensitive to 6-hydroxydopamine (6-OHDA) than a mouse sarcoma cell line. Treatment of the cells with 6-OHDA and ascorbic acid decreased the cytotoxicity of 6-OHDA for the sarcoma cells and increased cytotoxicity for the 3 neuroblastoma cell lines.

Topics: Animals; Ascorbic Acid; Cell Line; Cells, Cultured; Dose-Response Relationship, Drug; Drug Synergism; Humans; Hydroxydopamines; Mice; Neoplasms, Experimental; Neuroblastoma; Oxidopamine; Sarcoma

Topics: Adenocarcinoma, Papillary; Ascorbic Acid; Female; Hemangioendothelioma; Humans; Lymphoma, Non-Hodgkin; Male; Sarcoma; Thyroid Neoplasms

This series presents further evidence for an association between reticulosis of the intestine and steatorrhoea. Although some patients have a definite past history of gluten enteropathy, it seems likely that in certain patients the reticulosis itself is the primary cause of the steatorrhoea.

Topics: Ascorbic Acid; Blood Transfusion; Body Weight; Bone Marrow Examination; Celiac Disease; Diet; Diet Therapy; Fats; Feces; Folic Acid; Humans; Intestinal Neoplasms; Intestinal Perforation; Intestine, Small; Iron; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Nandrolone; Neomycin; Neoplasms; Pathology; Prednisone; Sarcoma; Steatorrhea; Surgical Procedures, Operative; Vitamin A; Vitamin B 12; Vitamin B Complex; Vitamins; Water-Electrolyte Balance

Topics: Adrenalectomy; Animals; Ascorbic Acid; Neoplasms; Neoplasms, Experimental; Rats; Sarcoma; Vitamins

Topics: Animals; Ascorbic Acid; Humans; Neoplasms; Neoplasms, Experimental; Sarcoma; Sarcoma, Experimental

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Ascorbic Acid; Histamine; Lymphoma; Lymphoma, Non-Hodgkin; Sarcoma; Vitamins

Topics: Animals; Ascorbic Acid; Benz(a)Anthracenes; Glutathione; Liver; Rats; Sarcoma

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Fibrosarcoma; Humans; Neoplasms; Sarcoma