Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By differential hybridization, we have isolated 14 cDNA clones corresponding to genes that are more highly expressed in the flat revertant cell line R1 than in the parental human Ha-ras oncogene-transformed NIH/3T3 cell line (EJ-NIH/3T3). From cross-hybridization experiments, we determined that 5 sequence families accounted for the 14 clones. DNA sequencing revealed that four out of five selected cDNA clones represented mitochondrial genes (cytochrome b, cytochrome c oxidase subunit II, NADH dehydrogenase subunits 1 and 4, respectively), whereas one cDNA clone was homologous to the alpha 2 (type I collagen gene. Although a Southern blot analysis of the studied cell lines showed similar copy numbers of mitochondrial genomes, the transcript levels of the mitochondrial genes were high in R1, intermediate in NIH/3T3 and low in EJ-NIH/3T3 and partially revertant R2 cell lines. alpha 2 (type I) collagen mRNA levels were high in R1 and NIH/3T3, intermediate in R2 and low in EJ-NIH/3T3 cells. These results suggest that a complex alteration of the expression of mitochondrial and extracellular matrix components may be closely associated with the flat reversion of the transformed cells.
Cancer Lett 1991 Jul 26
PMID:Identification of genes that exhibit increased expression after flat reversion of NIH/3T3 cells transformed by human activated Ha-ras oncogene. 187 59

The triarylmethane derivative Victoria Blue-BO (VB-BO) and the chalcogenapyrylium (CP) dyes have potential for use in photochemotherapy, because they are taken up by the mitochondria of malignant cells and cause cell death. To clarify the mechanism of cell killing we examined the phototoxic effects of VB-BO and a series of three CP dyes on bioenergetic function in isolated rat liver mitochondria. Without photoirradiation, and irrespective of the respiratory substrate used, each of the compounds tested induced some uncoupling of oxidative phosphorylation. Visible irradiation of VB-BO produced an inhibition of mitochondrial respiration when glutamate plus malate, but not succinate, was used as the respiratory substrate. With photoirradiation VB-BO was also shown to inhibit rotenone-sensitive NADH-cytochrome c reductase activity, but it had no effect on succinate-cytochrome c reductase activity. These data indicate that photoactivation of VB-BO produces selective inhibition of mitochondrial respiratory complex I. Photoirradiation of the CP dyes inhibited both complex I and complex II initiated respiratory activity. With photoirradiation, the CP dyes also inhibited both NADH- and succinate-cytochrome c reductase activities, as well as other membrane-bound enzymes, cytochrome c oxidase and succinate dehydrogenase, but not the mitochondrial matrix enzyme, citrate synthetase, or the cytosolic enzyme, lactate dehydrogenase. alpha-Tocopherol protected bioenergetic activities against CP dye photodamage. These results suggest that mitochondrial photosensitization by CP compounds is mediated by the production of membrane-damaging singlet oxygen which causes nonspecific damage to membranes and membrane-bound enzymes.
Cancer Res 1990 Dec 15
PMID:Mitochondrial toxicity of cationic photosensitizers for photochemotherapy. 217 36

m-Iodobenzylguanidine (MIBG) is a functional analogue of the neurotransmitter norepinephrine. Radio-iodinated 131I-MIBG is used clinically as a tumor-targeted radiopharmaceutical agent in the diagnosis and treatment of adrenergic tumors. Native MIBG has previously been demonstrated to be cytotoxic in cultured cells and to produce anti-tumor responses in animals when non-toxic schedules are used. In this study the effect of MIBG was investigated on isolated rat liver mitochondria and on various tumor cell lines (human neuroblastoma SK-N-SH, mouse neuroblastoma N1E115 and mouse lymphosarcoma S49). Results revealed that MIBG inhibits respiration of isolated liver mitochondria at complex I of the respiratory chain, without affecting F1 ATP-ase. In cell lines, impairment of the mitochondrial respiration was evident from reduced oxygen consumption and decreased intracellular ATP levels. In response to this effect, the glycolytic flux was stimulated as shown by increased glucose consumption and lactic acid production. Cytotoxicity of MIBG was proportional to drug-induced alterations in glucose metabolism.
Int J Cancer 1990 Aug 15
PMID:Impaired mitochondrial respiration and stimulated glycolysis by m-iodobenzylguanidine (MIBG). 238 75

Previous studies with Adriamycin-sensitive and -resistant (ADRR) MCF-7 human breast tumor cell lines indicated that Adriamycin formed significantly less hydroxyl radical (.OH) as the result of enhanced detoxification of reactive oxygen intermediates in the ADRR cell line. In order to further define the sites of drug activation and the role of detoxification mechanisms in free radical levels, subcellular fractions were isolated from these two cell lines and free radical formation in the presence of Adriamycin was examined by using electron spin resonance spectroscopy. Studies reported here show that considerable NADPH-cytochrome P-450 reductase and NADH dehydrogenase activities were present in microsomes and mitochondria, respectively, and in nuclei obtained from these cells, and the relative activity of NADH dehydrogenase was 2-fold higher in the mitochondrial fraction of ADRR cells compared to the mitochondrial fraction from the parental wild type cells. In the presence of Adriamycin and a reducing cofactor (NADPH or NADH), Adriamycin semiquinone free radical, superoxide anion, and .OH were detected in all these fractions. Although only a small difference in the relative amount of oxy radical formation was detected in tumor microsomes, both mitochondria and nuclei of ADRR cells showed an overall 2-fold decreased formation of oxy radicals. The formation of the free radicals was significantly inhibited by superoxide dismutase, catalase, and dimethyl sulfoxide, indicating that free .OH generation was both superoxide and hydrogen peroxide dependent. The addition of purified glutathione peroxidase likewise inhibited .OH formation in a dose-dependent fashion. Similarly, when the lysate from ADRR cells, which contains 12- to 14-fold more glutathione peroxidase than Adriamycin-sensitive cells, was added to reaction mixtures containing Adriamycin-sensitive cells and Adriamycin, the .OH formation was diminished. Decreased free radical formation in nuclei and mitochondria, as a result of detoxification of hydrogen peroxide by glutathione peroxidase, may be significant in the protection of ADRR cells from Adriamycin-induced cell killing.
Cancer Res 1989 Jul 15
PMID:Adriamycin activation and oxygen free radical formation in human breast tumor cells: protective role of glutathione peroxidase in adriamycin resistance. 254 60

The ability of injected Photofrin II, a preparation enriched in hydrophobic dihaematoporphyrin ethers and esters, to photosensitize selected mitochondrial and cytosolic enzymes during illumination in vitro was examined. Preparations of R3230AC mammary tumours, obtained at designated times after a single dose of Photofrin II, displayed a time-dependent photosensitivity. Maximum inhibition of mitochondrial enzymes occurred at 24 hours post-treatment, whereas no inhibition of the cytosolic enzyme, pyruvate kinase, was observed over the 168 hour time course. At the selected 24 hour time point, mitochondrial enzyme photosensitisation was found to be drug dose (5.25 mg kg-1 Photofrin II) and light dose dependent, the rank order of inhibition being cytochrome c oxidase greater than F0F1 ATPase greater than succinate dehydrogenase greater than NADH dehydrogenase. We conclude that porphyrin species contained in Photofrin II accumulate in mitochondria of tumour cells in vivo and produce maximum photosensitisation at 24-72 hours after administration to tumour-bearing animals. The time course observed here with Photofrin II is similar to that seen previously with the more heterogenous haematoporphyrin derivative preparation in this in vivo-in vitro model.
Br J Cancer 1989 Jan
PMID:In vitro photosensitization of tumour cell enzymes by photofrin II administered in vivo. 254 13

Five ionic cyclopentadienyltitanium (IV) derivatives were investigated for their activity against fluid Ehrlich ascites tumor. Four compounds were built up by the intact bis(cyclopentadienyl)titanium(IV) ("titanocene") unit, forming the cationic moiety together with two covalently bound ligands, with certain anions being bonded via electrostatic forces: the acetonitrile complex [(C5H5)2TiCl(NCCH3)]+[FeC14]- (I), the 2'2'-bipyridyl derivative [(C5H5)2Ti(bipy)]2+[CF3SO3]2 (II), the o-phenanthroline complex [(C5H5)2Ti(phen)]2+[CF3SO3]2 (III), and the N-methyl-o-aminothiophenolate derivative [(C5H5)2Ti[o-S(NACH3)C6H4]]+I- (IV). Another ionic cyclopentadienyltitanium derivative investigated was the five-coordinate bis(dithiolene) chelate (C5H5)Ti(1,2,4-S2C6H3CH3)2]-N(C2H5)4)+ (V), the cyclopentadienyltitanium moiety representing the anionic part of the complex salt. All complexes were ionic, salt-like compounds, distinguished by good water solubility. Whereas complexes I, III, and V, given at optimal dose levels, effected maximal cure rates of only 70%-80%, all animals were cured after receiving complexes II and IV at dose ranges of 200-220 and 240-300 mg/kg, respectively. The antitumor activity of complex I was confirmed against solid experimental tumor systems B16 melanoma, colon 38 carcinoma, and Lewis lung carcinosarcoma. Because of their improved solubility in water and pronounced antitumor activity (especially that of II and IV against fluid Ehrlich ascites tumor), ionic cyclopentadienyl titanium complexes are considered to be an interesting new type of antitumor agent.
Cancer Chemother Pharmacol 1989
PMID:Ionic titanocene complexes: a new type of antitumor agent. 272 Aug 88

In the accompanying paper (Davies, K. J. A., and Doroshow, J. A. (1986) J. Biol. Chem. 261, 3060-3067), we have demonstrated that anthracycline antibiotics are reduced to the semiquinone form at Complex I of the mitochondrial electron transport chain. In the experiments presented in this study we examined the effects of doxorubicin (Adriamycin), daunorubicin, and related quinonoid anticancer agents on superoxide, hydrogen peroxide, and hydroxyl radical production by preparations of beef heart submitochondrial particles. Superoxide anion formation was stimulated from (mean +/- S.E.) 1.6 +/- 0.2 to 69.6 +/- 2.7 or 32.1 +/- 1.5 nmol X min-1 X mg-1 by the addition of 90 microM doxorubicin or daunorubicin, respectively. However, the anthracycline 5-iminodaunorubicin, in which an imine group has been substituted in the C ring quinone moiety, did not increase superoxide production over control levels. In the presence of rotenone, initial rates of oxygen consumption and superoxide formation were identical under comparable experimental conditions. Furthermore, H2O2 production increased from undetectable control levels to 2.2 +/- 0.3 nmol X min-1 X mg-1 after treatment of submitochondrial particles with doxorubicin (200 microM). The hydroxyl radical, or a related chemical oxidant, was also detected after the addition of an anthracycline to this system by both ESR spectroscopy using the spin trap 5,5-dimethylpyrroline-N-oxide and by gas chromatographic quantitation of CH4 produced from dimethyl sulfoxide. Hydroxyl radical production, which was iron-dependent in this system, occurred in a nonlinear fashion with an initial lag phase due to a requirement for H2O2 accumulation. We also found that two quinonoid anti-cancer agents which produce less cardiotoxicity than the anthracyclines, mitomycin C, and mitoxantrone, stimulated significantly less or no hydroxyl radical production by submitochondrial particles. These experiments suggest that injury to cardiac mitochondria which is produced by anthracycline antibiotics may result from the generation of the hydroxyl radical during anthracycline metabolism by NADH dehydrogenase.
 ...
PMID:Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. 300 79

We investigated mechanisms of mitochondrial phototoxicity caused by the cationic cyanine dye N,N'-bis(2-ethyl-1,3-dioxylene)kryptocyanine (EDKC), examining the role of the mitochondrial membrane potential on the dye uptake by carcinoma cells in vitro, and both the dark and photosensitizing effects of the dye on the function of isolated mouse liver mitochondria. When human bladder carcinoma cells (EJ) were pretreated with 2,4-dinitrophenol or nigericin, cellular uptake of EDKC decreased or increased, respectively, consistent with dye uptake that is dependent on membrane potentials. In isolated liver mitochondria, during NADH linked substrate oxidation (using glutamate plus malate or beta-hydroxybutyrate as substrates), low concentrations of the dye (0.25-0.5 microM) sensitized mitochondria to illumination with long wavelength light and inhibited both basal and ADP-stimulated respiration. Similar effects were observed during succinate oxidation, but only at higher concentrations of EDKC (greater than 5 microM) and at 10-fold greater light doses. NADH coenzyme Q reductase (Complex I) activity was inhibited by dye with or without light to an extent comparable to the inhibition of glutamate plus malate oxidation. Activity of cytochrome c oxidase, the terminal enzyme in the electron transport chain, was photosensitized with high dye doses (greater than 5 microM) and light, but the extent of inhibition was much less than the inhibition of respiration with succinate as substrate. ATP synthetase (F0F1 ATPase) activity was minimally affected by 4.0 microM EDKC with or without 24 J/cm2 light. We conclude that at low concentrations of dye, respiratory Complex I is a primary target for EDKC dark and light-induced toxicities. If Complex I is bypassed by using succinate as a respiratory substrate, the mitochondria can tolerate much higher dye concentrations and light doses.
Cancer Res 1987 Dec 15
PMID:Mechanisms of mitochondrial photosensitization by the cationic dye, N,N-bis(2-ethyl-1,3-dioxylene)kryptocyanine (EDKC): preferential inactivation of complex I in the electron transport chain. 311 97

This investigation examined the effect of the anthracycline antitumor agents on reactive oxygen metabolism in rat heart. Oxygen radical production by doxorubicin, daunorubicin, and various anthracycline analogues was determined in heart homogenate, sarcoplasmic reticulum, mitochondria, and cytosol, the major sites of cardiac damage by the anthracycline drugs. Superoxide production in heart sarcosomes was significantly increased by anthracycline treatment; for doxorubicin, the reaction appeared to follow saturation kinetics with an apparent Km of 112.62 microM, required NADPH as cofactor, was accompanied by the accumulation of hydrogen peroxide, and probably resulted from the transfer of electrons to molecular oxygen by the doxorubicin semiquinone after reduction of the drug by sarcosomal NADPH:cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4). Superoxide formation was also significantly enhanced by the anthracycline antibiotics in the mitochondrial fraction. Doxorubicin stimulated mitochondrial superoxide formation in a dose-dependent manner that also appeared to follow saturation kinetics (apparent Km of 454.55 microM); however, drug-related superoxide production by mitochondria required NADH rather than NADPH and was significantly increased in the presence of rotenone, which suggested that the proximal portion of the mitochondrial NADH dehydrogenase complex [NADH:(acceptor) oxidoreductase, EC 1.6.99.3] was responsible for the reduction of doxorubicin at this site. In heart cytosol, anthracycline-induced superoxide formation and oxygen consumption required NADH and were significantly reduced by allopurinol, a potent inhibitor of xanthine oxidase (xanthine:oxygen oxidoreductase, EC 1.2.3.2). Reactive oxygen production was detected in all of our studies despite the presence of both superoxide dismutase (superoxide:superoxide oxidoreductase, EC 1.15.1.1) and glutathione peroxidase (glutathione:hydrogen peroxide oxidoreductase, EC 1.11.1.9) in each cardiac fraction. These results suggest that free radical formation by the anthracycline antitumor agents, which occurs in the same myocardial compartments that are subject to drug-induced tissue injury, may damage the heart by exceeding the oxygen radical detoxifying capacity of cardiac mitochondria and sarcoplasmic reticulum.
Cancer Res 1983 Feb
PMID:Effect of anthracycline antibiotics on oxygen radical formation in rat heart. 629 97

This study investigated the effect of the anthracycline antibiotics on oxygen radical metabolism by cardiac mitochondrial reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase [NADH:(acceptor) oxidoreductase, EC 1.6.99.3]. Superoxide formation by NADH dehydrogenase after anthracycline treatment appeared to follow saturation kinetics with an apparent Km of 167.3, 73.3, 64.0, or 47.6 microM for doxorubicin, daunorubicin, rubidazone, or aclacinomycin A, respectively. Superoxide formation by NADH dehydrogenase after doxorubicin treatment occurred with a pH optimum of 7.6 and was accompanied by the production of hydrogen peroxide. Furthermore, drug-related hydroxyl radical generation was detected in this enzyme system by the evolution of methane gas from dimethyl sulfoxide. Hydroxyl radical production proceeded only in the presence of superoxide anion, hydrogen peroxide, and trace amounts of iron or a chelate of iron and ethylenediaminetetraacetate and thus was probably the by-product of a transition metal-catalyzed Haber-Weiss reaction. The antitumor agents mitoxantrone and actinomycin D did not significantly enhance reactive oxygen metabolism by NADH dehydrogenase. These results suggest that the specific activation of the anthracycline antibiotics to free radicals by NADH dehydrogenase leads to the formation of a variety of reactive oxygen species that may contribute to the mitochondrial toxicity of these drugs.
Cancer Res 1983 Oct
PMID:Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide, and hydroxyl radical production by NADH dehydrogenase. 630 69


1 2 3 4 5 6 7 8 9 10 Next >>