Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper, we report on our studies of the effects of MIBG, a structural analogue of norepinephrine, on SK-N-BE(2c) cells. In micromolar concentrations, MIBG caused almost complete inhibition of the proliferation of SK-N-BE(2c) cells. In intact SK-N-BE(2c) cells, addition of MIBG led to a decrease of the ATP to ADP ratio. A progressive increase of the lactate to pyruvate ratio (due to increased lactate production) was observed after incubation of the cells with glucose and increasing concentrations of MIBG. In cells treated with digitonin, MIBG inhibited malate driven ATP synthesis. Comparable inhibition of ATP synthesis with succinate as a substrate required higher concentrations of MIBG. These results indicate that, apart from inhibition of complex I, MIBG was capable of inhibiting at least one other complex of the respiratory chain. Although maximal inhibition of ATP synthesis was observed at a concentration of 10 microM, optimal inhibition of cell proliferation occurred at a MIBG concentration > 25 microM. This suggests that MIBG also influences other cellular processes apart from mitochondrial ATP synthesis, resulting in additional inhibition of cell proliferation.
Eur J Cancer 1995
PMID:Meta-iodobenzylguanidine (MIBG) inhibits malate and succinate driven mitochondrial ATP synthesis in the human neuroblastoma cell line SK-N-BE(2c). 757 73

Integrating microdensitometry has been used to quantitate changes in 4 cytoplasmic enzymes (NADH dehydrogenase, succinate dehydrogenase, acid phosphatase and alpha-naphthyl butyrate esterase), DNA, RNA and glycogen in developing macrophages from 17 patients with non-Hodgkin's lymphoma and 19 normal subjects. Cytochemical measurements were made at intervals over 6 days of suspension culture; over 16 000 individual cells were examined in total and the results subjected to analysis of variance. While the levels of enzymes and RNA of both groups showed increases over the period of culture, the levels of alpha-naphthyl butyrate esterase in the patients' cells were consistently lower than the corresponding values for the normal cells and glycogen levels were higher, these differences satisfying the pre-determined requirements for statistical significance. It is concluded that (a) maturational changes take place in cytochemical constituents of developing macrophages of non-Hodgkin's lymphoma (b) there are disturbances affecting the amounts of the specific enzyme alpha-naphthyl butyrate esterase and glycogen (c) these abnormalities may be part of a compromise of host defense mechanisms by the disease, although a pre-existing defect in esterase increasing the susceptibility to malignancy is another possibility, and (d) the methods used may be of value in future investigations of the cause of the disturbances and their correction.
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PMID:Abnormalities of esterase and glycogen in developing macrophages in non-Hodgkin's lymphoma: a quantitative cytochemical study. 757 45

Alterations in the energy metabolism of cancer cells have been reported for many years. However, the deleterious mechanisms involved in these deficiencies have not yet been clearly proved. The main goal of this study was to decipher the harmful mechanisms responsible for the respiratory chain deficiencies in the course of diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis, where mitochondrial DNA abnormalities had been previously reported. The respiratory activity of freshly isolated hepatoma mitochondria, assessed by oxygen consumption experiments and enzymatic assays, presented a severe complex I deficiency 19 months after DENA treatment, and later on, in addition, a defective complex III activity. Since respiratory complex subunits are encoded by both nuclear and mitochondrial genes, we checked whether the respiratory chain defects were due to impaired synthesis processes. The specific immunodetection of complex I failed to show any alterations in the steady-state levels of both nuclear and mitochondrial encoded subunits in the hepatomas. Moreover, in vitro protein synthesis experiments carried out on freshly isolated hepatoma mitochondria did not bring to light any modifications in the synthesis of the mitochondrial subunits of the respiratory complexes, whatever the degree of tumor progression. Finally, Southern blot analysis of mitochondrial DNA did not show any major mitochondrial DNA rearrangements in DENA-induced hepatomas. Because the synthetic processes of respiratory complexes did not seem to be implicated in the respiratory chain impairment, these deficiencies could be partly ascribed to a direct toxic impact of highly reactive molecules on these complexes, thus impairing their function. The mitochondrial respiratory chain is an important generator of noxious, reactive oxygen free radicals such as superoxide and H2O2, which are normally catabolized by powerful antioxidant scavengers. Nineteen months after DENA treatment, a general collapse of the antioxidant enzymatic system was demonstrated in the hepatomas, as recurrently observed in cancer cells. This oxidant versus antioxidant imbalance was characterized by the establishment of oxidative stress in the course of hepatocarcinogenesis, as partly shown by the important decrease of glutamine synthetase activity, an enzyme whose function is highly sensitive to oxidant reactions. This disequilibrium would result in a net increase of the steady-state concentration of superoxide generated between respiratory complexes I and III in the mitochondria. Once generated, superoxide would likely inactivate complexes I and III via oxidant reactions on their superoxide-sensitive [4Fe, 4S] clusters. The role of mitochondrial respiratory chain impairment in chemical carcinogenesis and/or the persistence of the cancerous state is further discussed.
Cancer Res 1995 Jul 15
PMID:Impairment of the mitochondrial respiratory chain activity in diethylnitrosamine-induced rat hepatomas: possible involvement of oxygen free radicals. 760 23

To understand the mechanism of action of the antitumor arotinoid mofarotene (Ro 40-8757), differential screening of cDNA libraries with cDNA probes prepared from treated or untreated breast-cancer cells was performed. Several genes were identified that appeared to be regulated by mofarotene, including a mitochondrial gene encoding a subunit of NADH dehydrogenase (NDI). This gene was down-regulated in the breast-cancer cell line MDA-MB-231 after treatment with the arotinoid for 3 to 6 hr. Down-regulation of NDI was detected in 2 other breast-carcinoma cell lines (ZR-75-I and MCF-7) and a pancreatic cancer cell line (BxPC3), but not in the normal fibroblast cell line Wi-38 or several other tumor cell lines. This effect was blocked by addition of cycloheximide to the medium. The retinoids, all-trans and 9-cis retinoic acids, did not affect the expression of NDI in MDA-MB-231 cells, demonstrating that mofarotene was not acting through the nuclear retinoic-acid receptors. In the estrogen-receptor-expressing breast-cancer line ZR-75-I, tamoxifen had no effect on NDI expression. The cytotoxic drugs doxorubicin, 5-FU and vincristine also had no effect on regulation of this gene. Two mitochondrial proteins encoded in the nucleus, ATPase beta subunit and mitochondrial transcription factor I, were not down-regulated by mofarotene. Addition of mofarotene to cells incubated in glucose-free medium led to their death. These results indicate that down-regulation of mitochondrial gene transcription is specific to mofarotene and may explain, in part, the anti-proliferative effects of this compound.
Int J Cancer 1994 Sep 15
PMID:Down-regulation of mitochondrial gene expression by the anti-tumor arotinoid mofarotene (Ro 40-8757). 792 84

Anthraquinone derivatives are important anti-cancer drugs possessing undesirable cardiotoxic properties related to their peroxidating activity. Previous studies have suggested that this activity can be caused by the binding of a singlet oxygen molecule to an anthraquinone, followed by the one-electron reduction of the complex formed, and its further dissociation into anthraquinone and the superoxide anion radical. In this study, we have carried out semi-empirical PM3 calculations of the energetics of the formation of peroxides and hydroperoxides from hydroxy, amino and imino derivatives of 9,10-anthracenedione. These calculations were supplemented with ab initio calculations, using STO-3G, 4-31G and 6-31G basis sets, on the energetics of oxygen binding to 1,4-dihydroxy and 1,4-diaminobenzene. It was found that for anthraquinones possessing hydroxyl groups, the formation of hydroperoxides is significantly favored energetically compared with the formation of peroxides. In the case of anthraquinones containing only amino groups, the formation of hydroperoxides is less favorable, owing to a greater enthalpy of amino group deprotonation compared with that of hydroxyl group. The effect of electrostatic solvation on the energetics of oxygen addition was also investigated using the Conductor-like Screening Model (COSMO) approach. The effect of solvation on peroxide formation was found to be small, while in the case of hydroperoxides solvation was found to lower the enthalpy of this reaction by approximately 10 kcal/mol for epsilon = 78 (simulating an aqueous environment). Significant stabilization of hydroperoxides was estimated in weakly polar media (epsilon = 4) which can simulate the quinone-reducing center of the mitochondrial NADH dehydrogenase. The enthalpies obtained for oxygen addition to anthraquinones involving the formation of the most stable of the peroxide and hydroperoxide species are in good correlation with the rates of NADPH oxidation stimulated by these compounds and, in turn, with their peroxidating properties. This correlation can be directly implemented in the design of non-peroxidating anthraquinone-derived anti-cancer drugs.
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PMID:Enthalpy of oxygen addition to anthraquinone derivatives determines their ability to mediate NADH oxidation. 794 27

The 51-kDa flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase (Complex I) [NADH dehydrogenase (ubiquinone), flavoprotein 1 (51 kDa); EC 1.6.5.3] plays an important role in the formation of the NADH-binding site and is believed to be the principal site of entry for electrons donated by NADH into the respiratory chain. Human cDNA fragments of the 51-kDa protein were generated by polymerase chain reaction and used to localize the gene (NDUFV1) for this subunit to 11q13 by two separate techniques. This region of the human genome is strongly implicated in a number of different forms of cancer.
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PMID:Chromosomal localization of the human gene encoding the 51-kDa subunit of mitochondrial complex I (NDUFV1) to 11q13. 828 51

Polymerase chain reaction (PCR) was used to analyze a rarely deleted region of mitochondrial DNA (mtDNA) from 39 human renal cell carcinomas (RCC) and matched normal kidney tissue removed during radical nephrectomy. One tumor specimen (E.R.) had a unique PCR product approximately 250 base pairs (bp) smaller than the PCR product found in the normal E.R. kidney. Sequence analysis of the tumor-specific PCR fragment revealed a 264 bp deletion in the first subunit (NDI) of NADH:ubiquinone oxidoreductase (complex I) of the electron transport chain. Southern analysis of the RCCs demonstrated that approximately 50% of the mtDNA molecules in the primary RCC contained a unique 3.2 kb EcoRV restriction fragment found only in E.R. tumor mtDNA. Northern analysis demonstrated preferential transcription of the truncated NDI mRNA. None of the five metastases or any normal tissue from E.R. contained levels of the NDI deletion detectable by PCR. This is the first reported case of an intragenic NDI mtDNA deletion.
Genes Chromosomes Cancer 1996 Feb
PMID:Novel mitochondrial DNA deletion found in a renal cell carcinoma. 883 72

Renal cell carcinoma (RCC), a human kidney cancer from the proximal tubular epithelium, accounts for about 3% of adult malignancies. Molecular and cytogenetic analysis have highlighted deletions, translocations, or loss of heterozygosity in the 3p21-p26, a putative RCC locus, as well as in 6q, 8p, 9pq, and 14pq. Studies on phenotypic expression of human kidney tissue and on post-translational modifications in RCC have not yet provided a marker for early renal cell carcinoma diagnosis. Current diagnostic methods do not help to detect the tumor before advanced stages. We therefore used two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) to study normal and tumor kidney tissues in ten patients suffering from RCC. A human kidney protein map in the SWISS-2DPAGE database accessible through the ExPASy WWW Molecular Biology Server was established. Of 2789 separated polypeptides, 43 were identified by gel comparison, amino acid analysis, N-terminal sequencing, and/or immunodetection. The comparison between normal and tumor kidney tissues showed four polypeptides to be absent in RCC. One of them was identified as ubiquinol cytochrome c reductase (UQCR), whose locus has elsewhere been tentatively assigned to chromosome 19p12 or chromosome 22. A second polypeptide was identified as mitochondrial NADH-ubiquinone oxido-reductase complex I whose locus is located on chromosome 18p11.2 and chromosome 19q13.3. These result suggest that the lack of UQCR and of mitochondrial NADH-ubiquinone oxidoreductase complex I expression in RCC may be caused by unknown deletions, or by changes in gene transcription or translation. It might indicate that mitochondrial disfunction plays a major role in RCC genesis or evolution.
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PMID:Renal cell carcinoma and normal kidney protein expression. 915 Sep 47

In this paper we report the effects of the neuroblastoma-seeking agent meta-iodobenzylguanidine (MIBG) on NADH-driven superoxide formation and NADH-driven lipid peroxidation in beef heart submitochondrial particles. MIBG is a structural analogue of noradrenaline and is capable of inhibiting complex I and complex III of the respiratory chain. The results of our studies show that MIBG enhanced both NADH-driven superoxide formation and NADH-driven lipid peroxidation at concentrations that are likely to exist inside mitochondria of the target cells of neuroblastoma patients treated with [131I]MIBG. The effect of MIBG is comparable to that of rotenone (an inhibitor of complex I) rather than that of antimycin (an inhibitor of complex III). These results suggest that the formation of superoxide and lipid peroxidation contributes to the cytotoxicity of [131I]MIBG.
Eur J Cancer 1997 Mar
PMID:The effect of the neuroblastoma-seeking agent meta-iodobenzylguanidine (MIBG) on NADH-driven superoxide formation and NADH-driven lipid peroxidation in beef heart submitochondrial particles. 915 26

The effect of methylglyoxal on the oxygen consumption of mitochondria of both normal and leukaemic leucocytes was tested by using different respiratory substrates and complex specific artificial electron donors and inhibitors. The results indicate that methylglyoxal strongly inhibits mitochondrial respiration in leukaemic leucocytes, whereas, at a much higher concentration, methylglyoxal fails to inhibit mitochondrial respiration in normal leucocytes. Methylglyoxal strongly inhibits ADP-stimulated alpha-oxoglutarate and malate plus NAD+-dependent respiration, whereas, at a higher concentration, methylglyoxal fails to inhibit succinate and alpha-glycerophosphate-dependent respiration. Methylglyoxal also fails to inhibit respiration which is initiated by duroquinone and cannot inhibit oxygen consumption when the N,N,N', N'-tetramethyl-p-phenylenediamine by-pass is used. NADH oxidation by sub-mitochondrial particles of leukaemic leucocytes is also inhibited by methylglyoxal. Lactaldehyde, a catabolite of methylglyoxal, can exert a protective effect on the inhibition of leukaemic leucocyte mitochondrial respiration by methylglyoxal. Methylglyoxal also inhibits l-lactic acid formation by intact leukaemic leucocytes and critically reduces the ATP level of these cells, whereas methylglyoxal has no effect on normal leucocytes. We conclude that methylglyoxal inhibits glycolysis and the electron flow through mitochondrial complex I of leukaemic leucocytes. This is strikingly similar to our previous studies on mitochondrial respiration, glycolysis and ATP levels in Ehrlich ascites carcinoma cells [Ray, Dutta, Halder and Ray (1994) Biochem. J. 303, 69-72; Halder, Ray and Ray (1993) Int. J. Cancer 54, 443-449], which strongly suggests that the inhibition of electron flow through complex I of the mitochondrial respiratory chain and inhibition of glycolysis by methylglyoxal may be common characteristics of all malignant cells.
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PMID:Selective inhibition of mitochondrial respiration and glycolysis in human leukaemic leucocytes by methylglyoxal. 916 22


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