Enzymatic and nonenzymatic formation of reactive oxygen species from 6-anilino-5,8-quinolinequinone

Hasegawa, Takehisa; Bando, Atsushi; Tsuchiya, Koichiro; Abe, Shinji; Okamoto, Momoko; Kirima, Kazuyoshi; Ueno, S.; Yoshizumi, Masanori; Takahashi, Toshiaki

doi:10.1016/j.bbagen.2003.10.008

Cited by 28 publications

(34 citation statements)

References 35 publications

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“…A significant increase in ROS formation was observed as early as 1 min after addition of LY83583 (1 M) to 786-0 cells. This is in agreement with a previous report where LY83583-induced ROS formation in PC-12 cells was observed by electron paramagnetic resonance analysis after a 2-min incubation period (Hasegawa et al, 2004). A similar increase in ROS production was detected using a second fluorescent probe DCFH (data not shown).…”

Section: Ly83583-induced 786-0 Apoptosis Is Ros-dependent But Gc-indesupporting

confidence: 82%

“…LY83583 competitively inhibits soluble GC, lowering the production of cyclic GMP in a wide range of tissues (Schmidt et al, 1985;O'Donnell and Owen, 1986) with the formation of reactive oxygen species (ROS) intermediates (Lee and Wurster, 1995). LY83583-induced ROS formation can be either enzymatic-or nonenzymatic-dependent (Hasegawa et al, 2004). Increased GC activity with a corresponding increase in cGMP has previously been reported in renal tumors (Braughler et al, 1982).…”

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confidence: 99%

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Induction of Apoptosis in Renal Cell Carcinoma by Reactive Oxygen Species: Involvement of Extracellular Signal-Regulated Kinase 1/2, p38δ/γ, Cyclooxygenase-2 Down-Regulation, and Translocation of Apoptosis-Inducing Factor

Ambrose

Ryan²,

O’Sullivan³

et al. 2006

Molecular Pharmacology

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Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, RCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of RCCs. We now report that 6-anilino-5,8-quinolinequinone (LY83583), an inhibitor of cyclic GMP production, induced growth arrest and apoptosis of the RCC cell line 786-0. It did not prove deleterious to normal renal epithelial cells, an important aspect of chemotherapy. To address the cellular mechanism(s), we used both genetic and pharmacological approaches. LY83583 induced a time-and dose-dependent increase in RCC apoptosis through dephosphorylation of mitogen-activated protein kinase kinase 1/2 and its downstream extracellular signal-regulated kinases (ERK) 1 and -2. In addition, we observed a decrease in Elk-1 phosphorylation and cyclooxygenase-2 (COX-2) down-regulation. We were surprised that we failed to observe an increase in either c-Jun NH 2 -terminal kinase or p38␣ and -␤ mitogen-activated protein kinase activation. In contradiction, reintroduction of p38␦ by stable transfection or overexpression of p38␥ dominant negative abrogated the apoptotic effect. Cell death was associated with a decrease and increase in Bcl-x L and Bax expression, respectively, as well as release of cytochrome c and translocation of apoptosis-inducing factor. These events were associated with an increase in reactive oxygen species formation. The antioxidant N-acetyl L-cysteine, however, opposed LY83583-mediated mitochondrial dysfunction, ERK1/2 inactivation, COX-2 down-regulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCC, which remains highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.Renal cell carcinoma (RCC) is the sixth leading cause of cancer death; the worldwide incidence is increasing at an annual rate of 2% (Boring et al., 1994). By the time metastatic disease is diagnosed, it is present in approximately 30% of patients, and an additional 30 to 40% develop metastases within a period of months or years after nephrectomy (Tourani et al., 2003). RCC has a poor prognosis owing to its late presentation and resistance to hormonal therapy (Motzer and Russo, 2000), chemotherapy (Amato, 2000), and radiotherapy (Bukowski, 1997). Cytokine treatments of patients with RCC have produced insufficient response rates, Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.105.020875.ABBREVIATIONS: RCC, renal cell carcinoma; LY83583 , 6-anilino-5,8-quinolinequinone; GC, guanylate cyclase; ROS, reactive oxygen species; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH 2 -terminal kinase; FCS, fetal calf serum; MAb, monoclonal antibody; MKK, mitogen-activated protein kinase kinase kinase; MEK, mitogen-activa...

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Section: Ly83583-induced 786-0 Apoptosis Is Ros-dependent But Gc-indesupporting

confidence: 82%

mentioning

confidence: 99%

Induction of Apoptosis in Renal Cell Carcinoma by Reactive Oxygen Species: Involvement of Extracellular Signal-Regulated Kinase 1/2, p38δ/γ, Cyclooxygenase-2 Down-Regulation, and Translocation of Apoptosis-Inducing Factor

Ambrose

Ryan²,

O’Sullivan³

et al. 2006

Molecular Pharmacology

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“…DPI inhibits oxidation of pyridine nucleotides by the artificial acceptor HAR, showing the same titration curve as NADH:DBQ reductase (not shown). Recently, moderate increase of H 2 O 2 release by heart mitochondria during the oxidation of endogenous substrates was observed after the addition of DPI (23); however, this effect could have been mediated by the effect on other NAD(P)H-dependent enzymes such as mitochondrial nitric oxide synthase (45, 46), NAD(P)H dehydrogenase (47), or dehydrogenases of ␣-keto acids (48) rather than by inhibition of complex I. At the same time, DPI strongly inhibits mitochondrial H 2 O 2 production during the oxidation of succinate by heart (23) or brain mitochondria (24).…”

Section: Discussionmentioning

confidence: 99%

Superoxide Radical Formation by Pure Complex I (NADH:Ubiquinone Oxidoreductase) from Yarrowia lipolytica

Galkin¹,

Brandt

2005

Journal of Biological Chemistry

152

110

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Generation of reactive oxygen species (ROS) is increasingly recognized as an important cellular process involved in numerous physiological and pathophysiological processes. Complex I (NADH:ubiquinone oxidoreductase) is considered as one of the major sources of ROS within mitochondria. Yet, the exact site and mechanism of superoxide production by this large membrane-bound multiprotein complex has remained controversial. Here we show that isolated complex I from Yarrowia lipolytica forms superoxide at a rate of 0.15% of the rate measured for catalytic turnover. Superoxide production is not inhibited by ubiquinone analogous inhibitors. Because mutant complex I lacking a detectable iron-sulfur cluster N2 exhibited the same rate of ROS production, this terminal redox center could be excluded as a source of electrons. From the effect of different ubiquinone derivatives and pH on this side reaction of complex I we concluded that oxygen accepts electrons from FMNH 2 or FMN semiquinone either directly or via more hydrophilic ubiquinone derivatives.Over the last decade the processes leading to the production of superoxide and other reactive oxygen species (ROS) 1 have gained much attention. ROS seem to be involved in apoptosis, the development of various pathological states, aging, and the regulation of cell metabolism. It is generally accepted that production of reactive oxygen species is an inherent property of the mitochondrial respiratory chain of eucaryotic cells. Oxidation of certain redox centers in complex I and III by molecular oxygen results in the production of superoxide anion radical O 2. (see Ref. 1 for a review). Superoxide can then convert into hydrogen peroxide, the highly active hydroxyl radical (OH ⅐ ), and other ROS. It has been shown that O 2 . production by complex I occurs in the mitochondrial matrix, whereas the cytochrome bc 1 complex reduces oxygen primarily on the intermembrane side (2, 3) (see, however, Ref. 4). It has been demonstrated for the cytochrome bc 1 complex that oxygen reduction occurs at the Q P site and is increased markedly under conditions of "oxidant-induced reduction" (5, 6). However, much less is known about the site and mechanism of O 2 . generation in complex I. Thermodynamically, any of the complex I redox centers in the reduced state is capable of donating an electron to molecular oxygen to form a superoxide anion. Eucaryotic NADH:ubiquinone oxidoreductase (complex I or type I NADH dehydrogenase) is the largest and most complex enzyme of the respiratory chain, residing in the inner membrane of mitochondria. In mammals, the enzyme is composed of 46 different subunits (7) and contains non-covalently bound FMN and up to eight iron-sulfur clusters as redox cofactors. Two complex I-associated, electron paramagnetic resonancedetectable semiquinone species with different spin relaxation times have been characterized (8, 9). Complex I catalyzes the transfer of electrons from matrix NADH to membrane ubiquinone coupled to the translocation of four protons across the membrane (10, 11...

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“…7D) as reported previously. 36) When SOD (100 U/ml) was co-incubated with HUVECs and stimulated by LY83583, the EPR signals of DMPO/˙OH were suppressed (Fig. 7E).…”

Section: Effect Of Nifedipine or No-nif On Production Of Reactive Oxymentioning

confidence: 99%

“…36) Here, we used the technique to investigate whether NO-NIF could scavenge reactive oxygen species (ROS) in cultured HUVECs. Nifedipine or NO-NIF was added to the cell suspension 5 min prior to the addition of DMPO and LY83583.…”

Section: Effect Of Nifedipine or No-nif On Production Of Reactive Oxymentioning

confidence: 99%

Antioxidant Effects of Photodegradation Product of Nifedipine

Horinouchi

Tsuchiya

Taoka

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Enzymatic and nonenzymatic formation of reactive oxygen species from 6-anilino-5,8-quinolinequinone

Cited by 28 publications

References 35 publications

Induction of Apoptosis in Renal Cell Carcinoma by Reactive Oxygen Species: Involvement of Extracellular Signal-Regulated Kinase 1/2, p38δ/γ, Cyclooxygenase-2 Down-Regulation, and Translocation of Apoptosis-Inducing Factor

Induction of Apoptosis in Renal Cell Carcinoma by Reactive Oxygen Species: Involvement of Extracellular Signal-Regulated Kinase 1/2, p38δ/γ, Cyclooxygenase-2 Down-Regulation, and Translocation of Apoptosis-Inducing Factor

Superoxide Radical Formation by Pure Complex I (NADH:Ubiquinone Oxidoreductase) from Yarrowia lipolytica

Antioxidant Effects of Photodegradation Product of Nifedipine

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