Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine

Velsor, Leonard W.; Kovacevic, Miro; Goldstein, Mark A.; Leitner, Heather; Lewis, William; Day, Brian J.

doi:10.1016/j.taap.2004.03.005

Cited by 68 publications

(53 citation statements)

References 42 publications

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“…2C). Moreover, cisplatin induced a decrease in the ratio of complexes I/II, which has previously been associated with the formation of mitochondrial superoxide (O 2 .-) (38). These findings suggest that, at the concentration used in our studies (under 40 μM), cisplatin's target is mtDNA rather than direct inhibition of the electron transport chain (10)(11)(12)(13).…”

Section: Discussionsupporting

confidence: 65%

Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

Kachadourian

Leitner²,

Day³

2007

Int J Oncol

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Abstract. Adjuvant therapies that enhance the anti-tumor effects of cis-diammineplatinum(II) dichloride (cisplatin, CDDP) are actively being pursued. Growing evidence supports the involvement of mitochondrial dysfunction in the anti-cancer effect of cisplatin. We examined the potential of using selective flavonoids that are effective in depleting tumor cells of glutathione (GSH) to potentiate cisplatin-mediated cytotoxicity in human lung adenocarcinoma (A549) cells. We found that cisplatin (40 μM, 48-h treatment) disrupts the steady-state levels of mitochondrial respiratory complex I, which correlates with elevated mitochondrial reactive oxygen species (ROS) production and cytochrome c release. The flavonoids, 2',5'-dihydroxychalcone (2',5'-DHC, 20 μM) and chrysin (20 μM) potentiated the cytotoxicity of cisplatin (20 μM), which could be blocked by supplementation of the media with exogenous GSH (500 μM). Both 2',5'-DHC and chrysin were more effective than the specific inhibitor of GSH synthesis, L-buthionine sulfoximine (BSO, 20 μM), in inducing GSH depletion and potentiating the cytotoxic effect of cisplatin. These data suggest that the flavonoid-induced potentiation of cisplatin's toxicity is due, in part, to synergetic pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and the flavonoids by depleting cellular GSH, an important antioxidant defense.

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Section: Discussionsupporting

confidence: 65%

Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

Kachadourian

Leitner²,

Day³

2007

Int J Oncol

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“…36 Cardiac mtDNA samples were isolated (mtDNA Extractor CT Kit, Wako Chemicals USA, Inc., Richmond, VA, USA), and analyzed for abundance of 8-OHdG (as a marker for oxidative stress to mtDNA 37,38 ) relative to abundance of 2-deoxyguanosine (2dG; Â 10 À5 ) by HPLC coupled with coulometric electrochemical and spectrophotometric detection (CoulArray Model 5600; ESA Inc., Chelmford, MA, USA). Nucleoside concentrations were calculated from multipoint standard curves generated daily with freshly prepared standards at concentrations that encompassed those observed in the samples.…”

Section: Sds Page Coomassie Blue Staining and Western Blottingmentioning

confidence: 99%

“…Such Pol g mutations may exhibit only mild enzyme dysfunction without a phenotype in the native, undisturbed condition. However, a mitochondrial dysfunction phenotype could occur in selected tissues if a challenge with NRTIs that deplete mtDNA 32 and cause oxidative stress 36 were added. If these events (mutation of polymerase and disturbed nucleotide pools from NRTIs) were to coincide, significant side effects could result.…”

Section: Tg Y955cmentioning

confidence: 99%

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

Lewis

Day

Kohler

et al. 2007

Laboratory Investigation

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107

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“…Methods used resembled those used by us recently 26 and applied to isolated cardiac mitochondria obtained from TG and WT hearts.…”

Section: Immunoblotting Of Mitochondrial Complex Imentioning

confidence: 99%

Targeted Transgenic Overexpression of Mitochondrial Thymidine Kinase (TK2) Alters Mitochondrial DNA (mtDNA) and Mitochondrial Polypeptide Abundance

Hosseini

Kohler

Haase

et al. 2007

The American Journal of Pathology

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Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-␥. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity.

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Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine

Cited by 68 publications

References 42 publications

Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

Targeted Transgenic Overexpression of Mitochondrial Thymidine Kinase (TK2) Alters Mitochondrial DNA (mtDNA) and Mitochondrial Polypeptide Abundance

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