Study of in vitro and in vivo effects of the piperidine nitroxide Tempol—a potential new therapeutic agent for gliomas

Gariboldi, Marzia Bruna; Ravizza, Raffaella; Petterino, Claudio; Castagnaro, Massimo; Finocchiaro, Gaetano; Monti, Elena

doi:10.1016/s0959-8049(02)00742-6

Cited by 41 publications

(28 citation statements)

References 22 publications

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“…A later study of HL60 leukemia cells that lack p53 tumor suppression revealed that Tempol induced a time and dose-dependent increase in expression of the downstream antiproliferative gene p21 resulting in G1 arrest [64,65]. As a result of this finding, the anti-tumor effect of Tempol against glioma cells in anin vitro and in vivo murine xenograft model was studied [66]. Tumors from Tempol-treated mice treated showed increased evidence of apoptosis using a TUNEL assay and direct visualization of cells and showed decreased neovascularization on histological staining.…”

Section: Chemoprevention and Anticancer Activitymentioning

confidence: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

467

387

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Cyclic nitroxides are a diverse range of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as biophysical tools. During the past 15-20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described including their ability to degrade superoxide and peroxide, inhibit Fenton reactions and undergo radical-radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. While much remains to be done, many applications have been well studied and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.

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Section: Chemoprevention and Anticancer Activitymentioning

confidence: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

467

387

View full text Add to dashboard Cite

show abstract

“…4-Hydroxy-2,2,6,6-tetramethylpiperidine-Noxyl (TEMPOL) is a nitroxide with properties as a radioprotector in vitro and in vivo that were studied extensively (26)(27)(28)(29). Although found to be effective, the required high millimolar concentrations, partially because of its poor partitioning into cells and mitochondria, set a limit for broader applications of TEM-POL (30). Recent developments in targeted delivery of antioxidants, including nitroxides, to mitochondria offer new opportunities in radioprotection of cells and tissues (31,32).…”

Section: Introductionmentioning

confidence: 99%

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

Jiang¹,

Belikova²,

Hoye³

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To evaluate the in vitro radioprotective effect of the mitochondria-targeted hemigramicidin S-conjugated 4-amino-2,2,6,6-tetramethyl-piperidine-N-oxyl (hemi-GS-TEMPO) 5-125 in γ-irradiated mouse embryonic cells and adenovirus-12 SV40 hybrid virus transformed human bronchial epithelial cells BEAS-2B and explore the mechanisms involved in its radioprotective effect.Methods and Materials-Cells were incubated with 5-125 before (10 minutes) or after (1 hour) γ-irradiation. Superoxide generation was determined by using dihydroethidium assay, and lipid oxidation was quantitated by using a fluorescence high-performance liquid chromatography-based Amplex Red assay. Apoptosis was characterized by evaluating the accumulation of cytochrome c in the cytosol and externalization of phosphatidylserine on the cell surface. Cell survival was measured by means of a clonogenic assay.Results-Treatment (before and after irradiation) of cells with 5-125 at low concentrations (5, 10, and 20 μM) effectively suppressed γ-irradiation-induced superoxide generation, cardiolipin oxidation, and delayed irradiation-induced apoptosis, evaluated by using cytochrome c release and phosphatidylserine externalization. Importantly, treatment with 5-125 increased the clonogenic survival rate of γ-irradiated cells. In addition, 5-125 enhanced and prolonged γ-irradiation-induced G 2 /M phase arrest.Conclusions-Radioprotection/mitigation by hemi-GS-TEMPO likely is caused by its ability to act as an electron scavenger and prevent superoxide generation, attenuate cardiolipin oxidation in mitochondria, and hence prevent the release of proapoptotic factors from mitochondria. Other mechanisms, including cell-cycle arrest at the G 2 /M phase, may contribute to the protection.

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“…Increasing evidence has revealed that nitroxides have antioxidative and anticancer activity. Gariboldi et al also demonstrated that treatment with nitroxide decreased the rate of tumor vascularization and reduced microvessel density (18). 4-isothiocyanate-2,2,6,6-tetramethyl piperidinooxyl (4-ISO-Tempo) is one of the nitroxides that exhibits significant antioxidant activity.…”

Section: -Isothiocyanatementioning

confidence: 99%

4-isothiocyanate-2, 2, 6, 6-tetramethyl piperidinooxyl inhibits angiogenesis by suppressing VEGFR2 and Tie2 phosphorylation

et al. 2016

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Abstract. Reactive oxygen species (ROS) are involved in the signaling pathway and are triggered by angiogenic factors, including vascular endothelial growth factor and angiopoietins. 4-isothiocyanate-2, 2, 6, 6-tetramethyl piperidinooxyl (4-ISO-Tempo) is one of the nitroxides that exhibits antioxidant activity. However, the anti-angiogenic effect of 4-ISO-Tempo remains unknown. The aim of this study was to investigate the effect of 4-ISO-Tempo on tumor proliferation and angiogenesis as well as its underlying mechanisms. Our results revealed that 4-ISO-Tempo significantly inhibited the viability of neoplastic and endothelial cells. Furthermore, the effective concentration of 4-ISO-Tempo on human microvascular endothelial cell 1 (HMEC-1) was lower than that on human lung adenocarcinoma A549 and human colon cancer SW620 cells. This suggested that endothelial cells were more sensitive to 4-ISO-Tempo than tumor cells. Furthermore, we demonstrated that 4-ISO-Tempo also suppressed secretion of matrix metallo proteinase (MMP)-2 and MMP-9, and migration and tube formation of HMEC-1 cells. The mechanism is attributed to the decreasing ROS generation and further phosphorylation of vascular endothelial growth factor receptor 2 and Tie2. Our findings suggest that 4-ISO-Tempo should be investigated for its usefulness in anti-angiogenesis therapies.

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Study of in vitro and in vivo effects of the piperidine nitroxide Tempol—a potential new therapeutic agent for gliomas

Cited by 41 publications

References 22 publications

The chemistry and biology of nitroxide compounds

The chemistry and biology of nitroxide compounds

A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

4-isothiocyanate-2, 2, 6, 6-tetramethyl piperidinooxyl inhibits angiogenesis by suppressing VEGFR2 and Tie2 phosphorylation

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