Antiproliferative Effect of the Piperidine Nitroxide Tempol on Neoplastic and Nonneoplastic Mammalian Cell Lines

Gariboldi, Marzia Bruna; Lucchi, Simona; Caserini, Claudia; Supino, Rosanna; Oliva, Cesare; Monti, Elena

doi:10.1016/s0891-5849(97)00372-9

Cited by 67 publications

(52 citation statements)

References 24 publications

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“…Unlike Atm-deficient mice, p53-deficient mice did not demonstrate increased thymic oxidative stress as measured by DCF, and Tempol did not further reduce these normal levels. Previous studies have shown that the p53 gene is activated by phosphorylation to suppress tumors in response to oxidative stress [60][61][62]. Tempol was found to phosphorylate p53 resulting in an increase in downstream anti-proliferative gene expression.…”

Section: Chemoprevention and Anticancer Activitymentioning

confidence: 91%

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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: 91%

“…Although Tempol was previously shown to have no significant cytotoxicity, [16,63] Tempol was found to have an antiproliferative effect on MCF-7 breast cancer cells [60]. Treated cells accumulated in G 1 then paused in G 2 /M phase ultimately undergoing apoptosis as revealed by DNA fragmentation studies.…”

Section: Chemoprevention and Anticancer Activitymentioning

confidence: 96%

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

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“…Much evidence suggests that Tempol acts as an antioxidant agent at 5 mM concentration in lens epithelial cells (17), hepatic satellite cells (18), and endothelial cells (19). In contrast, it is also reported that Tempol exhibits cytoxic effects by inducing excessive ROS at concentration as low as 1 mM in Chinese hamster ovary cells (20), breast cancer cells (6) and human leukemia HL-60 cells (21). Our results indicate that Tempol as a pro-oxidant inhibits cell growth in As4.1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, mutagenic effects has been reported in different bacterial strains (5). Of note, Tempol as a pro-oxidant induces the cell cycle arrest and apoptosis depending on cell types (6). Therefore, in order to clarify these discrepancies among the different effects of Tempol, further study needs to be performed for re-evaluating its real biological functions and roles.…”

Section: Introductionmentioning

confidence: 99%

“…The activity of caspase-3 was assessed using caspase-3 Colorimetric Assay kits (R&D Systems, Inc.) according to the manufacturer's instructions. In brief, 1ⅹ10 6 cells were incubated with the designated doses of Tempol for 48 h then washed in PBS and suspended 5 volumes of lysis buffer (20 mM HEPES pH 7.9, 20% glycerol, 200 mM KCl, 0.5 mM EDTA, 0.5% NP40). Protein concentration was determined by the Bradford method.…”

Section: Introductionmentioning

confidence: 99%

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Tempol inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and apoptosis

Han

Park

2011

Oncol Rep

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Abstract.A stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-osyl (Tempol) is widely used as an antioxidant in vitro and in vivo. In this study, we investigated the effects of Tempol on the growth of As4.1 juxtaglomerular cells in relation to cell cycle and cell death. Tempol dose-dependently decreased the growth of As4.1 cells with an IC 50 of ~1 mM at 48 h. DNA flow cytometry analysis and BrdU staining indicated that Tempol induced S phase arrest, which is accompanied by a downregulation of cyclin A. Tempol also induced apoptotic cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; ∆Ψm), an activation of caspase-3 and cleavage of poly(ADP-ribose)polymerase-1 (PARP-1). Furthermore, Tempol increased reactive oxygen species (ROS) levels, and the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). MEK and JNK inhibitors significantly attenuated a growth inhibition in Tempol-treated As4.1 cells. In conclusion, Tempol inhibited the growth of As4.1 cells via cell cycle arrest and apoptosis. Tempol also activated ERK and JNK signaling, which was responsible for cell growth inhibition. Our present data provide useful information for the toxicological effects of Tempol in juxtaglomerular cells in relation to cell growth inhibition and cell death. IntroductionTempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl or 4-hydroxy-tempo) is a stable piperidine nitroxide, which is widely employed in electron spin resonance spectroscopy (1). It is also known that Tempol protects cells from oxidative damage in vitro and in vivo (2). Several antioxidant mechanisms have been proposed to account for these protective effects. It may act as a mimic of superoxide dismutase (SOD) and it can reduce the formation of hydroxyl radicals either by scavenging superoxide anion or by reducing intracellular concentration of Fe(II) (3). Usually, such beneficial effects are observed up to a few µM. However, the prospect of moving it from the experimental to the clinical arena has prompted more detailed studies on their possible toxicity. Much evidence suggests that Tempol impairs ferritin synthesis and Fe metabolisms, consequently leading to cell death (4). In addition, mutagenic effects has been reported in different bacterial strains (5). Of note, Tempol as a pro-oxidant induces the cell cycle arrest and apoptosis depending on cell types (6). Therefore, in order to clarify these discrepancies among the different effects of Tempol, further study needs to be performed for re-evaluating its real biological functions and roles.The mitogen-activated protein kinases (MAPKs) are a large family of serine/threonine kinases, which are major comp onents of signaling pathways in cell proliferation, differentiation, and cell death (7). There are currently three known MAPKs: the extracellular signal-regulated kinase (ERK1/2), the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 (7). Each MAPK pathway has relatively different upstream activat...

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Nitroxide TEMPOL impairs mitochondrial function and induces apoptosis in HL60 cells

Monti

Supino

Colleoni

et al. 2001

J of Cellular Biochemistry

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The piperidine nitroxide TEMPOL induces apoptosis in a number of tumor cell lines through free radical-dependent mechanisms. As mitochondria play a major role in apoptosis as both source and target for free radicals, the present study focuses on mitochondrial effects of TEMPOL in a human promyelocytic leukemic cell line (HL-60). On 24-h exposure to TEMPOL, the following alterations were observed: 1) decrease in both the intracellular and mitochondrial glutathione pools; 2) impairment of oxidative phosphorylation; and 3) decrease in mitochondrial membrane potential. In addition, TEMPOL was found to specifically target complex I of the respiratory chain, with minor effects on complexes II and IV, suggesting that mitochondrial effects might play a role in TEMPOL-induced oxidative stress and apoptosis, and that TEMPOL might sensitize tumor cells to the pro-apoptotic effects of cytotoxic agents.

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Antiproliferative Effect of the Piperidine Nitroxide Tempol on Neoplastic and Nonneoplastic Mammalian Cell Lines

Cited by 67 publications

References 24 publications

The chemistry and biology of nitroxide compounds

The chemistry and biology of nitroxide compounds

Tempol inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and apoptosis

Nitroxide TEMPOL impairs mitochondrial function and induces apoptosis in HL60 cells

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