Nitroxide-mediated protection against X-ray-and neocarzinostatin-induced DNA damage

DeGraff, William; Krishna, Murali C.; Kaufman, Dwight; Mitchell, James B.

doi:10.1016/0891-5849(92)90142-4

Cited by 37 publications

(16 citation statements)

References 30 publications

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“…Previous in vitro studies suggested that at least 5-10 mM tempol is required to provide radioprotection, and a protection factor as high as 2.2 was achieved with 100 mM tempol (15). Our data showing activation of ERK1 by tempol (10 mM) are consistent with these and other reports of a protective role of tempol against radiation-induced mutagenicity and double strand breaks and hydrogen peroxide-induced mutagenicity (15,(57)(58)(59). Surprisingly, however, tempo (10 mM) had no detectable effect on ERK1 activity, suggesting that a dissociation may also exist between ERK signaling and antioxidant activity of certain nitroxides.…”

Section: Discussionsupporting

confidence: 82%

Nitroxides Tempol and Tempo Induce Divergent Signal Transduction Pathways in MDA-MB 231 Breast Cancer Cells

Suy¹,

Mitchell²,

Ehleiter³

et al. 1998

Journal of Biological Chemistry

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Tempol and tempo are stable free radical nitroxides that possess antioxidant properties. In this study, we examined the effects of these compounds on components of the mitogen-activated protein kinase signal transduction cascade. Tempo treatment (15 min) of MDA-MB 231 human breast cancer cells resulted in significant levels of tyrosine phosphorylation of several as yet unidentified proteins compared with equimolar concentration of tempol (10 mM). Both compounds caused tyrosine phosphorylation and activation of Raf-1 protein kinase (30 min, 2-3-fold). Interestingly, however, only tempol caused increased extracellular signal-regulated kinase 1 activity (2 h, ϳ3-fold). On the other hand, tempo, but not tempol, potently activated stress-activated protein kinase (2 h, >3-fold). Consistent with these data, tempol was found to be noncytotoxic, whereas tempo induced apoptotic cell death (2 h, >50%). Tempo treatment also resulted in significant elevation of ceramide levels at 30 min (54% over control) and 1 h (71% over control) posttreatment, preceding stress-activated protein kinase activation and apoptosis. These data suggest that in the absence of an environmental oxidative stress, tempol and tempo elicit distinct cellular signaling pathways. The recognition of the molecular mechanisms of nitroxide action may have important implications for biological effectiveness of these compounds.

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Section: Discussionsupporting

confidence: 82%

Nitroxides Tempol and Tempo Induce Divergent Signal Transduction Pathways in MDA-MB 231 Breast Cancer Cells

Suy¹,

Mitchell²,

Ehleiter³

et al. 1998

Journal of Biological Chemistry

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“…These studies not only showed that Tempol was not mutagenic or toxic to AS52 cells, but that it was actually protective against the cytotoxic and mutagenic effects of H 2 O 2 and hypoxanthine/xanthine oxidase. Tempol was also found to reverse chromosomal aberrations in human lymphocytes exposed to ionizing radiation and limited mutations caused by carcinogens such as neocarzinostatin [16]. These results demonstrated the benefit of using these compounds as protectors against free radical-mediated damage.…”

Section: Cellular Studies Mutagenicitymentioning

confidence: 77%

“…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: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

459

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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“…Therefore, we addressed whether DDR efficiency is affected in OS cells isolated from DKO Δ Osx1 or p53 ΔOsx1 mice. We examined cells for the presence of γH2AX foci, an early marker of DSBs (30), at different time points after treatment with neocarzinostatin (NCS), a well-characterized inducer of DSBs (31). Using immunofluorescence, we observed that DKO Δ Osx1 cells display elevated levels of spontaneous γH2AX foci formation (Fig.…”

Section: Resultsmentioning

confidence: 99%

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

et al. 2016

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Osteosarcoma (OS) is a highly metastatic form of bone cancer in adolescents and young adults which is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in pre-osteoblasts (WwoxΔosx1) displayed a severe inhibition of osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. Deletion of p53 in WwoxΔosx1 mice rescued the osteogenic defect. In addition, the Wwox;p53Δosx1 double knockout mice developed poorly differentiated osteosarcomas that resemble human OS in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared to mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared to p53 inactivation alone. These findings provide evidence that a WWOX-p53 network regulates normal bone formation and that disruption of this network in osteoprogenitors results in accelerated OS. The Wwox;p53Δosx1 double knockout establishes a new OS model with significant advancement over existing models.

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Nitroxide-mediated protection against X-ray-and neocarzinostatin-induced DNA damage

Cited by 37 publications

References 30 publications

Nitroxides Tempol and Tempo Induce Divergent Signal Transduction Pathways in MDA-MB 231 Breast Cancer Cells

Nitroxides Tempol and Tempo Induce Divergent Signal Transduction Pathways in MDA-MB 231 Breast Cancer Cells

The chemistry and biology of nitroxide compounds

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

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