NADPH Oxidases NOXs and DUOXs as Putative Targets for Cancer Therapy

Weyemi, Urbain; Redon, Christophe E.; Parekh, Palak R.; Dupuy, Corinne; Bonner, William M.

doi:10.2174/1871520611313030013

Cited by 42 publications

(16 citation statements)

References 125 publications

(60 reference statements)

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“…A parallel line of research has demonstrated that superoxide production by NADPH oxidase complexes is elevated in a high proportion of cancer cell lines (7, 15). It appears that NADPH oxidase activation and dysfunctional mitochondria collaborate to increase superoxide production in a high proportion of cancers.…”

Section: Increased Superoxide Production May Rationalize Selective Sementioning

confidence: 99%

Increasing Superoxide Production and the Labile Iron Pool in Tumor Cells may Sensitize Them to Extracellular Ascorbate

McCarty

Contreras

2014

Front. Oncol.

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Low millimolar concentrations of ascorbate are capable of inflicting lethal damage on a high proportion of cancer cells lines, yet leave non-transformed cell lines unscathed. Extracellular generation of hydrogen peroxide, reflecting reduction of molecular oxygen by ascorbate, has been shown to mediate this effect. Although some cancer cell lines express low catalase activity, this cannot fully explain the selective sensitivity of cancer cells to hydrogen peroxide. Ranzato and colleagues have presented evidence for a plausible new explanation of this sensitivity – a high proportion of cancers, via NADPH oxidase complexes or dysfunctional mitochondria, produce elevated amounts of superoxide. This superoxide, via a transition metal-catalyzed transfer of an electron to the hydrogen peroxide produced by ascorbate, can generate deadly hydroxyl radical (Haber–Weiss reaction). It thus can be predicted that concurrent measures which somewhat selectively boost superoxide production in cancers will enhance their sensitivity to i.v. ascorbate therapy. One way to achieve this is to increase the provision of substrate to cancer mitochondria. Measures which inhibit the constitutive hypoxia-inducible factor-1 (HIF-1) activity in cancers (such as salsalate and mTORC1 inhibitors, or an improvement of tumor oxygenation), or that inhibit the HIF-1-inducible pyruvate dehydrogenase kinase (such as dichloroacetate), can be expected to increase pyruvate oxidation. A ketogenic diet should provide more lipid substrate for tumor mitochondria. The cancer-killing activity of 42°C hyperthermia is to some degree contingent on an increase in oxidative stress, likely of mitochondrial origin; reports that hydrogen peroxide synergizes with hyperthermia in killing cancer cells suggest that hyperthermia and i.v. ascorbate could potentiate each other’s efficacy. A concurrent enhancement of tumor oxygenation might improve results by decreasing HIF-1 activity while increasing the interaction of ascorbic acid with oxygen. An increased pool of labile iron in cancer cells may contribute to the selective susceptibility of many cancers to i.v. ascorbate; antagonism of NF-kappaB activity with salicylate, and intravenous iron administration, could be employed to further elevate free iron in cancers.

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Section: Increased Superoxide Production May Rationalize Selective Sementioning

confidence: 99%

Increasing Superoxide Production and the Labile Iron Pool in Tumor Cells may Sensitize Them to Extracellular Ascorbate

McCarty

Contreras

2014

Front. Oncol.

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“…In contrast, DUOX2 expression is normal or even decreased in the majority of the differentiated thyroid carcinomas [57,58]. …”

Section: Nox4mentioning

confidence: 99%

Role of the NADPH Oxidases DUOX and NOX4 in Thyroid Oxidative Stress

Carvalho

Dupuy

2013

Eur Thyroid J

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Somatic mutations are present at high levels in the rat thyroid gland, indicating that the thyrocyte is under oxidative stress, a state in which cellular oxidant levels are high. The most important class of free radicals, or reactive metabolites, is reactive oxygen species (ROS), such as superoxide anion (O₂^-), hydroxyl radical (OH) and hydrogen peroxide (H₂O₂). The main source of ROS in every cell type seems to be mitochondrial respiration; however, recent data support the idea that NADPH:O(₂) oxidoreductase flavoproteins or simply NADPH oxidases (NOX) are enzymes specialized in controlled ROS generation at the subcellular level. Several decades ago, high concentrations of H₂O₂ were detected at the apical surface of thyrocytes, where thyroid hormone biosynthesis takes place. Only in the last decade has the enzymatic source of H₂O₂ involved in thyroid hormone biosynthesis been well characterized. The cloning of two thyroid genes encoding NADPH oxidases dual oxidases 1 and 2 (DUOX1 and DUOX2) revealed that DUOX2 mutations lead to hereditary hypothyroidism in humans. Recent reports have also described the presence of NOX4 in the thyroid gland and have suggested a pathophysiological role of this member of the NOX family. In the present review, we describe the participation of NADPH oxidases not only in thyroid physiology but also in gland pathophysiology, particularly the involvement of these enzymes in the regulation of thyroid oxidative stress.

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“…The “free radical theory of aging” suggests that aging results from the accumulation of random molecular damage caused by ROS (Harman 1956), although alternative explanations of aging have also been proposed (Blagosklonny 2008). Tumors, including glioblastomas, typically display dysregulation of the redox balance that develops in cancer cells in response to the intracellular production of ROS and the depletion of antioxidant proteins (Weyemi and others 2013). Deviations from the normal redox homeostasis and oxidative damage have been detected in several degenerative neurological disorders, such as in Alzheimer’s disease and Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis (Acar and others 2003; Adibhatla and Hatcher 2008; D’Amico and others 2013; Jomova and others 2010; Mark and others 1997; Shi and Gibson 2007).…”

Section: Detrimental Effects Of Ros and Rns During Nervous System Devmentioning

confidence: 99%

Cross Talk between Cellular Redox Status, Metabolism, and p53 in Neural Stem Cell Biology

Forsberg

Giovanni

2014

The Neuroscientist

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In recent years, the importance of the cellular redox status for neural stem cell (NSC) homeostasis has become increasingly clear. Similarly, the transcription factor and tumor suppressor p53 has been implicated in the regulation of cell metabolism, in antioxidant response, and in stem cell quiescence and fate commitment. Here, we explore the known and putative functions of p53 in antioxidant response and metabolic control and examine how reactive oxygen species, p53, and related cellular signaling may regulate NSC homeostasis, quiescence, and differentiation. We also discuss the role that PI3K-Akt-mTOR signaling plays in NSC biology and oxidative signaling and how p53 contributes to the regulation of this signaling cascade. Finally, we invite reflection on the several unanswered questions of the role that p53 plays in NSC biology and metabolism, anticipating future directions.

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NADPH Oxidases NOXs and DUOXs as Putative Targets for Cancer Therapy

Cited by 42 publications

References 125 publications

Increasing Superoxide Production and the Labile Iron Pool in Tumor Cells may Sensitize Them to Extracellular Ascorbate

Increasing Superoxide Production and the Labile Iron Pool in Tumor Cells may Sensitize Them to Extracellular Ascorbate

Role of the NADPH Oxidases DUOX and NOX4 in Thyroid Oxidative Stress

Cross Talk between Cellular Redox Status, Metabolism, and p53 in Neural Stem Cell Biology

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