Photoinduced Generation of Hydrogen Peroxide and Hydroxyl Radicals in Melanins

Korytowski, Witold; Pilas, Barbara; Sarna, Tadeusz; Kalyanaraman, Balaraman

doi:10.1111/j.1751-1097.1987.tb05362.x

Cited by 160 publications

(116 citation statements)

References 17 publications

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“…However, under extreme conditions, for example harmful levels of UVA radiation, melanin can also have deleterious effects. These include toxicity 42,43 , the ability to produce reactive oxygen species (ROS) 44 and photodegradation leading to hydrogen peroxide production 45 . Pheomelanin may also have a carcinogenic effect that contributes to malignant melanoma formation as one study found that albinos with melanocytes incapable of producing melanin had a very low incidence of melanoma, with only 27 cases reported in the literature 46 .…”

Section: Melanocytes and Melaninmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Section: Melanocytes and Melaninmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…UV radiation is the main physiological stimulus for human skin pigmentation; recent work suggests this process may be mediated by nitric oxide activation of guanylate cyclase, in manner similar to the initiation of endothelial cell relaxation (47). It has been well characterized that UV irradiation of both eumelanin and pheomelanin can lead to the production of superoxide and peroxide from reaction of the photo-excited pigment with oxygen (48)(49)(50), but the photo-yields are small compared with the ability of melanin itself to attenuate such ROS. Melanoma cells, even with low levels of endogenous anti-oxidants such as GSH, are relatively resistant to photo-induced stress (51).…”

Section: Response Of Melanin To Uv Lightmentioning

confidence: 99%

Redox Regulation in Human Melanocytes and Melanoma

Meyskens

Farmer

Fruehauf

2001

Pigment Cell Research

207

159

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totic phenotype in the transformed cell. This conceptual frameThe human melanocyte is continuously exposed to intrinsic and work offers testable steps to determine the role of redox extrinsic sources of reactive biochemical species, but is finely tuned via the intrinsic anti-oxidant and radical properties of alterations in the carcinogenic evolution, prevention and treatmelanin to suppress the build-up of an altered redox phenoment of melanoma and other diseases of the melanocyte. type. We propose that this control is lost during melanomageKey words: Transcription factor, NF-kB, AP-1, Reactive nesis and inappropriate redox-sensitive transcriptional factor oxygen species, Glutathione, Superoxide anion activations occur which result in enhancement of an anti-apopand glutathione (GSH), melanin as an anti-oxidant and cellular pro-oxidant, response of melanin to ultraviolet (UV) light, anti-oxidant levels and melanomagenesis, redox regulation of transcription factors, and a conceptual framework for the pathogenesis of melanoma based on altered redox control.In response to UV light an inflammatory response is generated involving the production of massive amounts of various cytokines and growth factors by keratinocytes, a vigorous inflammatory/immunologic host response, and in some cases angiogenesis. Each one of these responses generates or stimulates the production of reactive oxygen or nitrogen species. Additionally, UV light interacts directly with biochemical constituents of the melanocyte to generate intracellular reactive oxygen species (ROS), hydrogen peroxide and/or superoxide anion. The sum total of these alterations is that melanocytes are subjected to an panoply of redox changes with secondary effects on melanin synthesis and a variety of signaling cascades.We suggest that alterations in these processes are fundamentally involved in the pathogenesis of melanoma and perhaps other pathologic states. These observations encum-

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“…Much evidence suggests that melanin is a major photosensitizer involved in the causation of melanoma by sunlight in pigmented species. In vitro studies of isolated melanin show that it is an efficient photosensitizer, producing a range of oxidizing species (21,23,32) that are capable of exerting biological effects such as causing DNA damage (33) and forming lesions such as 8-hydroxydeoxyguanosine that are mutagenic (34,35). This potential for photosensitization by melanin was supported in this Xiphophorus model, with previous data (n Ͼ 600 fish) showing that unpigmented fish did not show melanoma causation on UV irradiation (16).…”

Section: Relevance Of the Action Spectrum For ⌽Ox To Melanoma Causatimentioning

confidence: 99%

“…The insoluble polymer melanin contains stable free radicals, and characterization of these radicals by EPR spectroscopy is a method of choice for its study (18,19). Central to its role in melanoma causation, however, is that in vitro illumination of melanin by UV and blue light generates further metastable reactive melanin radicals (that might react directly with biological molecules) and that also release reactive oxidants such as superoxide (and hence hydrogen peroxide and potentially hydroxyl radicals) with identical action spectra (20)(21)(22)(23) (shown in Reaction 1)…”

mentioning

confidence: 99%

UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production

Wood¹,

Berwick²,

Ley

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

109

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Controversy continues both as to which wavelengths of sunlight cause melanoma and the mechanisms by which these different wavelengths act. Direct absorption of UVB by DNA is central in albino animal models, but melanin-pigmented models have shown major contributions by wavelengths longer than UVB that are thought to be mediated by photosensitized oxidant production. The only model for which the action spectrum of melanoma causation is known is a genetically melanoma-susceptible specific cross of Xiphophorus fish. We used electron paramagnetic resonance to quantitatively detect the UV induction of reactive melanin radicals in situ in the melanin-containing cells in the skin of this model and derived the action spectrum for melanin-photosensitized oxidant production (⌽ ox). This action spectrum was identical to that for melanoma induction (⌽ mel). These results confirm the hypothesis that melanin-photosensitized radical production is the major causative step of melanoma in this model and demonstrate that the wavelengths and mechanisms of melanoma causation in different models are dependent on the presence of melanin. This approach should be applicable to humans, thus providing an accurate surrogate for ⌽ mel for prevention studies.action spectrum ͉ free radical C utaneous malignant melanoma incidence continues to increase (1), yet prevention strategies are hindered by a lack of knowledge of which wavelengths of sunlight cause melanoma, and the mechanisms by which these different wavelengths cause melanoma are not understood. Although nonmelanoma skin cancers are predominantly caused by UVB wavelengths, melanoma causation has efficiently been observed by wavelengths longer than UVB, such as UVA, with this observation supported by both experimental animal (2-4) and human epidemiological evidence (5-7). However, the role of UVA in melanoma causation still remains controversial (8, 9). Similarly, there is controversy over the mechanisms by which these different wavelengths act. The prevailing view is that UVA leads to DNA photooxidation, with melanin thought to be the important photosensitizer when present, whereas UVB leads to pyrimidine dimer formation through direct absorption by DNA (6, 10). The relative importance of UVB and UVA in these processes is, however, currently under scrutiny, because some have found that UVA appears able to produce pyrimidine dimers in cultured cells (11,12), whereas melanin can act as an efficient UVB sensitizer in vivo (13), and so these questions need further investigation.The question of which wavelengths cause a biological effect, in this case melanoma, is best evaluated through measuring the wavelength dependence of that effect to generate its action spectrum (14). Although melanoma has been observed in many species (15), there is only one model in which the action spectrum of melanoma causation has been determined, namely select interspecies crosses of Xiphophorus fish (4, 16). Despite the phylogenetic distance between Xiphophorus and humans, and the differences in skin structure...

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Photoinduced Generation of Hydrogen Peroxide and Hydroxyl Radicals in Melanins

Cited by 160 publications

References 17 publications

Role of the pro-survival molecule Bfl-1 in melanoma

Role of the pro-survival molecule Bfl-1 in melanoma

Redox Regulation in Human Melanocytes and Melanoma

UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production

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