Vitamin C Derivative Ascorbyl Palmitate Promotes Ultraviolet-B-Induced Lipid Peroxidation and Cytotoxicity in Keratinocytes

Meves, Alexander; Stock, Sibylle N.; Beyerle, Astrid; Pittelkow, Mark R.; Péus, Dominik

doi:10.1046/j.1523-1747.2002.19521.x

Cited by 40 publications

(36 citation statements)

References 34 publications

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“…Moderate skin photoprotection by topical application of antioxidants has been demonstrated in many experiments on animal and human skin, and inhibition of mouse skin photocarcinogenesis by these agents has been observed as reviewed recently [2]. However, the therapeutic efficacy of topical antioxidants is limited by their sacrificial depletion, potential photodegradation, and spontaneous UV-enhanced redox chemistry which can exert prooxidant effects and interfere with physiological redox signaling [4,21]. Due to these limitations, topical antioxidants can only play an adjuvant role in skin protection against photo-oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress

Wondrak¹,

Cabello²,

Villeneuve³

et al. 2008

Free Radical Biology and Medicine

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Strong experimental evidence suggests the involvement of photo-oxidative stress mediated by reactive oxygen species as a crucial mechanism of solar damage relevant to human skin photoaging and photocarcinogenesis. Based on the established role of antioxidant response element (ARE)-mediated gene expression in cancer chemoprevention, we tested the hypothesis that small molecule Nrf2-activators may serve a photo-chemopreventive role by targeting skin cell photo-oxidative stress. A luciferase-based reporter gene assay was used as a primary screen for the identification of novel agents that modulate the Nrf2-Keap1 signaling pathway. A series of cinnamoyl-based electrophilic Michael acceptors including cinnamic aldehyde and methyl-1-cinnamoyl-5-oxo-2-pyrrolidine-carboxylate was identified as potent Nrf2-activators. Hit confirmation was performed in a secondary screen, based on immunodetection of Nrf2 protein upregulation in human Hs27 skin fibroblasts, HaCaT keratinocytes, and primary skin keratinocytes. Bioefficacy profiling of positive test compounds in skin cells demonstrated compound-induced upregulation of hemeoxygenase I and NAD(P)H-quinone oxidoreductase, two Nrf2 target genes involved in the cellular antioxidant response. Pretreatment with cinnamoylbased Nrf2-activators suppressed intracellular oxidative stress and protected against photooxidative induction of apoptosis in skin cells exposed to high doses of singlet oxygen. Our pilot studies suggest feasibility of developing cinnamoyl-based Nrf2-activators as novel photochemopreventive agents targeting skin cell photo-oxidative stress.

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Section: Introductionmentioning

confidence: 99%

Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress

Wondrak¹,

Cabello²,

Villeneuve³

et al. 2008

Free Radical Biology and Medicine

View full text Add to dashboard Cite

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“…Paradoxically, some sunscreens and sun-blockers act as potent triplet state UV sensitizers, enhancing light-driven formation of ROS and skin cell photodamage (Gulston and Knowland, 1999). Although moderate skin photoprotection by topical application of antioxidants has been demonstrated in many experiments on animal and human skin (Packer and Valacchi, 2002), the therapeutic effectiveness of skin administration of antioxidants is limited by their sacrificial depletion, their pronounced spontaneous redox chemistry, and their negative interference with the highly regulated skin antioxidant network (Meves et al, 2002). Harmful interaction of chemical antioxidants with essential redox signaling in human skin may be anticipated because recent reports point to a significant potential for antioxidant enhanced carcinogenesis in transgenic mice with up-regulated antioxidant responses (Lu et al, 1997).…”

mentioning

confidence: 99%

Identification of Quenchers of Photoexcited States as Novel Agents for Skin Photoprotection

Wondrak

Jacobson

2004

J Pharmacol Exp Ther

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Photooxidative stress is a key mechanism in UVA-induced skin photodamage. Photoexcited states of endogenous UVA chromophores such as porphyrins, melanin precursors, and crosslink-fluorophores of skin collagen exert skin photodamage by direct reaction with substrate molecules (type I photosensitization) or molecular oxygen (type II), leading to formation of reactive oxygen species. Based on our previous research on the role of photoexcited states of endogenous skin chromophores as sensitizers of photooxidative stress, we describe here the identification of a novel class of chemopreventive agents for topical skin photoprotection: quenchers of photoexcited states (QPES). QPES compounds antagonize the harmful excited state chemistry of endogenous sensitizers by physical quenching, facilitating the harmless return of the sensitizer excited state to the electronic ground state by energy dissipation. To identify QPES compounds suitable for development, we designed a primary screening assay based on QPES suppression of photosensitized plasmid cleavage using conditions that exclude antioxidants. This screen is followed with a screen to test for nonsacrificial quenching of dye-sensitized singlet oxygen ( 1 O 2 ) formation by electron paramagnetic resonance detection of 2,2,6,6-tetramethyl-piperidine-1-oxyl, a stable free radical indicative of 1 O 2 formation. These initial screens identified a pyrrolidine pharmacophore with pronounced QPES activity, and L-proline and other noncytotoxic proline derivatives containing this pharmacophore were then screened for efficacy in cellular models of sensitized photodamage. These compounds showed QPES protection against dye-sensitized and psoralen-UVA-induced apoptosis and suppression of proliferation in cultured human skin keratinocytes and fibroblasts. Furthermore, QPES photoprotection of reconstructed full thickness human skin exposed to solar simulated light has been demonstrated.

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“…However, VC is known to produce ROS when given concomitantly with sulindac, 23) and lipid component of ascorbyl palmitate is reported to contribute to the generation of oxidized lipid metabolites that are epidermal cell toxicity. 24) Consequently, we expected VC to promote sorafenib-induced apoptosis. However, sorafenib-induced apoptosis in HaCaT cells was suppressed by the VC derivative, suggesting that the repressive effect of the VC derivative on epidermal keratinocyte toxicity induced by sorafenib does not mediate the mechanisms of apoptosis by ROS.…”

Section: Discussionmentioning

confidence: 99%

Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib

Yamamoto

Shichiri

Ishida³

et al. 2017

Biological & Pharmaceutical Bulletin

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Hand-foot skin reaction is recognized as one of the most common adverse events related to multiple tyrosine kinase inhibitors, but an effective prevention method has not been identified. The chief aim of this study was to find a mechanism-based preventive method for the skin toxicity induced by sorafenib using vitamin C derivatives. The effects of ascorbyl-2-phosphate magnesium (P-VC-Mg) on the molecular and pathological changes induced by sorafenib were investigated in human keratinocyte HaCaT cells. The cell growth inhibition and apoptotic effects of sorafenib were attenuated by P-VC-Mg. Moreover, P-VC-Mg inhibited the decrease of signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of apoptosis suppressors treated by sorafenib. HaCaT cells transfected with the STAT3 dominant-negative form (STAT3DN) and STAT3 small interfering RNA (siRNA) combined with P-VC-Mg did not exhibit the attenuation of cell growth inhibition. Interestingly, after exposure to sorafenib in a three dimensional (3D) skin model assay, the basal layer was significantly thickened and the granular and spinous layers became thinner. In contrast, after exposure to sorafenib with P-VC-Mg, the thickness of the basal, granular, and spinous layers was similar to that of the control image. These findings suggest that P-VC-Mg attenuates sorafenibinduced apoptosis and pathological changes in human keratinocyte cells and in the 3D skin model mediated by the maintenance of STAT3 activity.Key words vitamin C; multi-targeted tyrosine kinase inhibitor; hand-foot skin reaction (HFSR); ascorbic acidThe treatment for metastasis renal cell carcinoma has led to significant advances by molecular targeted drugs. However, some safety issues have recently emerged. In particular, adverse reactions induced by multiple tyrosine kinase inhibitors (mTKIs) are some of the major causes for the interruption of therapy involving these drugs. 1) Dermatological adverse events, also called hand−foot skin reaction, manifest topically in the palmar and plantar regions, and the pathological mechanism underlying these events is unclear. Because there are few treatment options for renal cell carcinoma and hepatocellular carcinoma, the success of therapy is determined by the length of efficient treatment and the management of adverse reactions. Therefore, appropriate management of the side effects will lead to an improvement in not only the QOL, but also the outcome of therapy 2,3) Although the dermatological adverse reactions induced by mTKIs are recognized as serious problems in clinical practice, a preventive method based on the pathological mechanism of these drugs has not been established.Previously, we reported that the inhibition of signal transducer and activator of transcription 3 (STAT3) contributes to the mechanism for keratinocyte toxicity induced by mTKIs, 4) and that the development of hand-foot skin reaction induced by mTKIs is associated with STAT3 polymorphisms. 5)STAT3 is a well-known transcriptional factor that regulates ce...

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Vitamin C Derivative Ascorbyl Palmitate Promotes Ultraviolet-B-Induced Lipid Peroxidation and Cytotoxicity in Keratinocytes

Cited by 40 publications

References 34 publications

Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress

Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress

Identification of Quenchers of Photoexcited States as Novel Agents for Skin Photoprotection

Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib

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