The Topical Antimicrobial Zinc Pyrithione Is a Heat Shock Response Inducer That Causes DNA Damage and PARP-dependent Energy Crisis in Human Skin Cells
Reads0
Chats0
TLDR
It is demonstrated for the first time that cultured primary human skin keratinocytes and melanocytes display an exquisite vulnerability to nanomolar concentrations of ZnPT resulting in pronounced induction of heat shock response gene expression and impaired genomic integrity.Abstract:
The differentiated epidermis of human skin serves as an essential barrier against environmental insults from physical, chemical, and biological sources. Zinc pyrithione (ZnPT) is an FDA-approved microbicidal agent used worldwide in clinical antiseptic products, over-the-counter topical antimicrobials, and cosmetic consumer products including antidandruff shampoos. Here we demonstrate for the first time that cultured primary human skin keratinocytes and melanocytes display an exquisite vulnerability to nanomolar concentrations of ZnPT resulting in pronounced induction of heat shock response gene expression and impaired genomic integrity. In keratinocytes treated with nanomolar concentrations of ZnPT, expression array analysis revealed massive upregulation of genes encoding heat shock proteins (HSPA6, HSPA1A, HSPB5, HMOX1, HSPA1L, and DNAJA1) further confirmed by immunodetection. Moreover, ZnPT treatment induced rapid depletion of cellular ATP levels and formation of poly(ADP-ribose) polymers. Consistent with an involvement of poly(ADP-ribose) polymerase (PARP) in ZnPT-induced energy crisis, ATP depletion could be antagonized by pharmacological inhibition of PARP. This result was independently confirmed using PARP-1 knockout mouse embryonic fibroblasts that were resistant to ATP depletion and cytotoxicity resulting from ZnPT exposure. In keratinocytes and melanocytes, single-cell gel electrophoresis and flow cytometric detection of γ-H2A.X revealed rapid induction of DNA damage in response to ZnPT detectable before general loss of cell viability occurred through caspase-independent pathways. Combined with earlier experimental evidence that documents penetration of ZnPT through mammalian skin, our findings raise the possibility that this topical antimicrobial may target and compromise keratinocytes and melanocytes in intact human skin.read more
Citations
More filters
Journal ArticleDOI
Comparative evaluation of antimicrobials for textile applications.
TL;DR: Each antimicrobial technology has specific risks and benefits that should be taken into account in evaluating the suitability of different antimicrobial products, and results indicated that nanoscale silver and silver salts that achieve functionality with very low application rates offer clear potential benefits for textile use.
Journal ArticleDOI
Resveratrol Prevents Epigenetic Silencing of BRCA-1 by the Aromatic Hydrocarbon Receptor in Human Breast Cancer Cells
TL;DR: The hypothesis that epigenetic silencing of the BRCA-1 gene by the AhR is preventable with Res is supported and provide the molecular basis for the development of dietary strategies based on natural AhR antagonists.
Journal ArticleDOI
Protective effects of novel derivatives of vitamin D3 and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and P53 defense mechanisms
Anyamanee Chaiprasongsuk,Zorica Janjetovic,Tae Kang Kim,Stuart G. Jarrett,John A. D'Orazio,Michael F. Holick,Edith K.Y. Tang,Robert C. Tuckey,Uraiwan Panich,Wei Li,Andrzej Slominski,Andrzej Slominski +11 more
TL;DR: Pretreatment of keratinocytes with 1,25(OH)2D3 or CYP11A1-derived vitamin D3- or lumisterol hydroxy-derivatives, protected them against UVB-induced damage via activation of the Nrf2-dependent antioxidant response and p53-phosphorylation, as well as by the induction of the DNA repair system.
Journal ArticleDOI
Systematic Quantification of Population Cell Death Kinetics in Mammalian Cells
TL;DR: This results provide the first comprehensive survey of cell death kinetics and analysis of rapid-onset lethal compounds, and used STACK to profile the effects of over 1,800 bioactive compounds on cell death in two human cancer cell lines, resulting in a large and freely available dataset.
Journal ArticleDOI
The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death.
Shuxi Qiao,Shasha Tao,Montserrat Rojo de la Vega,Sophia L. Park,Amanda A Vonderfecht,Suesan L Jacobs,Donna D. Zhang,Georg T. Wondrak +7 more
TL;DR: Amodiaquine (AQ), a clinical 4-aminoquinoline antimalarial with unexplored cancer-directed chemotherapeutic potential, causes autophagic-lysosomal and proliferative blockade in melanoma cells that surpasses that of its parent compound chloroquine.
References
More filters
Journal ArticleDOI
A simple technique for quantitation of low levels of DNA damage in individual cells
TL;DR: Human lymphocytes were exposed to X-irradiation or treated with H2O2 and the extent of DNA migration was measured using a single-cell microgel electrophoresis technique under alkaline conditions and this technique appears to be sensitive and useful for detecting damage and repair in single cells.
Journal ArticleDOI
Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing.
Raymond R. Tice,E. Agurell,Diana Anderson,B. Burlinson,Andreas Hartmann,H. Kobayashi,Y. Miyamae,Emilio Rojas,J.-C. Ryu,Y. F. Sasaki +9 more
TL;DR: The expert panel reached a consensus that the optimal version of the Comet assay for identifying agents with genotoxic activity was the alkaline (pH > 13) versions of the assay developed by Singh et al.
Journal ArticleDOI
γ-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin
TL;DR: The role of γ-H2AX in DNA damage response in the context of chromatin is reviewed and the use of this modification as a surrogate marker for mechanistic studies of DSB induction and processing is discussed.
SURVEY AND SUMMARY c-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin
TL;DR: In this article, the role of the histone H2A variant, H2AX, in DNA double-strand break (DSBs) induction and processing has been discussed.
Journal ArticleDOI
Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.
Zhao-Qi Wang,Bernhard Auer,Laura Stingl,H. Berghammer,D. Haidacher,Manfred Schweiger,Erwin F. Wagner +6 more
TL;DR: The generation of viableADPRT-/-mice negates an essential role for this enzyme in normal chromatin function, but the impaired proliferation and the onset of skin lesions in older mice suggest a function for ADPRT in response to environmental stress.