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Cellular oxidative stress contributes to solar ultraviolet (UV) radiation‐induced skin photoaging and photocarcinogenesis. Light‐driven electron and energy transfer reactions involving non‐DNA chromophores are a major source of reactive oxygen species (ROS) in skin, and the molecular identity of numerous endogenous chromophores acting as UV‐photosensitizers has been explored. Methylglyoxal (MG), a glycolytic byproduct bearing a UV‐active α‐dicarbonyl‐chromophore, is generated under metabolic conditions of increased glycolytic flux, associated with posttranslational protein adduction in human tissue. Here, we undertook a photophysical and photochemical characterization of MG substantiating its fluorescence properties (Stokes shift), phosphorescence lifetime, and quantum yield of singlet oxygen (1O2) formation. Strikingly, upon UV‐excitation (290 nm), a clear emission (around 490 nm) was observed (phosphorescence‐lifetime: 224.2 milliseconds). At micromolar concentrations, MG acts as a UVA‐photosensitizer targeting human HaCaT‐keratinocytes inducing photooxidative stress and caspase‐dependent cell death substantiated by zVADfmk‐rescue and Alexa‐488 caspase‐3 flow cytometry. Transcriptomic analysis indicated that MG (photoexcited by noncytotoxic doses of UVA) elicits expression changes not observable upon isolated MG‐ or UVA‐treatment, with upregulation of the proteotoxic (CRYAB, HSPA6) and oxidative (HMOX1) stress response. Given the metabolic origin of MG and its role in human pathology, future investigations should address the potential involvement of MG‐photosensitizer activity in human skin photodamage. [ABSTRACT FROM AUTHOR]

UV‐chromophores contained in human skin may act as endogenous sensitizers of photooxidative stress and can be employed therapeutically for the photodynamic elimination of malignant cells. Here, we report that 6‐formylindolo[3,2‐b]carbazole (FICZ), a tryptophan‐derived photoproduct and endogenous aryl hydrocarbon receptor agonist, displays activity as a nanomolar sensitizer of photooxidative stress, causing the photodynamic elimination of human melanoma and nonmelanoma skin cancer cells in vitro and in vivo. FICZ is an efficient UVA/Visible photosensitizer having absorbance maximum at 390 nm (ε = 9180 L mol−1 cm−1), and fluorescence and singlet oxygen quantum yields of 0.15 and 0.5, respectively, in methanol. In a panel of cultured human squamous cell carcinoma and melanoma skin cancer cells (SCC‐25, HaCaT‐ras II‐4, A375, G361, LOX), photodynamic induction of cell death was elicited by the combined action of solar simulated UVA (6.6 J cm−2) and FICZ (≥10 nm), preceded by the induction of oxidative stress as substantiated by MitoSOX Red fluorescence microscopy, comet detection of Fpg‐sensitive oxidative genomic lesions and upregulated stress response gene expression (HMOX1, HSPA1A, HSPA6). In SKH1 "high‐risk" mouse skin, an experimental FICZ/UVA photodynamic treatment regimen blocked the progression of UV‐induced tumorigenesis suggesting feasibility of harnessing FICZ for the photooxidative elimination of malignant cells in vivo. [ABSTRACT FROM AUTHOR]