Keratinocyte Carcinoma and Photoprevention: The Protective Actions of Repurposed Pharmaceuticals, Phytochemicals and Vitamins

Abstract

Ultraviolet radiation (UVR) arising from sun exposure represents a major risk factor in the development of keratinocyte carcinomas (KCs). UVR exposure induces dysregulated signal transduction, oxidative stress, inflammation, immunosuppression and DNA damage, all of which promote the induction and development of photocarcinogenesis. Because the incidence of KCs is increasing, better prevention strategies are necessary. In the concept of photoprevention, protective compounds are administered either topically or systemically to prevent the effects of UVR and the development of skin cancer. In this review, we provide descriptions of the pathways underlying photocarcinogenesis and an overview of selected photoprotective compounds, such as repurposed pharmaceuticals, plant-derived phytochemicals and vitamins. We discuss the protective potential of these compounds and their effects in pre-clinical and human trials, summarising the mechanisms of action involved in preventing photocarcinogenesis.

Keywords: cancer; cancer prevention; keratinocyte carcinoma; mechanism of action; photocarcinogenesis; phytochemicals; skin; skin cancer; ultraviolet radiation.

Figure 1

Simplified schematic of (A): UV-induced DNA damage caused by direct UV absorption by the DNA molecules resulting in DNA lesions such as 6–4 photoproducts (6–4PPs) or cyclobutane pyrimidine dimers (CPDs) which are repaired by XPC and the nuclear excision repair pathway; (B): UV-induced oxidative stress caused by increased reactive oxygen species (ROS) production resulting in damaged DNA (8-oxo-hydroxyguanine lesions), lipid (lipid peroxidation; LPO) and protein (carbonylation and other irreversible changes) molecules; (C): UV-induced inflammation, immunosuppression and signal transduction caused by dysregulated mitogen-activated protein kinase (MAPK) activity resulting in activation and transcription of inflammatory mediators. Furthermore, UV radiation induces immunosuppressive mediators via the photoisomersiation of trans-urocanic acid (UCA) to cis-UCA. Abbreviations: AMPK: AMP-activated protein kinase, AP-1: activator protein 1, COX-2: cyclooxygenase 2, IL: interleukin, PGE₂: prostaglandin E_2, TLR4: Toll-like receptor 4.

Figure 2

Crosstalk linking UV-induced events: DNA damage, oxidative stress, inflammation, immunosuppression and dysregulated signal transduction as presented in Figure 1. All five events are involved in crosstalk, creating an environment that promotes photocarcinogenesis. Abbreviations: AMPK: AMP-activated protein kinase, AP-1: activator protein 1, COX-2: cyclooxygenase 2, IL: interleukin, MAPK: mitogen-activated protein kinase, NER: nuclear excision repair, PGE₂: prostaglandin E₂, ROS: reactive oxygen species, TNF: tumour necrosis factor, t(trans)/c(cis)-UCA: urocanic acid.

Figure 3

Overview of the reviewed compounds and their mechanisms. The Venn diagram represents four of the five UV-induced events (DNA damage, oxidative stress, inflammation and immunosuppression). UV-induced events targeted by each compound are shown. Dysregulated signal transduction is not included in the figure as it can be reflected as induction and stimulation of the other four UV-induced events. Abbreviations: NSAIDs, non-steroidal anti-inflammatory drugs.