Abstract by Celina Pihl
Cutaneous squamous cell carcinoma is the second most common type of keratinocyte carcinoma with 2.4 million cases a year. Ultraviolet radiation (UVR) contributes to most of these cases, representing a major risk factor. Topical sunscreen is under-used with considerable adherence challenges. Oral photoprotection presents an emerging alternative. Through oral intake of photoprotective compounds, such as phytochemicals or pharmaceuticals, photoprotection may be boosted. Nicotinamide is reported to prevent the formation of new keratinocyte carcinomas in high-risk patients, but further optimisation of efficacy is still possible. The overall aim of this thesis was to explore the efficacy of orally delivered photoprotectants to protect against UVR-induced squamous cell carcinoma development, with an additional focus on exploring nicotinamide combinations.
The studies were performed in a hairless mouse model treated with the photoprotectants through either their drinking water or feed. The mice were exposed to UVR three times per week to induce tumour development. Photoprotection was primarily evaluated by the time until tumour onset.
Photoprotection was demonstrated by two phytochemical compounds, phloroglucinol and syringic acid, demonstrating a delay in tumour onset compared to UVR control mice (Study I). Phloroglucinol was shown to reduce tumour number but not size, indicating a protective role in the initial stages of tumour development. In contrast, the phytochemicals quercetin and fisetin accelerated tumour onset, with quercetin further increasing tumour growth (Study II). The opposite effects of the included phytochemicals highlight the bidirectional impact phytochemicals may have on carcinogenesis, indicating a need for caution. Four repurposed pharmaceuticals (Study III), including metformin thought to be photoprotective, and two phytochemicals (Study I and II) failed to impact tumour development, showcasing a lack of oral photoprotection potential for compounds otherwise considered to be photoprotective. Nicotinamide treatment provided effective protection in all three studies.
Given the photoprotection of nicotinamide, study IV explored combinational treatments with compounds of different mechanisms of action. Treatments included: nicotinamide monotherapy, nicotinamide combined with phloroglucinol, an antioxidant, and nicotinamide combined with metformin thought to act anti-proliferative. All treatments delayed tumour onset compared to UVR control mice. Nicotinamide combined with phloroglucinol was comparable to monotherapy, whereas the metformin combination was inferior. Nicotinamide combined with phloroglucinol reduced DNA damage compared to both the UVR control and monotherapy, indicating an improved photoprotection mechanism.
Overall, the studies provide important insight into potential compounds for oral photoprotection, indicating that nicotinamide remains an excellent candidate. Furthermore, the successful results of nicotinamide and phloroglucinol treatment demonstrate an avenue for enhancing photoprotection that should be further explored with additional compounds to improve skin cancer prevention.