Department of Dermatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.
Department of Dermatology, Aalborg University Hospital, Aalborg, Denmark.
Dermatology. 2024;240(3):453-461. doi: 10.1159/000538445. Epub 2024 Apr 10.
INTRODUCTION: Ultraviolet radiation (UVR) is the primary risk factor for keratinocyte carcinomas. Oral supplementation with nicotinamide (NAM) is reported to reduce the formation of new keratinocyte carcinomas. NAM's photoprotection is mediated by enhanced DNA repair. We wanted to explore whether NAM in combination with antiproliferative (metformin [Met]) or antioxidant (phloroglucinol [PG]) compounds could potentially enhance its photoprotective effects. METHODS: Hairless mice (C3.Cg-Hrhr/TifBomTac) were treated orally with either a standard dose of NAM monotherapy (NAM-mono; 600 mg/kg) or NAM (400 mg/kg) combined with Met (200 mg/kg) (NAM-Met) or PG (75 mg/kg) (NAM-PG). Mice were irradiated with 3.5 standard erythema doses of UVR three times per week to induce tumour development. Photoprotective effects were based on (i) tumour onset of the first three tumours, (ii) skin photodamage, and (iii) DNA damage (cyclobutane pyrimidine dimers [CPDs] and pyrimidine-pyrimidone (6-4) photoproducts [6-4PPs]). RESULTS: All mice treated with NAM demonstrated a delay in tumour onset and reduced tumour burden compared to the UV control group (NAM, NAM-Met, NAM-PG vs. UV control: p ≤ 0.015). NAM-mono and NAM-PG increased time until all three tumours with no difference between them, indicating a similar degree of photoprotection. NAM-mono had no effect on DNA damage compared to the UV control group (p > 0.05), whereas NAM-PG reduced 6-4PP lesions (p < 0.01) but not CPDs (p > 0.05) compared to NAM-mono. NAM-Met delayed the onset of the third tumour compared to the UV control but demonstrated a quicker onset compared to NAM-mono, suggesting inferior photoprotection compared to nicotinamide monotherapy. CONCLUSION: NAM-PG was as effective in delaying UVR-induced tumour onset as NAM-mono. The reduction in 6-4PP lesions may indicate that the mechanism of NAM-PG is better suited for photoprotection than NAM-mono. NAM-mono was superior to NAM-Met, indicating a dose dependency of NAM's photoprotection. These results highlight the potential for combining photoprotective compounds to enhance photoprotection.
简介：紫外线辐射（UVR）是角质细胞癌的主要危险因素。据报道，口服烟酰胺（NAM）补充剂可减少新角质细胞癌的形成。NAM 的光保护作用是通过增强 DNA 修复来介导的。我们想探讨 NAM 与抗增殖（二甲双胍[Met]）或抗氧化（间苯三酚[PG]）化合物联合使用是否可能增强其光保护作用。
方法：无毛小鼠（C3.Cg-Hrhr/TifBomTac）经口给予标准剂量的 NAM 单药治疗（NAM-单药；600mg/kg）或 NAM（400mg/kg）联合 Met（200mg/kg）（NAM-Met）或 PG（75mg/kg）（NAM-PG）。每周三次用 3.5 个标准红斑剂量的 UVR 照射小鼠，以诱导肿瘤发展。光保护效果基于（i）前三个肿瘤的肿瘤发病，（ii）皮肤光损伤和（iii）DNA 损伤（环丁烷嘧啶二聚体[CPDs]和嘧啶-嘧啶酮（6-4）光产物[6-4PP]）。
结果：与 UVR 对照组相比，所有接受 NAM 治疗的小鼠的肿瘤发病时间延迟且肿瘤负担降低（NAM、NAM-Met、NAM-PG 与 UV 对照组相比：p≤0.015）。NAM-单药和 NAM-PG 增加了达到所有三个肿瘤的时间，彼此之间没有差异，表明具有相似程度的光保护作用。与 UVR 对照组相比，NAM-单药对 DNA 损伤没有影响（p＞0.05），而 NAM-PG 减少了 6-4PP 损伤（p＜0.01）但没有减少 CPDs（p＞0.05）与 NAM-单药相比。与 UVR 对照组相比，NAM-Met 延迟了第三个肿瘤的发病时间，但与 NAM-单药相比，发病时间更快，表明与 NAM 单药治疗相比，光保护作用较差。
结论：NAM-PG 延迟 UVR 诱导的肿瘤发病与 NAM-单药一样有效。6-4PP 病变的减少可能表明 NAM-PG 的作用机制比 NAM-单药更适合光保护。NAM-单药优于 NAM-Met，表明 NAM 光保护作用存在剂量依赖性。这些结果强调了联合使用光保护化合物以增强光保护作用的潜力。
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