Metformin shows anti‐neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa‐associated aggressive cutaneous squamous cell carcinoma

Abstract

BackgroundWhile most cutaneous squamous cell carcinomas (cSCC) are treatable, certain high‐risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation, and unproductive healing, RDEB patients have a 68% cumulative risk of developing life‐threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target.ObjectivesWe sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC.MethodsWe evaluated the cell energetics profiles of RDEB‐SCC cells by analysing available gene expression data against multiple gene signatures and single gene targets linked to metabolic reprogramming. Additionally, we employed real‐time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti‐neoplastic properties of the metformin against human and murine high‐risk cSCCs in vitro and in vivo.ResultsGene expression analyses highlighted a divergence in cell energetics profiles between RDEB‐SCC and non‐malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real‐time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB‐SCC cells. Against this background, metformin exerted an anti‐neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast‐growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 129% increase in median overall survival.ConclusionsOur data indicate that metformin exerts anti‐neoplastic properties in aggressive cSCCs that exhibit high‐risk features by interfering with respiration and glycolytic processes.

Efficacy of Combinational Treatment versus Nicotinamide Monotherapy in the Prevention of Ultraviolet Radiation-Induced Skin Cancer

“…Metformin is reported to reduce UVR-induced DNA damage and proliferation through its activation of AMPK and affect metabolic reprogramming, resulting in reduced tumour development in murine models [19,20]. Nicotinamide's actions are thought to be multifaceted mediated by both DNA repair through increased p53 expression and reductions in inflammation and immunosuppression [16,[31][32][33][34].…”

“…Nicotinamide functions as a photoprotectant by enhancing DNA repair [16]. In contrast, phloroglucinol is thought to act as an antioxidant [17,18], whereas metformin treatment is shown to reduce proliferation and neoplastic properties through its activation of AMPK [19,20]. Based on these observations and other reports of photoprotection [18,19,[21][22][23], we wanted to determine whether combining nicotinamide with compounds demonstrating different mechanisms of action would enhance its photoprotection.…”