Can Riboflavin and its Derivatives Light Up the Future of Skin Cancer Photodynamic Therapy?

🔍 Key Finding 3-methyltetraacetyl-riboflavin (3MeTARF), a riboflavin derivative, shows significantly enhanced phototoxicity against melanoma and skin cancer cells compared to riboflavin, triggering apoptosis through oxidative stress and MAPK activation upon blue light irradiation. Furthermore, riboflavin and its derivatives are promising photosensitizers for photodynamic therapy due to their non-toxicity and potential for targeted treatment of superficial skin lesions.

🔬 Methodology Overview

• Design: Narrative review.
• Data Sources: Published literature.
• Selection Criteria: Studies on riboflavin and its derivatives as photosensitizers, photodynamic therapy (PDT), blue light in dermatology, and skin cancer treatment.
• Analysis Approach: Qualitative synthesis of findings from in vitro and in vivo studies, focusing on photochemical and photophysical properties, biological effects, and mechanisms of action.
• Scope: Potential use of riboflavin and its derivatives, particularly 3MeTARF, in PDT for skin cancers, highlighting advantages and limitations, and suggesting future research directions.

📊 Results

• 3MeTARF shows significantly greater phototoxicity (5-10 times) compared to riboflavin in in vitro studies. This suggests a stronger potential for PDT applications.
• 3MeTARF induces apoptosis in melanoma (WM115) and skin cancer (A431) cells under blue light irradiation (438 nm). Necrotic cell death was minimal (<6%).
• The mechanism of 3MeTARF-induced apoptosis involves reactive oxygen species generation, oxidative stress, MAPK activation (p38 and JNK phosphorylation), caspase 3/7 activation, and PARP cleavage. Inhibiting p38 and JNK phosphorylation reduces caspase activation and PARP cleavage.
• Riboflavin and 3MeTARF show no dark toxicity in vitro at concentrations up to 50 μM and 10 μM, respectively. Higher concentration dark toxicity for 3MeTARF is undetermined.
• FMN-mediated PDT caused melanoma xenograft regression in mice (85-90% volume reduction in 50 days) after systemic injection and blue light irradiation (450 nm, 20 J/cm² for 15 min). Distant tumor growth inhibition was 20% for single PDT and 30% for double PDT.
• A431 cells accumulate riboflavin rapidly, reaching 53.5% uptake within 5 minutes and 87.1% within 30 minutes at 1 mM riboflavin concentration. Standard RPMI1640 medium contains significantly lower riboflavin (5-53 nM).
• Lumichrome, a riboflavin photodegradation product, exhibits selective antibacterial activity, being ten times more effective against Gram-positive than Gram-negative bacteria.

💡 Clinical Impact Riboflavin derivatives, particularly 3MeTARF, demonstrate enhanced phototoxicity against skin cancer cells compared to riboflavin, suggesting potential for improved blue-light-based photodynamic therapy for superficial skin cancers. This could lead to more effective and less phototoxic treatment options for non-melanoma skin cancers and early-stage melanoma.

🤔 Limitations

• Long-term light sensitivity of the skin
• Excessive tissue damage in the treated area
• Local disorders of metabolism
• Limited bioavailability of riboflavin due to poor solubility in nonpolar solvents
• Photodegradation/photobleaching of riboflavin, limiting therapeutic efficacy
• Unknown toxicity of 3MeTARF in higher concentrations or in the dark
• Under-researched metabolism and in vivo effects of 3MeTARF

✨ What It Means For You This research suggests 3MeTARF, a riboflavin derivative, may be a more effective photosensitizer for PDT of superficial skin cancers than riboflavin itself, due to its increased photostability and phototoxicity. Doctors should follow further research on 3MeTARF’s in vivo effects and metabolism to determine its clinical viability as a safe and effective PDT treatment option, particularly for melanoma and non-melanoma skin cancers. The use of blue light activation offers the advantage of treating superficial lesions while minimizing damage to deeper tissues.

Reference Insinska-Rak M, Sikorski M, Wolnicka-Glubisz A. Riboflavin and Its Derivates as Potential Photosensitizers in the Photodynamic Treatment of Skin Cancers. Cells. 2023;12:2304. https://doi.org/10.3390/cells12182304