6-Aminonicotinamide enhances the efficacy of 5-aminolevulinic acid-mediated photodynamic therapy for neuroblastoma

TL;DR

This study shows that combining 6-aminonicotinamide with photodynamic therapy improves treatment effectiveness in a type of childhood cancer called neuroblastoma.

Contribution

The study introduces a novel combination therapy using 6-aminonicotinamide to enhance photodynamic therapy in MYCN-amplified neuroblastoma.

Findings

6-aminonicotinamide increased the cytotoxicity of photodynamic therapy in neuroblastoma cells.

The combination therapy caused necrosis and lipid peroxidation in cancer cells.

The treatment suppressed the glutathione redox system, increasing reactive oxygen species.

Abstract

Photodynamic therapy (PDT) utilizing 5-aminolevulinic acid (5-ALA) as a photosensitizing precursor is an approved treatment modality for several types of cancers. However, the increased generation of antioxidants in cancer cells renders them resistant to PDT. MYCN-amplified neuroblastoma shows increased production of reactive oxygen species (ROS) and relies on the glutathione redox system for ROS detoxification. We tested the effectiveness of combining 6-aminonicotinamide (6-AN), a glucose-6-phosphate dehydrogenase inhibitor that modulates nicotinamide adenine dinucleotide phosphate and glutathione redox balance, with PDT for treating neuroblastoma.

Cellular protoporphyrin IX (PpIX) accumulation, cell proliferation, morphological changes, induction of cell death, redox status, and lipid peroxidation were evaluated in neuroblastoma cells treated with 5-ALA-mediated PDT with or without 6-AN.

6-AN enhanced cytotoxicity of 5-ALA-mediated PDT in MYCN-amplified neuroblastoma cells. The enhanced efficacy was attributed to the increase in intracellular PpIX along with the suppression of the glutathione redox system. An analysis of cell death mechanisms revealed that 5-ALA-mediated PDT combined with 6-AN induced necrosis with lipid peroxidation.

6-AN enhances the cytotoxicity of 5-ALA-mediated PDT and promotes membrane lipid peroxidation in neuroblastoma cells. 5-ALA-mediated PDT combined with 6-AN could be a potential treatment strategy for neuroblastoma.

The online version contains supplementary material available at 10.1186/s12885-025-15231-4.

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