MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer–related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. Significance: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.
The erbium-doped yttrium aluminum garnet (Er:YAG) laser is used to treat periodontal disease; however, its effectiveness at killing oral bacteria is not well known. Furthermore, the compounding effect of the combination of a laser treatment and irrigation methods with antimicrobials on bacterial viability is yet to be determined. The purpose of this in vitro study was to evaluate the effect of the Er:YAG laser with irrigation using chlorhexidine (CHX), hydrogen peroxide (H2O2), or sodium hypochlorite (NaOCl) on the viability of oral bacteria. Three bacterial species were used in our study: Streptococcus gordonii, Fusobacterium nucleatum, and Porphyromonas gingivalis. Bacteria were grown in an anaerobic chamber in brain heart infusion broth and incubated at 37 °C. Bacterial samples with an OD of 0.5 were irradiated with the Er:YAG laser at 2940 nm using a 400-µm Varian tip. The experiment was repeated four times using these parameters: 40 mJ, 40 Hz, and 1.6 W for 20 seconds with the 300 µs short pulse duration in contact mode. Treatment groups consisted of the following: (1) no treatment, (2) 0.5% H2O2 alone, (3) 0.5% NaOCl alone, (4) 0.03% CHX alone, (5) Er:YAG irradiation alone, (6) Er:YAG irradiation with 0.5% H2O2, (7) Er:YAG irradiation with 0.5% NaOCl, and (8) Er:YAG irradiation with 0.03% CHX. Microbial viability was determined through plating and colony counts and calculated into CFU/ml. Statistical analysis was done using a two-tailed paired t-test. The use of the Er:YAG laser alone failed to show statistically significant antibacterial activity against any of bacteria. The most effective mono-treatment with irrigation solutions for all three bacteria were 0.5% H2O2 and 0.5% NaOCl (p < 0.001 for each solution). Irrigation with 0.03% CHX was most effective against F. nucleatum (p < 0.01) and less against P. gingivalis and S. gordonii and showed the least antibacterial action alone but improved significantly in combination therapy (p < 0.05). The combined treatment with the Er:YAG showed the greatest and most significant improvement in the reduction of bacterial viability compared to any other treatment group (p < 0.05 for each combined treatment). Irradiation with the Er:YAG laser with the addition of 0.5% H2O2, 0.5% NaOCl, or 0.03% CHX under a short working time (20 s) resulted in a significant reduction of bacterial viability for all three bacterial species compared with any single treatment option. The combination of irradiation with the Er:YAG laser with the addition of 0.5% H2O2, 0.5% NaOCl, or 0.03% CHX resulted in a larger reduction of bacterial survival when compared to monotherapies with antimicrobial solutions or laser. The combination of the Er:YAG laser with a low concentration irrigant solution of 0.5% H2O2, 0.5% NaOCl, or 0.03% CHX could be an effective treatment protocol for the reduction of periodontal pathogens and thus suitable treatment for non-surgical periodontal therapy.
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