Redox Disruption Induced by Saquayamycin B1 Promotes Cytotoxicity in Resistant Melanoma Cells

Melanoma is an aggressive skin cancer characterized by rapid progression and frequent chemoresistance, which limits the success of current therapies. Saquayamycin B1 (SQ-B1), an angucycline isolated from Streptomyces sp. I072, was investigated for its antimelanoma activity with emphasis on redox disruption. The compound was purified using M9 fermentation followed by semipreparative liquid chromatography, and its structure was confirmed through 1D/2D nuclear magnetic resonance (NMR) and mass spectrometry. Cytotoxicity assays (MTT, 72 h) in SK-MEL-5, -113, -117, and -134 cells revealed IC₅₀ values between 5.01 and 0.99 μM. Pretreatment with N-acetylcysteine (NAC) rescued cell viability at IC₅₀ and sub-IC₅₀ concentrations, supporting a ROS-dependent mechanism. SQ-B1 (4 μM, 24 h) reduced the GSH/GSSG ratio (3.49  ±  0.70 vs. 12.35  ±  0.27 in controls) and increased O^2•- and NO^• levels, indicating marked oxidative imbalance. Molecular docking suggested strong binding of SQ-B1 to glutathione transferase (GSTP1-1; p ≈ 0.86) and glutathione reductase (GSR; p ≈ 0.97), with weaker affinity for GPx4 (p ≈ 0.35). Molecular dynamics confirmed stable interactions between SQ-B1 and GSR (RMSD plateau ~10 ns) with a total interaction energy of -201.0 kJ/mol. These findings indicate that SQ-B1 induces cytotoxicity through targeting of key redox regulators, highlighting its potential as a redox-modulating candidate for chemoresistant melanoma.