Baldassari Federica, Bonanomi Marcella, Mallia Sara, Bonas Matteo, Brivio Elisa, Aramini Tecla, Porro Danilo, Gaglio Daniela
Institute of Bioimaging and Complex Biological Systems, National Research Council (CNR), 20054 Segrate, MI, Italy.
National Biodiversity Future Center (NBFC), 90133 Palermo, PA, Italy.
Nutrients. 2025 Mar 22;17(7):1113. doi: 10.3390/nu17071113.
: Melanoma is an aggressive skin cancer with intratumor metabolic heterogeneity, which drives its progression and therapy resistance. Natural anthraquinones, such as emodin and aloe-emodin, exhibit anti-cancer properties, but their effects on metabolic plasticity remain unclear. This study evaluated their impact on proliferation and metabolic pathways in heterogenous melanoma human cell lines. : COLO 800, COLO 794, and A375 melanoma cell lines representing distinct metabolic phenotypes were analyzed. Targeted and untargeted metabolomics analyses integrated with Seahorse assays were performed to assess the effects of emodin and aloe-emodin on cell proliferation, mitochondrial function, and redox homeostasis. Glucose tracing using [U-C] glucose and metabolic flux analysis (MFA) were carried out to evaluate the glycolysis and TCA cycle dynamics. : Emodin and aloe-emodin inhibited proliferation by disrupting glycolysis, oxidative phosphorylation, and energy production across all cell lines. Both compounds impaired glucose metabolism, reduced TCA cycle intermediates, and induced mitochondrial ROS accumulation, causing oxidative stress and redox imbalance. Despite intrinsic metabolic differences, COLO 800 and COLO 794 upregulated antioxidant defenses; A375 enhanced one-carbon metabolism and amino acid pathways to maintain redox balance and nucleotide biosynthesis. : Emodin and aloe-emodin can disrupt the metabolic plasticity of melanoma cells by impairing glycolysis, mitochondrial function, and redox homeostasis. Their ability to target metabolic vulnerabilities across diverse phenotypes highlights their therapeutic potential for overcoming resistance mechanisms and advancing melanoma treatment strategies.
黑色素瘤是一种侵袭性皮肤癌，具有肿瘤内代谢异质性，这推动了其进展和治疗抗性。天然蒽醌类化合物，如大黄素和芦荟大黄素，具有抗癌特性，但其对代谢可塑性的影响仍不清楚。本研究评估了它们对异质性黑色素瘤人细胞系增殖和代谢途径的影响。分析了代表不同代谢表型的COLO 800、COLO 794和A375黑色素瘤细胞系。进行了靶向和非靶向代谢组学分析，并结合海马实验，以评估大黄素和芦荟大黄素对细胞增殖、线粒体功能和氧化还原稳态的影响。使用[U-C]葡萄糖进行葡萄糖示踪和代谢通量分析（MFA），以评估糖酵解和三羧酸循环动力学。大黄素和芦荟大黄素通过破坏所有细胞系中的糖酵解、氧化磷酸化和能量产生来抑制增殖。两种化合物均损害葡萄糖代谢，减少三羧酸循环中间产物，并诱导线粒体活性氧积累，导致氧化应激和氧化还原失衡。尽管存在内在代谢差异，但COLO 800和COLO 794上调了抗氧化防御；A375增强了一碳代谢和氨基酸途径，以维持氧化还原平衡和核苷酸生物合成。大黄素和芦荟大黄素可通过损害糖酵解、线粒体功能和氧化还原稳态来破坏黑色素瘤细胞的代谢可塑性。它们针对不同表型代谢脆弱性的能力突出了其克服耐药机制和推进黑色素瘤治疗策略的治疗潜力。
