PDF(Pubmed)
Abstract：
Lung cancer ranks as the predominant cause of cancer-related mortalities on a global scale. Despite progress in therapeutic interventions, encompassing surgical procedures, radiation, chemotherapy, targeted therapies and immunotherapy, the overall prognosis remains unfavorable. Imbalances in redox equilibrium and disrupted redox signaling, common traits in tumors, play crucial roles in malignant progression and treatment resistance. Cancer cells, often characterized by persistent high levels of reactive oxygen species (ROS) resulting from genetic, metabolic, and microenvironmental alterations, counterbalance this by enhancing their antioxidant capacity. Cysteine availability emerges as a critical factor in chemoresistance, shaping the survival dynamics of non-small cell lung cancer (NSCLC) cells. Selenium-chrysin (SeChry) was disclosed as a modulator of cysteine intracellular availability. This study comprehensively characterizes the metabolism of SeChry and investigates its cytotoxic effects in NSCLC. SeChry treatment induces notable metabolic shifts, particularly in selenocompound metabolism, impacting crucial pathways such as glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. Additionally, SeChry affects the levels of key metabolites such as acetate, lactate, glucose, and amino acids, contributing to disruptions in redox homeostasis and cellular biosynthesis. The combination of SeChry with other treatments, such as glycolysis inhibition and chemotherapy, results in greater efficacy. Furthermore, by exploiting NSCLC\'s capacity to consume lactate, the use of lactic acid-conjugated dendrimer nanoparticles for SeChry delivery is investigated, showing specificity to cancer cells expressing monocarboxylate transporters.
摘要：
在全球范围内，肺癌是癌症相关死亡率的主要原因。尽管在治疗干预方面取得了进展，包括外科手术，辐射,化疗,靶向治疗和免疫疗法，总体预后仍然不利。氧化还原平衡失衡和氧化还原信号中断，肿瘤的共同特征，在恶性进展和治疗抵抗中起关键作用。癌细胞,通常以遗传引起的持续高水平的活性氧（ROS）为特征，新陈代谢，和微环境的改变，通过增强它们的抗氧化能力来抵消这一点。半胱氨酸的可用性成为化学抗性的关键因素，塑造非小细胞肺癌（NSCLC）细胞的生存动态。公开了硒-chrysin(SeChry)作为半胱氨酸细胞内可用性的调节剂。这项研究全面表征了SeChry的代谢，并研究了其在NSCLC中的细胞毒性作用。SeChry处理诱导显著的代谢变化，特别是在硒化合物代谢中，影响关键途径，如糖酵解，糖异生,三羧酸（TCA）循环，和氨基酸代谢。此外,SeChry影响关键代谢物的水平，如乙酸盐，乳酸，葡萄糖，和氨基酸，导致氧化还原稳态和细胞生物合成的破坏。SeChry与其他治疗方法的结合，如糖酵解抑制和化疗，导致更大的疗效。此外，通过利用非小细胞肺癌消耗乳酸的能力，研究了乳酸共轭树枝状聚合物纳米颗粒用于SeChry递送的用途，对表达单羧酸转运蛋白的癌细胞显示特异性。
