Inhibition of Autophagosome Formation by the Benzoporphyrin Derivative Verteporfin
Inhibition of Autophagosome Formation by the Benzoporphyrin Derivative Verteporfin
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DOI：
10.1074/jbc.m110.139915
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发表时间：
2011-03-04
影响因子：
4.8
通讯作者：
Roberge, Michel
中科院分区：
文献类型：
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作者：
Donohue, Elizabeth;Tovey, Andrew;Roberge, Michel
自噬使细胞能够降解和回收细胞质物质，这既是一种内务管理机制，也是对细胞外应激（如营养剥夺）的反应。最近的研究表明，自噬也作为一种保护机制对几种癌症治疗药物起反应，使其成为一个有前景的治疗靶点。很少有药物抑制剂适合测试体内自噬抑制的治疗潜力是已知的。使用自动显微镜分析筛选bbbb3500种药物和药理学制剂，并鉴定出一种药物，维替波芬，作为自噬体积累的抑制剂。维替波芬是一种用于光动力治疗的苯并卟啉衍生物，但它可以在没有光激活的情况下抑制自噬。在自噬刺激下，维替波芬不抑制LC3/ at8加工或膜募集，但它抑制药物和饥饿诱导的自噬降解和细胞质物质进入自噬体的隔离。在饥饿条件下短暂暴露于维替泊芬会降低细胞活力，而在富营养培养基中的细胞不受药物治疗的影响。结构类似物分析表明，维替波芬的活性需要在卟啉核心的a环上存在取代的环己二烯，但它可以耐受C环和d环上的大量取代基。自噬抑制剂在fda批准的药物中的存在，将有助于研究自噬抑制在体内的治疗潜力。
Autophagy enables cells to degrade and recycle cytoplasmic materials both as a housekeeping mechanism and in response to extracellular stress such as nutrient deprivation. Recent studies indicate that autophagy also functions as a protective mechanism in response to several cancer therapy agents, making it a prospective therapeutic target. Few pharmacological inhibitors suitable for testing the therapeutic potential of autophagy inhibition in vivo are known. An automated microscopy assay was used to screen > 3,500 drugs and pharmacological agents and identified one drug, verteporfin, as an inhibitor of autophagosome accumulation. Verteporfin is a benzoporphyrin derivative used in photodynamic therapy, but it inhibits autophagy without light activation. Verteporfin did not inhibit LC3/Atg8 processing or membrane recruitment in response to autophagic stimuli, but it inhibited drug-and starvation-induced autophagic degradation and the sequestration of cytoplasmic materials into autophagosomes. Transient exposure to verteporfin in starvation conditions reduced cell viability whereas cells in nutrient-rich medium were unaffected by drug treatment. Analysis of structural analogs indicated that the activity of verteporfin requires the presence of a substituted cyclohexadiene at ring A of the porphyrin core but that it can tolerate a number of large substituents at rings C and D. The existence of an autophagy inhibitor among FDA-approved drugs should facilitate the investigation of the therapeutic potential of autophagy inhibition in vivo.