Synergistic Effect of the Flavonoid Catechin, Quercetin, or Epigallocatechin Gallate with Fluconazole Induces Apoptosis in Candida tropicalis Resistant to Fluconazole
Synergistic Effect of the Flavonoid Catechin, Quercetin, or Epigallocatechin Gallate with Fluconazole Induces Apoptosis in Candida tropicalis Resistant to Fluconazole
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DOI：
10.1128/aac.00651-13
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发表时间：
2014-03-01
影响因子：
4.9
通讯作者：
Nobre Junior, Helio Vitoriano
中科院分区：
文献类型：
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作者：
da Silva, Cecilia Rocha;de Andrade Neto, Joao Batista;Nobre Junior, Helio Vitoriano
类黄酮是一类酚类化合物，普遍存在于水果、蔬菜、谷物、花卉、茶叶和葡萄酒中。它们的化学结构和特性不同。这类化合物具有多种生物学功能，具有抗氧化、抗菌、抗炎和抗细胞凋亡等特性。本研究旨在评价黄酮类化合物与氟康唑对耐氟康唑热带念珠菌的体外相互作用，并探讨其协同作用机制。测试了类黄酮类(-)-水合儿茶素、水合儿茶素和(-)-表没食子儿茶素没食子酸酯在固定浓度下与氟康唑形成的三种组合。在所测试的浓度范围内，单用黄酮类化合物没有抗真菌活性，但与氟康唑联合使用时，有显著的协同作用。根据这一结果，我们开始评估参与这种协同作用的细胞死亡的可能机制。分离的黄酮类化合物不会引起受试菌株的形态变化或膜完整性的变化，但当它们与氟康唑共同处理时，这些变化是非常显著的。仅在联合处理中评估线粒体损伤和活性氧(ROS)的产生时，观察到了变化。黄酮类化合物与氟康唑联合使用，可显著提高受试菌的损伤率和DNA损伤频率。联合处理还导致磷脂酰丝氨酸外化增加，磷脂酰丝氨酸是早期细胞凋亡的重要标志。结论：黄酮类化合物与氟康唑联合使用时，对耐氟康唑热带毛滴虫具有一定的抗肿瘤活性，可通过磷脂酰丝氨酸暴露于细胞膜和细胞形态改变、线粒体去极化、细胞内ROS积聚、凝聚和DNA片段化等途径促进细胞凋亡。
Flavonoids are a class of phenolic compounds commonly found in fruits, vegetables, grains, flowers, tea, and wine. They differ in their chemical structures and characteristics. Such compounds show various biological functions and have antioxidant, antimicrobial, anti-inflammatory, and antiapoptotic properties. The aim of this study was to evaluate the in vitro interactions of flavonoids with fluconazole against Candida tropicalis strains resistant to fluconazole, investigating the mechanism of synergism. Three combinations formed by the flavonoids (-)-catechin hydrated, hydrated quercetin, and (-)-epigallocatechin gallate at a fixed concentration with fluconazole were tested. Flavonoids alone had no antifungal activity within the concentration range tested, but when they were used as a cotreatment with fluconazole, there was significant synergistic activity. From this result, we set out to evaluate the possible mechanisms of cell death involved in this synergism. Isolated flavonoids did not induce morphological changes or changes in membrane integrity in the strains tested, but when they were used as a cotreatment with fluconazole, these changes were quite significant. When evaluating mitochondrial damage and the production of reactive oxygen species (ROS) only in the cotreatment, changes were observed. Flavonoids combined with fluconazole were shown to cause a significant increase in the rate of damage and the frequency of DNA damage in the tested strains. The cotreatment also induced an increase in the externalization of phosphatidylserine, an important marker of early apoptosis. It is concluded that flavonoids, when combined with fluconazole, show activity against strains of C. tropicalis resistant to fluconazole, promoting apoptosis by exposure of phosphatidylserine in the plasma membrane and morphological changes, mitochondrial depolarization, intracellular accumulation of ROS, condensation, and DNA fragmentation.