PDF(Pubmed)
Abstract：
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies.
摘要：
肿瘤坏死因子相关的凋亡诱导配体（TRAIL）是一种有前途的抗癌药物，因为它选择性地诱导转化细胞的凋亡，而不改变健康细胞的细胞机制。不幸的是,TRAIL抗性机制在多种癌症类型中的存在代表了一个主要障碍，因此限制了TRAIL作为单一药物的使用。越来越多的研究表明，TRAIL介导的细胞凋亡可以通过与抗肿瘤药物联合治疗促进耐药肿瘤。从合成分子到天然产物。在后者中,黄酮类化合物，植物中最普遍的多酚，在抗性细胞系以及具有最小副作用的荷瘤小鼠中显示出改善TRAIL驱动的凋亡的显着能力。这里,我们总结了分子机制，例如死亡受体（DR）4和DR5的上调和关键抗凋亡蛋白的下调[例如，细胞FLICE抑制蛋白（c-FLIP），X-连锁凋亡抑制蛋白(XIAP),survivin],不同类别类黄酮的TRAIL敏化特性(例如，黄酮,黄酮醇，异黄酮,查尔酮,异戊二烯类黄酮）。最后,我们讨论局限性，主要与生物利用度问题有关，以及关于黄酮类化合物在TRAIL治疗中作为佐剂的临床应用的未来观点。
