Natural Product Albiziabioside A Conjugated with Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate To Induce Apoptosis-Ferroptosis-M2-TAMs Polarization for Combined Cancer Therapy
Natural Product Albiziabioside A Conjugated with Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate To Induce Apoptosis-Ferroptosis-M2-TAMs Polarization for Combined Cancer Therapy
复制标题
天然产物合欢二糖苷 A 与丙酮酸脱氢酶激酶抑制剂二氯乙酸酯缀合诱导细胞凋亡-铁死亡-M2-TAM 极化，用于癌症联合治疗
DOI：
10.1021/acs.jmedchem.9b00644
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发表时间：
2019
影响因子：
7.3
通讯作者：
Yang Liu
中科院分区：
文献类型：
--
作者：
Gaofei Wei;Jiahong Sun;Weijing Luan;Zhuang Hou;Shuai Wang;Shanshan Cui;Maosheng Cheng;Yang Liu
能量代谢的重新编程被认为是癌症的主要特征之一。靶向糖酵解以改变异常的葡萄糖代谢和恢复氧化磷酸化的治疗剂的开发已经成为癌症治疗的有效方法。通过这种方式，我们开发了一种结合物AlbA-DCA，它可以诱导细胞内ROS的显着增加，并减轻TME中乳酸的积累。同时，AlbA-DCA选择性地杀死癌细胞，并表现出优异的协同效应。机制研究证实AlbA-DCA可诱导细胞凋亡和铁凋亡。我们还证实，AlbA-DCA可以通过消除M2-TAM重塑肿瘤免疫抑制微环境，以抑制雌性BALB/c小鼠双4 T1肿瘤模型中的原发性和远端肿瘤进展。因此，合理设计天然皂苷和PDK抑制剂，诱导细胞凋亡-铁凋亡-M2-TAMs极化，增强肿瘤治疗是一种很有前景的策略，为肿瘤治疗提供了新的思路。
The reprogramming of energy metabolism is considered to be one of the main characteristics of cancer. The development of therapeutic agents targeting glycolysis to alter aberrant glucose metabolism and restore oxidative phosphorylation has emerged as an effective approach for cancer therapy. In this way, we have developed a conjugate AlbA-DCA, which can induce a marked increase in intracellular ROS and alleviate the accumulation of lactic acid in TME. Meanwhile, AlbA-DCA selectively kills cancer cells and exhibits an excellent synergistic effect. Mechanism studies confirm that AlbA-DCA can induce apoptosis and ferroptosis. We also confirm that AlbA-DCA can remold the tumor immunosuppression microenvironment via eliminating M2-TAMs to inhibit both primary and distal tumor progression in a dual-4T1 tumor model in female BALB/c mice. As a result, rational design of natural saponin and PDK inhibitor to induce apoptosis-ferroptosis-M2-TAMs polarization for enhanced cancer therapy is a promising strategy, thus providing a new idea for cancer therapy.